DRUGS USED IN NEOPLASTIC DISORDERS by Marc Imhotep Cray, M.D.

Marc Imhotep Cray MD

Safety precautions: chemotherapy drugs are hazardous For health professionals:  Many chemotherapy drugs are considered hazardous to healthy people. Reason why the nurses and doctors who give chemotherapy will take precautions to avoid direct contact with the drugs while administering them  Chemotherapy drugs can be dangerous to others in these ways: • They can cause abnormal changes in DNA. (They are mutagenic) • They may be able to alter development of a fetus or embryo, leading to birth defects (They are teratogenic) • They may be able to cause another type of cancer. (They are carcinogenic) • Some may cause skin irritation or damage. Nurses may wear special gloves, goggles, and gowns when preparing and giving you chemotherapy Pharmacists or nurses prepare the drugs in areas with special ventilation systems to avoid spattering and/or inhaling the droplets that can form while mixing Source: ACS Chemotherapy Principles

How to Learn Chemotherapeutic Agent Begin by learning drug classes (antimetabolites, alkylating agents, antibiotic/anti-tumor agents, etc.) and their MOA  Classify each individual drug according to these groups  Learn toxicity of each individual ChemoTx agent . “Chemo man”  Step 1 likes testing on toxicities of chemotherapeutic drugs.  Briefly study drugs that can help neutralize toxic effects of ChemoTx agents. • Most important one to know is mesna, which can prevent hemorrhagic cystitis in patients receiving cyclophosphamide.

Marc Imhotep Cray MD

How to learn Chemotherapeutic Agent (2)  Learning clinical uses of chemotherapeutic agents should be last on our list.  You do not have to know which drugs are used for all types of cancers, but there are a few on which you should focus. • Know the drugs that are useful for testicular cancer (etoposide, bleomycin, and cisplatin), choriocarcinoma (methotrexate and vincristine/vinblastine), acute myelogenous leukemia (cytarabine), and brain tumors (nitrosoureas) • You should also know that 5-fluorouracil can be given topically for actinic keratosis

Marc Imhotep Cray MD

Important Terms to know  Cell cycle-nonspecific (CCNS) drug An anticancer agent that acts on tumor stem cells when they are traversing cell cycle and when they are in resting phase  Cell cycle-specific (CCS) drug An anticancer agent that acts selectively on tumor stem cells when they are traversing cell cycle and not when they are in G0 phase  Growth fraction The proportion of cells in a tumor population that are actively dividing  Myelosuppressant A drug that suppresses formation of mature blood cells such as erythrocytes, leukocytes, and platelets. This effect is also known as “bone marrow suppression”  Oncogene A mutant form of a normal gene that is found in naturally occurring tumors and which, when expressed in noncancerous cells, causes them to behave like cancer cells Marc Imhotep Cray MD

Useful Abbreviations ADC Ara-C DHFR FDA FH 4 5-FU Mesna 6-MP MTX 6-TG

Marc Imhotep Cray MD

Antibody-drug conjugate Cytarabine Dihydrofolate reductase United States Food and Drug Administration Tetrahydrofolate 5-Fluorouracil Sodium 2-mercaptoethane sulfonate 6-Mercaptopurine Methotrexate 6-Thioguanine

Core Concepts and Learning Objectives

CHEMOTHERAPY I: OVERVIEW 1. The importance of tumor cell heterogeneity and the development of malignant cell resistance to chemotherapy as critical factors in determining treatment outcome. 2. The process of antineoplastic drug development. 3. The criteria determining the response to antineoplastic agents. 4. The toxicity of cancer chemotherapy. 5. The principles of management of the patient with cancer. 6. The importance of tumor staging in the management of the patient with cancer. 7. The principles of chemotherapy. 8. The rationale for the administration of adjuvant chemotherapy.

See: ACS Chemotherapy Principles Doc. Marc Imhotep Cray MD

Principles of Cancer Chemotherapy

Marc Imhotep Cray MD

Major Approaches to Treatment of Cancers Tumor cells are shown in red and nontumor cells in green. *In clinical use. Others are experimental

Brody Human Pharmacology: Mechanism-Based Therapeutics 6e. Elsevier, 2019. Pg. 1728.

Marc Imhotep Cray MD

Chemotherapy’s Main Clinical Usefulness Chemotherapy is useful for disseminated cancers that cannot be removed by surgery or as supplemental treatment after surgery or radiation  Using surgery or radiation to shrink tumor before ChemoTx ↑ number of dividing cells which ↑ effectiveness of ChemoTx  Most anticancer drugs affect cell division • They act preferentially on rapidly proliferating cells • Smaller tumors have a higher growth fraction o Consequently, they are more susceptible to anticancer drugs o Adjuvant ChemoTx is used w surgery or radiation to Tx undetectable metastases when they are small and highly sensitive to anticancer drugs

• A greater proportion of nondividing cells will survive ChemoTx compared to dividing cells Marc Imhotep Cray MD

Chemotherapy’s Objective Objective of ChemoTx in any given individual patient may be:  Curative, to obtain complete remission (e.g., Hodgkin disease)

 Palliative, to alleviate symptoms but with little expectation of complete remission (e.g., carcinoma of esophagus, with chemotherapy performed to ease the dysphagia)  Adjuvant, to improve chances for a cure or prolong period of disease-free survival when no detectable cancer is present but subclinical numbers of neoplastic cells are suspected (e.g., chemotherapy for breast cancer after surgical resection of all known tumor)  Debulking, to reduce tumor burden to allow for a more effective surgical removal of the tumor Marc Imhotep Cray MD

Therapeutic Overview Cancers in Which Complete Remission to Chemotherapy Is Common and Cures Are Achieved, Even in Advanced Disease*            

Acute lymphocytic leukemia (adults and children) Acute myelogenous leukemia Hodgkin disease (lymphoma) Non-Hodgkin lymphoma Choriocarcinoma Testicular cancer Burkitt lymphoma Ewing sarcoma Wilms tumor Small cell lung cancer *Depending on tumor type, complete Ovarian cancer remission may result in cure Hairy cell leukemia

Marc Imhotep Cray MD

Therapeutic Overview (2) Cancers in Which Objective Responses Are Achieved, but Chemotherapy Often Does Not Have Curative Potential in Advanced Disease            

Multiple myeloma Breast cancer Head and neck cancer Colorectal carcinomas Chronic lymphocytic leukemia Chronic myelogenous leukemia Transitional cell carcinoma of bladder Gastric adenocarcinomas Cervical carcinomas Melanoma Neuroblastoma Non–small cell lung cancer

Marc Imhotep Cray MD

Therapeutic Overview (3) Cancers in Which Only Occasional Objective Responses to Chemotherapy Are Achieved  Renal tumor  Pancreatic carcinomas  Hepatocellular carcinoma  Prostate carcinomas (hormone-unresponsive)

Marc Imhotep Cray MD

Basic Mechanisms by Which Antineoplastic Drugs Selectively Kill Tumor Cells  E represents enzymes, some of which are inhibited by these drugs  Key mechanisms of action for many of these drugs are: • Inhibition of DNA or RNA synthesis, • Production of miscoded nucleic acids, and • Formation of modified proteins

Brody Human Pharmacology: Mechanism-Based Therapeutics 6e. Elsevier, 2019. Pg. 1748. 15

Cell Cycle Kinetics  Cancer cell population kinetics and cancer cell cycle are important determinants of actions and clinical uses of anticancer drugs • Some anticancer drugs exert their actions on cells undergoing cycling (cell cyclespecific [CCS] drugs), and • others (cell cycle-nonspecific [CCNS] drugs) kill tumor cells in both cycling and resting phases of cell cycle (although cycling cell are more sensitive)  CCS drugs are usually most effective when cells are in a specific phase of cell cycle  Both types of drugs are particularly effective when a large proportion of tumor cells are proliferating (ie, when growth fraction is high)

Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 54–2 16

Cell Cycle Specific Anticancer Drugs  They are only effective against replicating cells, particularly malignancies w a high growth fraction  The cell cycle phases include: i. G1, phase after mitosis Some G1 cells can move into a resting, non-dividing state, G0 ii. S, DNA synthesis phase iii. G2, phase before mitosis iv. M, mitotic phase  Cell cycle phase specific drug classes include antimetabolites, bleomycin peptide antibiotics, vinca alkaloids (microtubule inhibitors), and etoposide i. ii.

Folic acid analog methotrexate (MTX) kills in S-phase (DNA synthesis phase) Vincristine and vinblastine kill in M-phase (mitotic phase)

Marc Imhotep Cray MD

Cell Cycle Nonspecific Anticancer Drugs Other drugs are cell cycle phase nonspecific  They are effective at killing nondividing cells as well as dividing cells  Cell cycle phase nonspecific drug classes include alkylating agents, most anticancer antibiotics, cisplatin, and nitrosoureas

Marc Imhotep Cray MD

The four phases of the cell cycle. G1 – the initial growth phase. S – the phase in which DNA is synthesized. G2 – the second growth phase in preparation for cell division. M – mitosis; where the cell divides to produce two daughter cells that continue the cell cycle.

Marc Imhotep Cray MD

Cancer therapyâ&#x20AC;&#x201D;cell cycle

First AID for the USMLE Step 1 2020, Pg. 438.

Marc Imhotep Cray MD

Cancer therapyâ&#x20AC;&#x201D;targets

First AID for the USMLE Step 1 2020, Pg. 438.

Marc Imhotep Cray MD

CANCER CELLS ARE KILLED IN A FIRST-ORDER MANNER  a constant percentage (or proportion) of cancer cells are killed w each course of therapy 

b/c of this log kill, additional rounds of chemotherapy are necessary in order to completely eradicate the tumor

 Proportion of cancer cells that are actively proliferating will predict response to ChemoTx  Cells not actively proliferating are generally unresponsive to ChemoTx  As cancers increase in size, more cancer cells exit replicative pool  During course of ChemoTx , cells in replication are selectively killed, leaving behind cells out of pool that can continue on •

If one were to completely surgically excise mass, then that would solve this issue, but even if mass cannot be removed, then at least one can debulk it, or use radiation therapy to kill more cells

 ChemoTx protocols can be designed to include more agents, thereby reducing cancer cell resistance, or by giving cycles of ChemoTx that get more cancer cells into replicative pool Marc Imhotep Cray MD

The Log-Kill Hypothesis Cytotoxic drugs act with first-order kinetics in a murine model of leukemia  In this model system a given dose kills a constant proportion of a cell population rather than a constant number of cells  The log-kill hypothesis proposes that magnitude of tumor cell kill by anticancer drugs is a logarithmic function For example, a 3-log-kill dose of an effective drug reduces a cancer cell population of 1012 cells to 109 (a total kill of 999 × 109 cells the same dose would reduce a starting population of 106 cells to 103 cells (a kill of 999 × 103 cells) • In both cases, dose reduces numbers of cells by 3 orders of magnitude, or “3 logs” • A key principle that stems from this finding and that is applicable to hematologic malignancies is an inverse relationship betw. tumor cell number and curability

Marc Imhotep Cray MD

Cancer Log-kill hypothesis Relationship, based on the log-kill hypothesis, of tumor cell number to 3 approaches to drug treatment and to no treatment (dashed line).  In the protocol diagrammed at top, infrequent treatment (indicated by arrows) prolongs survival but with recurrence of symptoms betw. Tx and eventual death.  With regimen diagrammed in middle section that is more intensive and begun earlier, cure results after many cycles of therapy.  In treatment diagrammed near bottom of graph, early surgery removes much of tumor burden, and intensive adjuvant chemotherapy has been used long enough to produce a cure. Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 54–1 24

Standard toxicities anticancer drugs 1. Myelosuppression is common because bone marrow is a rapidly proliferating tissue a. This is usually the dose-limiting side effect b. The leukopenia is greater than the thrombocytopenia, which is greater than the anemia c. Drugs for which bone marrow depression is not the dose-limiting toxicity include: i. Hormones ii. Vincristine iii. Bleomycin iv. Asparaginase v. Cisplatin vi. Monoclonal antibodies (MAbs) Marc Imhotep Cray MD

Standard toxicities anticancer drugs (2) 2. Other rapidly proliferating cells that are affected include: a. GI epithelium b. Germinal epithelium c. Hair follicles

Marc Imhotep Cray MD

Standard toxicities anticancer drugs (3) 3. Nausea and vomiting are common side effects that can be managed with antiemetics, including: a. Phenothiazines such as prochlorperazine (Compazine) b. Cannabinoids such as dronabinol (Marinol) c. Dopamine receptor antagonists such as metoclopramide (Reglan) d. Ondansetron (Zofran), a 5-HT3 antagonist e. Glucocorticoids, such as dexamethasone f. Antihistamines, such as diphenhydramine (Benadryl) g. Benzodiazepines, such as lorazepam (Ativan)

Marc Imhotep Cray MD

Standard toxicities anticancer drugs (4) 4. Tissue necrosis may occur at site of injection 5. Some anticancer drugs have unique organ toxicities a. Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin and mitoxantrone) are cardiotoxic b. Bleomycin induces pulmonary fibrosis c. Vinca alkaloids (vincristine, vinblastine and vinorelbine); platinum compounds (cisplatin, carboplatin and oxaliplatin); and taxanes (paclitaxel and docetaxel) are neurotoxic d. Cisplatin, carboplatin, and methotrexate are nephrotoxic Anthracyclines (eg, Doxorubicin, Daunorubicin); prevent w Dexrazoxane Marc Imhotep Cray MD

Minimizing ChemoTx Toxicities 6. Adverse side effects can be minimized by a variety of techniques including: a. Local perfusion of tumors b. Removing marrow pre-treatment and reimplanting it afterward c. Diuresis to prevent bladder toxicity d. Administering leucovorin (folinic acid) for megaloblastic anemia and prevention of MTX toxicity e. Urine alkalinization for MTX excretion f. Administering G-CSF (filgrastim) for neutropenia g. Administering allopurinol (Zyloprim) or rasburicase (Elitek) to treat hyperuricemia associated with tumor lysis syndrome, especially in leukemia and lymphoma patients Marc Imhotep Cray MD

Common Cancer Chemotherapy Toxicities Drug Side Effect / Toxicity Cyclophosphamide Hemorrhagic cystitis Diarrhea, 5-FU photosensitivity Bleomycin Vincas Taxanes Daunorubicin (Adriamycin)

Cisplatin

Tamoxifen Alkylating agents

Mechanism acrolein metabolite damages bladder epithelium (Rx: Mesna) damage of rapidly dividing GI epithelial cells interferes with fluid absorption from GI tract, resulting in watery bowel movements; 5-FU is â&#x20AC;&#x153;phototoxicâ&#x20AC;? when exposed to sunlight may be related to a combination of the production of toxic oxygen-free radicals & DNA Pulmonary Toxicity damage in the lung Neuropathy, Neuropathy may result from effects on neuronal microtubular assembly; constipation may in constipation turn result from GI neuropathy Neuropathy believed to result from disruption of neuronal microtubules evidence suggests that reactive oxygen species, generated by the interaction of doxorubicin Cardiac toxicity with iron, damage cardiac myocytes, causing cellular damage & loss of muscle fibers, which can result in CHF cisplatin is the most highly emetogenic agent; a proposed mechanism is that free radicals produced by cisplatin act on enterochromaffin cells to cause release of serotonin (5-HT); 5Emesis, renal toxicity HT3 receptor antagonists (e.g. ondansetron) are used to treat cisplatin induced emesis; renal toxicity may result from the ability of proximal tubular kidney cells to metabolize cisplatin to a Nephrotoxin, resulting in kidney damage Tamoxifen is a SERM and the increase in uterine (endometrial) cancer risk is related to Uterine cancer, tamoxifen's effect to behave as an estrogen partial agonist in the endometrium; the increase thrombosis in deep vein thrombosis appears to result from an effect of tamoxifen to increase platelet aggregation by a poorly understood mechanism Secondary leukemias DNA damage & resulting mutations caused by alkylating agents 30

Mesna (Mesnex) Chemotherapy adjuvant  Mesna is used therapeutically to reduce incidence of hemorrhagic cystitis and hematuria when a patient receives ifosfamide or cyclophosphamide for cancer chemotherapy • These two anticancer agents, in vivo, may be converted to urotoxic metabolites, such as acrolein

 MOA Mesna assists to detoxify these metabolites by reaction of its sulfhydryl group with α, β-unsaturated carbonyl containing compounds such as acrolein Marc Imhotep Cray MD

Key Chemotoxicities “CHEMO MAN”

First AID for the USMLE Step 1 2020, Pg. 444.

Other Problems with Chemotherapy 1. Immunocompromised patients usually have poorer responses to anticancer treatment

2. Centers of large tumors and CNS can serve as pharmacologic sanctuaries ď&#x201A;§

Cancer cells are relatively protected from cytolytic effects of systemic chemotherapy

3. Some ChemoTx agents, particularly alkylating agents, can cause new, treatment-induced cancers up to several years after treatment ď&#x201A;§ teratogenicity can also occur, again especially with alkylating agents Marc Imhotep Cray MD

Other Problems with ChemoTx (2) 4. Resistance can develop a. Some cancers are inherently resistant to certain agents; other cancers can develop resistance by mutation, especially after long-term administration of low doses of drug b. Resistance is minimized by short-term, intensive, intermittent Tx w combinations of drugs c. Multidrug resistance occurs due to stepwise selection for permeability glycoprotein (P glycoprotein) i. P glycoprotein actively pumps drugs out of the cell ii. b/c P glycoprotein is a multidrug efflux pump, its activity provides cross-resistance for several structurally unrelated drug classes iii. Some organs naturally express high levels of P glycoprotein, including kidneys, intestines, liver, and pancreasď&#x192; Cells of these organs are therefore more resistant to chemotherapy Marc Imhotep Cray MD

The Multidrug Resistance (MDR) Gene: Drug Specificity and Tissue Distribution Drugs Affected by MDR

Drugs Not Affected by MDR

Adriamycin

Methotrexate

Daunomycin

6-Thioguanine

Dactinomycin

Cytarabine

Plicamycin

Cyclophosphamide

Etoposide

BCNU

Vinblastine

Bleomycin

Vincristine

Cisplatin

Tissues with High MDR Expression

Marc Imhotep Cray MD

Tissues with Low MDR Expression

Colon

Bone marrow

Liver

Breast

Pancreas

Ovary

Kidney

Skin

Adrenal

Central nervous system

Combination Chemotherapy Combination Therapy is common and is often more effective against a wider variety of cell lines 1. Each drug in combination should be active against tumor to provide maximum cell killing within range of tolerance 2. Drugs should have different mechanisms of action to kill maximum number of cells in heterogeneous tumors 3. Drugs should have different toxicities so that they can all be given at full strength and emergence of resistance can be delayed 4. Drugs are usually admin. in Tx cycles and time must be allowed for host tissue recovery betw. cycles

Marc Imhotep Cray MD

Examples of Common Combination Drug Regimens Terminology Cancer Drugs MOPP

Hodgkin lymphoma

Mechlorethamine, vincristine, procarbazine, prednisone

ABVD

Hodgkin lymphoma

Doxorubicin, bleomycin, vinblastine, dacarbazine

BEP

Germ cell cancers

Bleomycin, etoposide, cisplatin

CMF

Breast cancer

Cyclophosphamide, methotrexate, 5-fluorouracil

CAF

Breast cancer

Cyclophosphamide, doxorubicin, 5-fluorouracil

CHOP CHOP-R

Non-Hodgkin lymphoma

Cyclophosphamide, doxorubicin, vincristine, prednisone Agents above + rituximab

Hyper-CVAD

Non-Hodgkin lymphoma

Hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone

FOLFIRI Cetuximab

Colorectal cancer

Leucovorin, 5-fluorouracil, irinotecan, cetuximab

PVC

Anaplastic oligodendrogliomas

Procarbazine, vincristine, lomustine

R-EPOCH

B-cell non-Hodgkin lymphoma

Rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin

XELIRI

Colorectal, esophageal, gastric cancer

Capecitabine, irinotecan

Marc Imhotep Cray MD

Brody Human Pharmacology: Mechanism-Based Therapeutics 6e. Elsevier, 2019. Pg. 1736.

Targeted therapies & Immunopharmacology Targeted therapies are becoming increasingly important in the treatment of cancer  Examples include bevacizumab, which targets vascular endothelial growth factor;  I131 tositumomab, rituximab, and Y-90-ibritumomab tiuxetan, which target CD20 and are used for treatment of chemotherapy-refractory nonHodgkin's lymphoma; and  Gefitinib and antibody cetuximab, which target epidermal growth factor receptor pathway  Immunotherapy includes biological response modifiers, which stimulate human immune system to destroy tumor cells  The α and β human interferons are examples of efficacious agents for hairy cell leukemia and certain skin cancers  Other compounds include tumor necrosis factor, human growth factors, and monoclonal antibodies Marc Imhotep Cray MD

Targeted therapies & Immunopharmacology (2) Notably important immuno-oncology targets are programmed death ligand 1 (PD-L1) and its cognate receptor, PD-1, which is found on activated T cells, B cells, and myeloid cells  PD-L1 up regulation allows melanoma, lung, renal, and gastric cancers to evade the host immune system PD-1 checkpoint inhibitors, such as nivolumab and pembrolizumab, have been approved Another example of effective immuno-oncology therapy is blocking antibody against cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) Ipilimumab, which down regulates cytotoxic T-lymphocytes and is used for treatment of melanoma Learn more about Targeted Therapies & CA Immunopharmacology in Cancer Chemotherapeutic Drugs Notes_Pg. 28-40 Marc Imhotep Cray MD

Chemotherapeutic Agents A Case-based Discussion Companion Notes: Cancer Chemotherapy Notes.pdf Cancer Chemotherapeutic Agents Rapid Review Q&A.pdf

Marc Imhotep Cray MD

Lange Pharmacology Flashcards, Fourth Edition, M-H 2018. Pg.264.

Marc Imhotep Cray MD

Classification of Anti-Neoplastic Agents by Site of Action

Marc Imhotep Cray MD

Classification of Anti-Neoplastic Agents by Site of Action

(See Reproductive)

Marc Imhotep Cray MD

Core Concepts and Learning Objectives

CHEMOTHERAPY II: ALKYLATING AGENTS 1. The characteristic indications for the alkylating agents and plant alkaloids commonly used in chemotherapy. 2 .The mechanism of action and mechanisms of resistance for the alkylating agents and plant alkaloids commonly used in chemotherapy. 3. The principal adverse effects of the commonly used alkylating agents and plant alkaloids.

Marc Imhotep Cray MD

Relevant Drugs: Cyclophosphamide Ifosfamide Cisplatin Carboplatin Oxaliplatin Busulfan Nitrosureas Procarbazine

Case#1 A 72-year-old woman presents to the emergency room complaining of the onset of pain and bleeding with urination over the past 24 hours. She denies any fever, flank pain, or history of kidney stones. Her past medical history is significant for breast cancer, for which she is currently receiving chemotherapy. Urinalysis is significant for copious amounts of blood and red blood cells. You admit the patient to the hospital for a urology workup and you begin to wonder if her symptoms might be related to her chemotherapeutic regimen. What is the Medication?

Marc Imhotep Cray MD

Cyclophosphamide Similar Drugs Ifosfamide Mechanism of Action  Cyclophosphamide is metabolized to a hydroxylated intermediate compound by cytochrome P-450 system in liver This hydroxylated intermediate then acts as an alkylating agent and cross-links DNA, thereby decreasing DNA and RNA synthesis  drug has also been implicated in the suppression of B- and T-cell function Clinical Uses  Used in treatment of a variety of solid and hematologic malignancies (e.g., breast, ovarian, non-Hodgkin lymphoma)  Immunosuppressive agent used to treat rheumatoid arthritis, SLE, Wegener granulomatosis, and nephrotic syndrome Marc Imhotep Cray MD

Cyclophosphamide (2) Side Effects/AEs Hemorrhagic cystitis (caused by accumulation of the metabolite, acrolein, in urine; incidence can be greatly reduced by giving patient copious fluids as well as MESNA [sodium 2-mercaptoethane sulfonate]); bone marrow suppression; GI upset; alopecia; infertility Other Mechlorethamine is another alkylating agent that is used as part of MOPP protocol (mechlorethamine, vincristine, procarbazine, and prednisone) in Tx of Hodgkin’s lymphoma. Procarbazine is another alkylating agent that is also used as part of MOPP protocol in treatment of Hodgkin’s disease as well as some brain tumors.  A metabolite of procarbazine inhibits monoamine oxidase, and thus patients taking this drug should not ingest foods containing tyramine (wine, smoked meat, cheese) due to risk of norepinephrine buildup causing a hypertensive crisis Marc Imhotep Cray MD

Case #2 A 51-year-old man presents to your oncology clinic for evaluation of his CML. He will be undergoing bone marrow transplantation in the coming weeks, and he will need to have his marrow ablated prior to his transplantation. You inform him that his bone marrow will be ablated with a combination of medications, including an alkylating agent that acts to damage DNA via the cross-linking of DNA strands. You explain to him that this medication has many side effects, including adrenal insufficiency, seizures, and pulmonary fibrosis. The patient realizes that there may be serious side effects, but is more than willing to undergo the treatment to prepare for potentially lifesaving bone marrow transplantation. What is the Medication?

Marc Imhotep Cray MD

Busulfan Mechanism of Action Busulfan acts as an alkylating agent that acts to damage DNA via cross-linking of DNA strands Clinical Uses ď&#x201A;§ Treatment of CML ď&#x201A;§ Also used in combination with other drugs to ablate bone marrow before bone marrow transplantation Side Effects/AEs Pulmonary fibrosis; bone marrow suppression; adrenal insufficiency with associated hyperpigmentation; seizures Black Box Warning: Busulfan is a potent cytotoxic drug that causes PROFOUND MYELOSUPPRESSION at the recommended dosage. It should be administered under the supervision of a qualified physician who is experienced in allogeneic hematopoietic stem cell transplantation, the use of cancer chemotherapeutic drugs and the management of patients with severe pancytopenia. Marc Imhotep Cray MD

Case#3 A 42-year-old man presents to your neurology clinic complaining of severe headaches that have been present almost every day for the past month. The pain is usually lateralized to the right side and is often present upon waking. Over the past few days, he has also experienced several episodes of projectile vomiting. Physical examination is significant for the presence of papilledema on funduscopic examination. You become concerned and send the patient for an MRI of the brain. The imaging study reveals a mass in the right temporal lobe. Characteristics of the mass on imaging are consistent with a likely malignancy. You refer the patient to a neurosurgeon as well as to an oncologist. You believe that he will need chemotherapy and radiation to treat his condition and you suspect that his chemotherapy regimen will likely include a class of drugs that can cross the blood-brain barrier and then cross-link DNA strands to inhibit DNA synthesis. What is the Medication? Marc Imhotep Cray MD

Nitrosoureas Similar Drugs Nitrosoureas include carmustine, lomustine, semustine, and streptozocin Mechanism of Action Drugs in this class are alkylating agents, which act to cross-link DNA strands, and thereby result in the inhibition of DNA and RNA synthesis Clinical Uses ď&#x201A;§ Chemotherapeutic agents used in the treatment of brain tumors (e.g., glioblastoma multiforme), multiple myeloma, and lymphomas. ď&#x201A;§ Streptozocin is also used in the treatment of insulinomas Side Effects/AEs CNS toxicity; bone marrow suppression; nephrotoxicity; pulmonary fibrosis.

Marc Imhotep Cray MD

Nitrosoureas (2) Black Box Warnings: BONE MARROW SUPPRESSION - notably thrombocytopenia & leukopenia. CARMUSTINE PULMONARY TOXICITY is dose related. Risk increases with cumulative doses > 1400 mg/m2, history of lung disease & duration of therapy. Delayed cases of pulmonary fibrosis have been reported 15 years after administration.

Of Note: Nitrosoureas are one of the few chemotherapeutic agents that are highly lipid-soluble and cross the blood-brain barrier, and thus are useful in treating CNS malignancies

Marc Imhotep Cray MD

Case#4 A 76-year-old man presents to your clinic complaining of a ringing in both of his ears that has been present over the past month. He also tells you that he seems to be having more trouble hearing during this period as well. His past medical history is significant for bladder cancer, for which he is currently being treated with chemotherapy. Physical examination is remarkable for gross sensorineural hearing loss bilaterally. You suspect that his hearing loss is related to one of his medications and you decide to call his oncologist to see if there is an alternative chemotherapeutic agent that can be used to treat his malignancy, but will not cause acoustic nerve damage. What is the Medication?

Marc Imhotep Cray MD

Cisplatin (cisâ&#x20AC;&#x201C;diamminedichloroplatinum) Similar Drugs Carboplatin Mechanism of Action Cisplatin acts as an alkylating agent, thereby inhibiting DNA and RNA synthesis by binding DNA strands and leading to formation of cross-links between strands Clinical Uses Chemotherapeutic agent used in treatment of many genitourinary tumors (testicular, ovarian, bladder), other solid tumors (small cell lung cancer, stomach, esophageal) and lymphomas Side Effects/AEs Nephrotoxicity; ototoxicity; neurotoxicity; bone marrow suppression

Marc Imhotep Cray MD

Cisplatin(2) Black Box Warnings: NEPHROTOXICITY, MYLEOSUPPRESSION & OTOTOXICITY 1.NEPHROTOXICITY is cumulative, dose related and severe. It has been noted in 28-36% of patients treated with a single dose of 50 mg/m2. It is first noted during the 2nd week after a dose & is manifested by elevations in BUN, creatinine & serum uric acid. Renal function must return to normal before another dose of cisplatin can be given. 2.MYLEOSUPPRESSION: dose related and severe. Occurs in 25-30% of patients. Nadirs in circulating platelets & leukocytes occur within 18-23 days in most patients, with recovering by day 39. 3.Nausea & vomiting - dose related and severe. Seen in almost all patients & begins within 1-4 hrs after treatment & may last for 24 hrs or more (may persist up to 1 week). 4.OTOTOXICITY is significant (observed in up to 31% of patients treated with a single dose of 50 mg/m2) - may be more pronounced in children 5.Anaphylactic like reactions have been reported (epinephrine, corticosteroids & antihistamines have been effective in alleviating symptoms). 6.Avoid overdose or confusion with carboplatin Marc Imhotep Cray MD

Cisplatin(3) Important Notes: Cisplatin-induced nephrotoxicity is dose-dependent and can be mitigated with use of amifostineď&#x192; acts as a scavenger of free radicals in tissues treated w cisplatin, as well as aggressive IV fluids to induce diuresis Mitomycin is another alkylating agent that damages DNA via crosslinking of DNA strands ď&#x201A;§ It is mostly used in combination with other agents to treat certain solid malignancies (e.g., breast, gastric, esophageal, pancreas, bladder) Marc Imhotep Cray MD

Core Concepts and Learning Objectives

CHEMOTHERAPY III: ANTI-METABOLITES 1. The characteristic indications for the use on antimetabolites commonly used in the treatment of cancer. 2. The mechanism of action of the antimetabolites commonly used in the treatment of cancer. 3. The mechanism of resistance to antimetabolites 4. The major adverse effects associated with antimetabolites commonly used in the treatment of cancer.

Marc Imhotep Cray MD

Relevant Drugs Methotrexate Pemetrexed Cytarabine Gemcitabine 5-Fluorouracil Capecitabine 6-Mercaptopurine 6-Thioguanine

Case#5 A 42-year-old woman presents to your rheumatology clinic for follow-up of her rheumatoid arthritis. She is currently being treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, but she states that her symptoms are still severe. Physical examination demonstrates swelling of the proximal interphalangeal and metacarpophalangeal joints of both hands, ulnar deviation of the fingers, and subcutaneous nodules over both of her elbows. You decide to start the patient on a medication that acts to inhibit dihydrofolate reductase and will thereby decrease her bodyâ&#x20AC;&#x2122;s supply of activated folic acid. What is the Medication?

Marc Imhotep Cray MD

Methotrexate Mechanism of Action  MTX inhibits dihydrofolate reductase, enzyme that transforms folic acid to active form, FH4 FH4 is a necessary precursor for formation of thymidylate  Without FH4, thymidylate supplies are diminished, thereby resulting in decreased DNA synthesis  MTX is a S phase specific ChemoTx agent Clinical Uses  Chemotherapeutic agent used to treat a variety of malignancies (e.g., ALL, lymphomas, breast cancer, head and neck cancer, osteosarcoma, choriocarcinoma).  Immunosuppressant used to treat many autoimmune disorders (e.g., RA, Crohn’s disease, scleroderma, psoriasis)  Abortifacient when administered with a prostaglandin (used to treat missed abortions or small ectopic pregnancies)

Side Effects/AEs Bone marrow suppression; nephrotoxicity (may crystallize in renal tubules); hepatotoxicity (steatosis); teratogen; pulmonary toxicity; mucositis; seizures; GI upset; alopecia

Marc Imhotep Cray MD

MTX (2) Important Notes:  Leucovorin (folinic acid) is often given in conjunction w MTX in order to minimize bone marrow suppression, which occurs b/c of lack of folate coenzymes  In the cell, leucovorin is converted to N5N10- methylene-FH4, which is a downstream product of reaction catalyzed by dihydrofolate reductase • Therefore, leucovorin acts to bypass the inhibited enzyme and provides an adequate supply of activated folate

 MTX has same molecular target as antibiotic, trimethoprim, and anti-parasitic drug, pyrithiamine, but MTX work to target different isoforms of dihydrofolate reductase

Marc Imhotep Cray MD

Black Box Warnings (abbreviated version): 1.Because of the possibility of serious toxic (and potentially fatal) reactions, methotrexate should be used only in life threatening neoplastic diseases or severe recalcitrant psoriasis or rheumatoid arthritis which is not responsive to other forms of therapy. 2.Include the use of antimetabolite (Leucovorin) therapy 3.Patients should be closely monitored for bone marrow, liver, kidney & lung toxicity. 4.Methotrexate has been reported to cause fetal death & congenital abnormalities. Not recommended for women of child bearing potential unless the benefits outweigh the risks. 5.Unexpected bone marrow suppression, aplastic anemia & GI toxicity have been reported with high doses of methotrexate & concurrent use of NSAIDs. 6.Methotrexate causes liver toxicity, fibrosis & cirrhosis, but generally only after prolonged use. 7.Malignant lymphomas, which may regress following withdrawal of methotrexate may occur with low dose treatment. 8.Diarrhea & ulcerative stomatitis require interruption of therapy, otherwise hemorrhagic enteritis & death from intestinal perforation may occur. 9.Similar to other cytotoxic drugs, methotrexate cay cause a â&#x20AC;&#x153;tumor lysis syndromeâ&#x20AC;? in patients with rapidly growing tumors. Appropriate measures should be taken should this occur. 10.Severe & occasionally fatal skin reactions have been reported. 11.Potentially fatal opportunistic infections (e.g. Pneumocystis jiroveci pneumonia) may occur. 12.Methotrexate combined with radiotherapy may increase the risk for necrosis of soft tissues & osteonecrosis. Marc Imhotep Cray MD

Case#6 A 10-year-old girl presents to your oncology clinic for follow-up of her acute lymphoblastic leukemia, for which she is currently receiving chemotherapy. She was recently discharged from the hospital 2 days prior to her appointment at your clinic. Her mother tells you that the patient developed an episode of acute gout while in the hospital, after which she was placed on allopurinol to prevent future gouty attacks. You immediately decide to alter the doses of the patientâ&#x20AC;&#x2122;s chemotherapeutic regimen, as allopurinol indirectly inhibits the metabolism of one of the drugs in the patientâ&#x20AC;&#x2122;s chemotherapeutic regimen and can thus result in increased serum levels of this drug. What is the Medication?

Marc Imhotep Cray MD

6-Mercaptopurine

Similar Drugs Azathioprine Mechanism of Action 6-MP is converted into thio-IMP (6-Thioinosine 5'-monophosphate) by HGPRT (Hypoxanthine-guanine phosphoribosyltransferase), an enzyme involved in the salvage pathway. Thio-IMP acts as a purine analogue, which inhibits purine synthesis through feedback inhibition of several enzymes involved in de novo purine synthesis. Thio-IMP is also converted to thio-GTP, which is incorporated into DNA and RNA, leading to strand instability Clinical Uses Chemotherapeutic agent used primarily in treatment of leukemias (especially acute lymphoblastic leukemia) as well as non-Hodgkin lymphoma Immunosuppressant used to treat inflammatory bowel disease and psoriasis and prevent allograft rejection Side Effects/AEs Bone marrow suppression; GI upset; increased susceptibility to infection Marc Imhotep Cray MD

6-MP Improtant Notes: DDI: 6-MP is metabolized by xanthine oxidase, an enzyme involved in purine degradation Allopurinol, a drug used to treat hyperuricemia and gout, is a potent inhibitor of xanthine oxidase  When allopurinol and 6-MP are given simultaneously levels of serum 6MP become ↑ b/c of ↓ metabolism of 6-MP by xanthine oxidase

Azathioprine a structural analogue of 6-MP & isconverted to 6-MP within cell  It is primarily used as an immunosuppressant in autoimmune diseases such as SLE, IBD, RA, ITP, multiple sclerosis, and allograft rejection  Side effects are similar to those caused by 6-MP, and include bone marrow toxicity as well as GI upset  Both azathioprine and 6-MP are S-phase specific chemotherapeutic agents Marc Imhotep Cray MD

Case #7 A 58-year-old man presents to your office for a follow-up visit. He was recently diagnosed with colon cancer and underwent colonic resection. He is currently receiving chemotherapy as an adjuvant treatment. At this visit, he tells you that he has noticed increased sensitivity of his eyes to light as well as painful ulcers on his lips and in his mouth. After examining his eyes and oral pharynx, you tell him that you suspect that his photosensitivity and mucosal ulcers are likely a side effect of one of the chemotherapeutic drugs being used to treat his colon cancer. What is the Medication?

Marc Imhotep Cray MD

5-Fluorouracil Mechanism of Action 5-FU is converted into 5-FdUMP, which then acts to inhibit thymidylate synthase, enzyme responsible for synthesizing thymine nucleotidesď&#x192; Inhibition of thymidylate synthase leads to a disruption of nucleotide synthesis b/c of a lack of thymidine; 5-FU can also be incorporated into RNA, leading to dysfunctional RNA processing Clinical Uses Chemotherapeutic agent used to treat a variety of adenocarcinomas (gastric, pancreatic, colon, breast, ovarian) and for basal cell carcinoma Side Effects/AEs Bone marrow suppression; photosensitivity; anorexia; oral ulcerations. Of Note 5-FU is a cell cycle-specific drug, acting during S phase of cell cycle

Marc Imhotep Cray MD

Case#8 A 36-year-old woman presents to your oncology clinic for follow-up of her acute myelogenous leukemia. She has been receiving several chemotherapeutic agents for the treatment of her disease. Her most recent treatment involved a cell cycle-specific drug that acts by competitively inhibiting DNA polymerase. She tells you that lately she has been feeling extremely tired and that she had a nosebleed last week that took a long time to stop bleeding. On physical examination, you note that she is a pale, thin woman with a 3/6 systolic flow murmur at the left upper sternal border and a diffuse petechial rash over her limbs. Concerned, you send her to the emergency room for blood tests, which you suspect will reveal pancytopenia that is most likely caused by her recent chemotherapy treatment. What is the Medication?

Marc Imhotep Cray MD

Cytarabine (cytosine arabinoside) Mechanism of Action In the cell, cytarabine is converted to araCTP (arabinofuranosylcytosine triphosphate), which acts to competitively inhibit DNA polymerase and thus impair DNA synthesis. araCTP can also be incorporated into DNA, leading to termination of DNA strand elongation during DNA synthesis ď&#x201A;§ Cytarabine is a cell cycle-specific agent, acting during S phase of cell cycle Clinical Uses Chemotherapeutic agent for the treatment of AML as well as lymphomas Side Effects/AEs Bone marrow suppression with resulting pancytopenia; alopecia; GI upset; ataxia Black Box Warnings: The main toxic effect of cytarabine injection is BONE MARROW SUPPRESSION with leukopenia, thrombocytopenia, and anemia. Marc Imhotep Cray MD

Cladrabine Cladrabine acts by interfering with DNA synthesis as well; After becoming activated through phosphorylation, cladrabine incorporates into growing DNA strands and leads to DNA strand breakage ď&#x201A;§ Because activated form of drug also inhibits ribonucleotide reductase, it also induces a depletion of adenosine triphosphate (ATP) ď&#x201A;§ Cladrabine is a cell cycle-non-specific agent, and thus can induce cell death in resting as well as proliferating cancer cells USE It is used primarily for treatment of hairy cell leukemia Side effects/AEs include bone marrow suppression, neurotoxicity, and nephrotoxicity.

Marc Imhotep Cray MD

CHEMOTHERAPY V: NATURAL PRODUCTS: PLANT ALKALOIDS Vinca alkaloids: Vincristine, Vinblastine and Vinorelbine. Taxanes: Paclitaxel and Docetaxel Podophyllotoxins: Etoposide and Tenisopide Camptothecan analogs: Irinotecan and Topotecan

Marc Imhotep Cray MD

Case#9 A 67-year-old man presents to your clinic complaining of a 20-pound weight loss, night sweats, and worsening malaise. He states that he has multiple family members who have been diagnosed with cancer, but he is not sure which type they have. He also says that he has not had any cancer screening, including colonoscopies, because of â&#x20AC;&#x153;insurance issues.â&#x20AC;? A stool occult blood test is positive, and a subsequent colonoscopy shows cancerous growths in the sigmoid colon. A follow-up PET scan shows metastatic spread of his cancer. After delivering the diagnosis to the patient and his family, you begin to discuss initial treatment options. You note that one medication used to treat metastatic colon cancer works by inhibiting the enzyme topoisomerase I. What is the Medication?

Marc Imhotep Cray MD

Irinotecan Similar Drugs Topotecan Mechanism of Action Irinotecan acts by inhibiting topoisomerase I, which leads to excessive DNA supercoiling and eventual DNA strand breakage and cell death Clinical Uses ď&#x201A;§ Chemotherapeutic agent used in Tx of recurrent or metastatic solid tumors (notably metastatic colon cancer for irinotecan and metastatic ovarian or cervical cancer for topotecan) ď&#x201A;§ Other cancers treated with these agents include pancreatic, esophageal, and small-cell lung cancer Side Effects/AEs Bone marrow suppression; GI upset. Notes: Irinotecan and topotecan are cell cycle-specific drugs, active during the S phase of cell cycle Marc Imhotep Cray MD

Irinotecan(2) Black Box Warnings: SEVERE DIARRHEA Both early & late (after >24 hrs) forms of DIARRHEA may occur & can be SEVERE. Early diarrhea may be accompanied by cholinergic symptoms & can be reduced by atropine. Late diarrhea can be life-threatening due to dehydration, electrolyte imbalance or sepsis. Late diarrhea should be treated promptly with loperamide. Patients with diarrhea should be carefully monitored & given fluid, electrolytes, antibiotics if needed. Administration of Irinotecan should be discontinued if severe diarrhea occurs.

Marc Imhotep Cray MD

Case#10 A 21-year-old man presents to the emergency room complaining of unsteady gait, which he began to notice over the past week. Upon further questioning, you learn that he was recently diagnosed with Hodgkin lymphoma and is currently receiving chemotherapy for his disease. Physical examination is significant for hyporeflexia in his lower extremities and right foot-drop. Laboratory studies are unremarkable and, notably, his platelets, white blood cell counts, and red blood cell counts are normal. As you prepare to admit the patient to the neurology service, you wonder if his neurologic deficits are related to his chemotherapeutic regimen. What is the Medication?

Marc Imhotep Cray MD

Vincristine and Vinblastine Mechanism of Action Vincristine (VC) and Vinblastine (VB) bind to tubulin, a microtubular protein, thereby leading to the depolymerization of mitotic spindle. Thus, cells are unable to progress past metaphase during mitosis or meiosis, leading to decreased cellular proliferation Clinical Uses  VC: Chemotherapeutic agent used in the treatment of ALL, lymphomas (part of the MOPP protocol used to treat Hodgkin’s disease), Wilms’ tumor, and Ewing’s sarcoma.  VB: Chemotherapeutic agent used to treat testicular cancer, breast cancer, non-small cell lung cancer, and various lymphomas

Side Effects/AEs  VC: Peripheral neuropathy; GI upset; alopecia; myelosuppression is rare and usually mild when it does occur  VB: Bone marrow suppression; GI upset; alopecia

Note: VC and VB are cell cycle-specific drugs, acting during M phase of cell cycle Marc Imhotep Cray MD

Case#11 A 43-year-old woman with metastatic breast cancer returns to your oncology clinic. She has undergone combination chemotherapy for her metastatic disease without a positive response. She is quite distraught and asks if her chemotherapy can be changed. You inform her that there is a new therapy for treatment of breast cancer in case combination chemotherapy fails. You decide to switch her regimen to include this other medication, which acts by interfering with the ability of the mitotic spindle to break down and thus halting mitosis. What is the Medication?

Marc Imhotep Cray MD

Paclitaxel Similar Drugs Docetaxel Mechanism of Action Paclitaxel binds to tubulin, a microtubular protein. The paclitaxel-tubulin complex acts to promote stabilization and polymerization of mitotic spindle leads to halt of mitosis during metaphase (anaphase cannot occur) Clinical Uses  Chemotherapeutic agent used in Tx of ovarian and breast cancer, small cell cancer of lung, advanced Kaposi sarcoma, and head and neck cancers  Paclitaxel has been used in past to coat coronary artery stents so as to prevent restenosis of artery at site of stent Side Effects/AEs Hypersensitivity reactions (rash); bone marrow suppression; neurotoxicity

Marc Imhotep Cray MD

Paclitaxel (2) Black Box Warnings: ANAPHYLAXIS & MYLEOSUPPRESSION 1.ANAPHYLAXIS & severe hypersensitivity reactions with dyspnea, hypotension, urticaria & angioedema requiring treatment have occurred in 2-4% of patients. Fatal reactions have occurred despite premedication. 2.ALL PATIENTS SHOULD BE PRETREATED with CORTICOSTEROIDS, DIPHENHYDRAMINE & H2 ANTAGONISTS. 3.Paclitaxel should not be given to patients with solid tumors that have baseline neutrophil counts of less than 1500 cells/mm3 & should NOT be given to patients with AIDS-related Kaposi's sarcoma if their baseline neutrophil count is less than 1000 cells/mm3. 4.Frequent peripheral blood cell counts should be performed to monitor the occurrence of bone marrow suppression (primarily neutropenia).

Marc Imhotep Cray MD

Core Concepts and Learning Objectives

CHEMOTHERAPY IV: ANTI-TUMOR ANTIBIOTIC AGENTS 1. The characteristic indications, mechanism of action, mechanism of resistance and adverse effects of doxorubicin and the other commonly used antibiotic and anti-tumor agents. 2. The concept of multiple drug resistance and its effects on effective chemotherapy. 3. The concept of cumulative toxicity and schedule independent toxicity. 4. The concept of the hormonally-sensitive neoplasms and their treatment. 5. The major side effects associated with antibiotic and antitumor agents commonly used in chemotherapy. Marc Imhotep Cray MD

Relevant Drugs: Doxorubicin Daunorubicin Idarubicin Dactinomycin Bleomycin

Case#13 A 14-year-old boy presents to your office for initiation of chemotherapy to treat his acute lymphoblastic leukemia. You explain to the boy and his mother that you will be using several different chemotherapy agents to treat his disease. One of the agents you will be administering acts by blocking DNA and RNA synthesis; however, this drug also causes the production of oxygen free radicals, which can damage cardiac tissue when given at high doses. You assure the patient that you will be carefully monitoring levels of this drug so as to avoid cardiac toxicity if possible. What is the Medication?

Marc Imhotep Cray MD

Anthracycline Antibiotics Class of anthracyclines includes doxorubicin, daunorubicin, and idarubicin Mechanism of Action Anthracyclines block DNA and RNA synthesis both through direct steric inhibition as well as by inhibiting topoisomerase II. They also cause production of oxygen free radicals, which lead to membrane damage Clinical Uses  Doxorubicin: used in treating a variety of solid tumors (breast, ovary, bladder, endometrium, stomach, lung) as well as in treating a variety of hematologic malignancies (acute leukemia, lymphoma, multiple myeloma) and in treating AIDS-related Kaposi sarcoma.  Daunorubicin: used in treating acute leukemia (AML, ALL, CML) and neuroblastoma  Idarubicin: used in treating acute myeloid leukemia Marc Imhotep Cray MD

Anthracyclines(2) Side Effects/AEs Cardiac toxicity; bone marrow suppression; GI distress; alopecia

Important Notes:  The cardiotoxic effects of anthracyclines are caused, in part, by production of oxygen free radicals within myocardial cells and subsequent damage of myocyte.  This adverse effect is cumulative, dose-dependent, and can be largely avoided by keeping doses below a certain lifetime dose and by administering dexrazoxane a compound that acts to decrease free radical formation

Marc Imhotep Cray MD

Anthracyclines (3) doxorubicin, daunorubicin Black Box Warnings: SEVERE MYELOSUPPRESSION & MYOCARDIAL TOXICITY 1.Daunorubicin for injection must be given into a rapidly flowing i.v. infusion. It must never be given by i.m. or s.c. routes due to local tissue necrosis. 2.MYOCARDIAL TOXICITY manifested in its most severe form as potentially fatal CHF may occur months to years after termination of therapy. The incidence increases after cumulative doses exceed 400-550 mg/m2 in adults or 300 mg/m2 in children >2yo, or 10 mg/kg in children <2yo. 3.SEVERE MYELOSUPPRESSION occurs at therapeutic doses, which may lead to infection or hemorrhage. 4.dosage should be reduced in patients with impaired hepatic or renal function. 5.Daunorubicin should only be given in a facility where physicians & staff are capable of rapidly responding to severe hemorrhagic conditions and/or overwhelming infection.

Marc Imhotep Cray MD

Case#14 A 2-year-old boy is brought to your oncology clinic after having been recently diagnosed with Wilms tumor. Physical examination is significant for a palpable left flank mass. You explain to the childâ&#x20AC;&#x2122;s mother that the best course of treatment will include surgical excision of the tumor and chemotherapy. You recommend the use of at least two drugs, one of which acts by interfering with RNA synthesis through the inhibition of DNA dependent RNA polymerase. Since this drug can also cause bone marrow suppression, the childâ&#x20AC;&#x2122;s blood cell counts, especially his platelets and leukocytes, will have to be monitored closely. What is the Medication?

Marc Imhotep Cray MD

Dactinomycin Similar Drugs Plicamycin Mechanism of Action Dactinomycin intercalates betw. cytosine-guanine base pairs of DNA, thereby acting to inhibit DNA-dependent RNA polymerase, and thereby impairing both DNA and RNA synthesis. Clinical Uses Used for several solid tumors including Wilms tumor, Ewing sarcoma, and metastatic testicular cancer. Also used in conjunction w MTX to treat gestational choriocarcinoma Side Effects/AEs Bone marrow suppression; GI upset; skin abnormalities at sites that have previously received radiation (“radiation recall”) Note Plicamycin has a similar MOA as dactinomycin, but is primarily used for Tx of some testicular cancers and Paget’s disease of bone Marc Imhotep Cray MD

Case#15 A 69-year-old man presents to your clinic complaining of shortness of breath that has become progressively worse over the past month. He tells you that he was diagnosed with testicular cancer 4 months ago, for which he is currently receiving chemotherapy. Physical examination is significant for an oxygen saturation of 89% on room air and decreased air movement on lung examination. When imaging studies reveal pulmonary fibrosis, you begin to suspect that this patientâ&#x20AC;&#x2122;s symptoms are likely related to his chemotherapeutic regimen. What is the Medication?

Marc Imhotep Cray MD

Bleomycin Mechanism of Action Bleomycin binds to DNA and triggers the formation of oxygen free radicals. The oxygen radicals then act to damage the DNA, leading to strand breaks and inhibition of DNA synthesis. Clinical Uses Chemotherapeutic agent for the treatment of testicular tumors, squamous cell carcinomas (head and neck, skin, penis, cervix), and Hodgkinâ&#x20AC;&#x2122;s lymphoma. Side Effects/AEs Pulmonary fibrosis; allergic reactions (fever, anaphylaxis); mucositis; skin changes Note that myelosuppression is rare with bleomycin Of Note Bleomycin is cell cycle-specific, thereby leading to accumulation of cells in G2 phase of cell cycle Marc Imhotep Cray MD

Bleomycin (2) Black Box Warnings: PULMONARY FIBROSIS is associated with bleomycin treatment. The most common presentation is pneumonitis, progressing to pulmonary fibrosis. It is more common in elderly patients receiving more than 400 units total dose, but has been seen in younger patients & those treated with lower doses. A severe IDIOSYNCRATIC REACTION of hypotension, mental confusion, chills, fever & wheezing has also been reported in 1% of lymphoma patients undergoing bleomycin treatment.

Marc Imhotep Cray MD

CHEMOTHERAPY V: TARGETED THERAPIES OF CANCER MISCELLANEOUS AGENTS 1. The concept of “targeted cancer therapy”. 2. The role of tyrosine kinases as targets for cancer therapy. 3. The potential benefits and toxicities of the commercially available targeted therapies. 4. The uses and side effects of miscellaneous anticancer agents.

Marc Imhotep Cray MD

Relevant Drugs Imatinib mesylate (Gleevec) Erlotinib (Tarceva) Cetuximab (Erbitux) Trastuzumab (Herceptin) Bevacizumab (Avastin) Rituximab (Rituxin) Asparaginase Hydroxyurea All-trans-retinoic acid Arsenic trioxide 89

Case#16 A 56-year-old gentleman with a past medical history significant for hypertension and tobacco use presents to your office complaining of hematuria. On physical exam, you palpate a flank mass on the left. Ultrasound confirms an irregular, noncystic, vascular lesion in his left kidney. Follow-up biopsy confirms your suspicion that the patient has a malignant growth in his kidney. You suspect that the patientâ&#x20AC;&#x2122;s chemotherapy regimen will include an agent to inhibit angiogenesis. What is the Medication?

Marc Imhotep Cray MD

Bevacizumab Mechanism of Action Bevacizumab is a monoclonal antibody specific for vascular endothelial growth factor (VEGF). By blocking the activity of VEGF, bevacizumab prevents angiogenesis, reducing vascular supply to tumors and retarding their growth. Clinical Uses ď&#x201A;§ Chemotherapeutic agent used in Tx of solid tumors (ovarian, colorectal, cervical, renal cell carcinoma) ď&#x201A;§ It is also used to treat dysregulated angiogenesis in wet age related macular degeneration

Marc Imhotep Cray MD

Bevacizumab (2) Side Effects/AEs Arterial thromboembolism; hypertension; hemorrhage. Related Notes ď&#x201A;§ Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR). Inhibiting EGFR prevents cell growth and induces apoptosis. It is used to treat solid cancers including head and neck cancer, non-small cell lung cancer, and colorectal cancer. Side effects include an acne like rash. ď&#x201A;§ Similar to bevacizumab, ranibizumab is a monoclonal antibody w activity against VEGF; It is used for Tx of macular degeneration

Marc Imhotep Cray MD

Case#17 A 50-year-old woman returns to your oncology clinic for a follow-up visit. She is currently on a multidrug regimen for metastatic breast cancer. She appears to be responding well after the addition of a chemotherapeutic agent aimed at the HER-2/neu receptors within her cancer cells. While she is in the office, you schedule her for an imaging study to evaluate her heart. She asks why this test needs to be done and you remind her that, although the new medication is highly effective against her type of breast cancer, it can also cause cardiac dysfunction in up to 10% of patients. What is the Medication?

Marc Imhotep Cray MD

Trastuzumab Mechanism of Action Trastuzumab acts as a monoclonal antibody against the HER-2/neu (erb-B2) receptor. The HER-2/neu receptor is involved in growth-promoting pathways of the cell; 20% to 30% of breast cancers will overexpress HER-2/neu, thereby contributing to uncontrolled cellular growth. Trastuzumab directly blocks HER-2/neu signaling and also induces antibody-dependent cell-mediated cytotoxicity. Clinical Uses Chemotherapeutic agent used to treat breast cancer and gastric cancer that overexpress HER-2 receptor. Side Effects/AEs Cardiac toxicity; neutropenia; GI upset.

Marc Imhotep Cray MD

Case#18 A 49-year-old man presents to your oncology office for follow-up of his chronic myelogenous leukemia, for which he is currently receiving chemotherapy. You ask him whether he is experiencing any nausea, vomiting, or diarrhea, all of which are common side effects of his medications. You also tell him that his blood counts are at the low end of normal, which is expected since his chemotherapeutic regimen can also cause bone marrow suppression. He was biochemistry major in college, so he is interested in knowing how the drugs that he is taking work. You explain to him that one of his medications acts by inhibiting ribonucleotide reductase, an enzyme involved in making deoxyribonucleotides, the building blocks for DNA. What is the Medication?

Marc Imhotep Cray MD

Hydroxyurea Mechanism of Action Hydroxyurea inhibits ribonucleotide reductase, the enzyme responsible for reducing ribonucleotides to deoxyribonucleotides. Inhibition of this enzyme results in decreased DNA synthesis. Hydroxyurea has also been shown to increase levels of fetal hemoglobin (Hb F), although exact mechanism for this effect is unknown. Clinical Uses ď&#x201A;§ Chemotherapeutic agent used to treat myeloproliferative disorders (e.g., CML, polycythemia vera) as well as melanoma ď&#x201A;§ Hydroxyurea has also been used in the treatment of sickle cell disease to promote production of Hb F over hemoglobin S Side Effects/AEs Bone marrow suppression; GI upset. Note Hydroxyurea is a cell cycle-specific agent, acting during S phase of cell cycle Marc Imhotep Cray MD

Case#19 A 64-year-old man with chronic myelogenous leukemia is being seen in your oncology clinic. He has been treated with Îą-interferon and cytarabine with no improvement. He asks you if there are any other options to treat his disease. You tell him that you would like to try a different agent that acts by inhibiting a tyrosine kinase on a mutated gene product, bcr-abl, which has been shown to be associated with his disease. What is the Medication?

Marc Imhotep Cray MD

Imatinib Mechanism of Action Imatinib acts as a competitive inhibitor of tyrosine kinase enzymes in abl, c-kit, and PDGF-R (Platelet-derived growth factor receptors ), all genes involved in cellular growth. By inhibiting tyrosine kinase enzymes, activation of these genes is severely decreased, and cellular growth is slowed Clinical Uses Chemotherapeutic agent used to treat CML, GISTs (gastrointestinal stromal tumor), and brain tumors Side Effects/AEs Fluid retention (edema); nausea; rash; heart failure Important Note CML is commonly assoc. w translocations betw. chromosomes 9 and 22, yielding what is known as Philadelphia chromosome. The translocation produces a fusion protein, bcr-abl, which is constitutively activeď&#x192; By inhibiting tyrosine kinase of abl portion of this mutated gene product wagents such as imatinib, cellular growth of CML is decreased

Marc Imhotep Cray MD

Types of Chemotherapeutic Agents:

A Classification Summary

Marc Imhotep Cray MD

Alkylating Agents Alkylating agents are most active in the resting phase of cell. These types of drugs are cell-cycle non-specific. Mustard gas derivatives: Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, and Ifosfamide.  Ethylenimines: Thiotepa and Hexamethylmelamine.  Alkylsulfonates: Busulfan.  Hydrazines and Triazines: Altretamine, Procarbazine, Dacarbazine and Temozolomide.  Nitrosureas: Carmustine, Lomustine and Streptozocin. Nitrosureas are unique because, unlike most types of chemo treatments, they can cross the blood-brain barrier. They can be useful in treating brain tumors.  Metal salts: Carboplatin, Cisplatin, and Oxaliplatin

Marc Imhotep Cray MD

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Plant Alkaloids Plant alkaloids are ChemoTx agents derived made from certain types of plants. Vinca alkaloids are made from periwinkle plant (catharanthus rosea). Taxanes are made from bark of Pacific Yew tree (taxus). Vinca alkaloids and taxanes are also known as antimicrotubule agents. The podophyllotoxins are derived from the May apple plant. Camptothecan analogs are derived from Asian "Happy Tree" (Camptotheca acuminata). Podophyllotoxins and camptothecan analogs are also known as topoisomerase inhibitors, which are used in certain types of chemotherapy. The plant alkaloids are cell-cycle specific. This means they attack cells during various phases of division  Vinca alkaloids: Vincristine, Vinblastine and Vinorelbine.  Taxanes: Paclitaxel and Docetaxel  Podophyllotoxins: Etoposide and Tenisopide  Camptothecan analogs: Irinotecan and Topotecan Marc Imhotep Cray MD

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Anti-tumor Antibiotics Antitumor antibiotics are ChemoTx agents made from natural products produced by species of soil fungus Streptomyces. These drugs act during multiple phases of cell cycle and are considered cell-cycle specific. There are several types of antitumor antibiotics: •Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Mitoxantrone, and Idarubicin •Chromomycins: Dactinomycin and Plicamycin •Miscellaneous: Mitomycin and Bleomycin

Marc Imhotep Cray MD

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Antimetabolites Antimetabolites are types of ChemoTx that are very similar to normal substances within cell. When cells incorporate these substances into cellular metabolism, they are unable to divide. Antimetabolites are cellcycle specific. They attack cells at very specific phases in cycle. Antimetabolites are classified according to substances with which they interfere.  Folic acid antagonist: Methotrexate  Pyrimidine antagonist: 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine  Purine antagonist: 6-Mercaptopurine and 6-Thioguanine  Adenosine deaminase inhibitor: Cladribine, Fludarabine, Nelarabine and Pentostatin

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Topoisomerase Inhibitors Toposiomerase inhibitors are types of ChemTx drugs that interfere with action of topoisomerase enzymes (topoisomerase I and II). During process of chemo Txs, topoisomerase enzymes control manipulation of structure of DNA necessary for replication. â&#x20AC;˘Topoisomerase I inhibitors: Irinotecan, topotecan â&#x20AC;˘Topoisomerase II inhibitors: Amsacrine, etoposide, etoposide phosphate, teniposide

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Miscellaneous Antineoplastics Several useful types of chemotherapy drugs are unique:  Ribonucleotide reductase inhibitor: Hydroxyurea  Adrenocortical steroid inhibitor: Mitotane  Enzymes: Asparaginase and Pegaspargase  Antimicrotubule agent: Estramustine  Retinoids: Bexarotene, Isotretinoin, Tretinoin (ATRA)  Beyond aforementioned types of ChemoTx agents, many other types of chemo treatments exist, such as targeted therapy, immunotherapy, and hormone therapy. Sources:  http://chemocare.com/chemotherapy/what-is-chemotherapy/types-of-chemotherapy.aspx  http://tmedweb.tulane.edu/pharmwiki/doku.php/cancer_chemotherapy Marc Imhotep Cray MD

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THE END

See next slide for links to tools and resources for further study.

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Further Study Cloud Folder: CA ChemoTx Ppts, Notes, SDL Tutorials and Video

Marc Imhotep Cray MD

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