Jekunen et al: Strategy of sensitizing tumor cells with adenovirus-p53 transfection strategy for inhibiting progression of local cancers. It is clear that even a modest change in drug sensitivity may bring some refractory tumors within a range that is treatable with conventional chemotherapy. Future therapy might couple standard cytotoxic agents with new biologic agents that attack specific molecular targets to reregulate the cell-cycle checkpoint. Human data supporting the effect of sensitizing chemotherapy with adenovirus p53 is still maturing, although we have not found a way to use systemic administration. We know that is s safe to perform intratumoral gene therapy with adenovirus either with a replication non-competent or replication competent vector. As yet, there is no clinical evidence to support a definite conclusion that adenovirus p53 provides a clinically meaningful improvement on conventional chemotherapy. However, it is clear that in some trial set ups it has been possible to demonstrate encouraging results and the possibility of a clinical sensitizing effect of p53 gene therapy on the chemotherapy used when specifically indicated. Intratumoral expression of transgenes and tumor-selective tissue destruction have been documented in phase I and phase II clinical trials of adenovirus p53 mediated gene therapy. However, durable responses and the clinical benefit seen have been limited, with of 10-15% response rates. The rationale of combining p53 gene therapy with a chemotherapeutic agent in the clinical setting has been noted to be as follows: combinations of agents with different toxicologic profiles can result in increased efficacy without increased overall toxicity, they may thwart the development of resistance to the single agents, they may offer a solution to the problem of heterogeneous tumor cell populations with different drug sensitivity profiles and they allow the physician to take advantage of possible synergies between drugs, resulting in increased anticancer efficacy in patients (Nielsen, Lipari et al, 1998). Several phase III clinical trials with adenovirus p53 therapy in head and neck cancer, NSCLC, and ovarian cancer, will be completed in the near future, and the role of gene therapy may become routine a part of treatment regimens.
V. Conclusion Several subsequent studies have confirmed that various malignant cell lines and tumors expressing mutant or deleted p53 are chemoresistant to a wide range of anticancer agents. However, other studies disagree suggesting that cells with impaired p53 function can become sensitized to various anticancer agents. Thus, the relationship between p53 status and chemosensitivity is complex and presumably depends on a number of factors, including the specific cytotoxic stimuli, tissue-specific differences, and the specific cellular context that incorporates the overall genetic machinery and the various intracellular signaling pathways (Chu and DeVita 2001). The relationship between p53 and chemotherapy depends on the chemotherapeutic agents used, the target and the critical tissues, and the intracellular signal transduction pathways affected. The theoretical basis of the sensitizing effect of chemotherapeutic agents in combination with adenovirus p53 has been presented and so have a number of supportive data. As adenovirus p53 has its own activity, there seems to be a possibility that the cytotoxicity may be enhanced at least in some cell lines by transfer of the gene into the tumor cells. This concept has reached the level of proof in some, although not all, experimental conditions. This leaves a room for doubt, as all spontaneous solid tumors are heterogeneous and there may always remain cell clones that fail to obey the sensitizing principle. It is clear that more evidence is needed to support this principle, especially clonogenic assays and classical interaction studies. Although the in vivo experiments are convincing and strongly positive, it may not be altogether correct to extrapolate these results into clinical practice. There is a relative lack of pharmacokinetic studies and pharmacokinetic interaction studies in adenovirus p53 gene therapy. Several strategies may be used to develop p53-based anticancer therapies, with the goal of resensitizing tumor cells to conventional chemotherapy (Chang 2000). These include reintroduction of the gene encoding wild-type p53 and methods for restoring normal p53 function to mutant p53. In addition, methods are being developed that target the p53-mdm-2 interaction of using lack of wild-type p53 in tumors to protect normal tissue from the adverse effects of chemotherapy. Replacement of the wild-type p53 by intratumoral transfection has already reached the phase III stage of clinical trials. Transfection of p53 can be combined with radioimmunotherapy as part of a tumor manipulation scheme (Kairemo, Jekunen et al, 1999). Increasing suppressor gene p53 expression in tumor cells improves the sensitivity of the tumor cells to routine chemotherapy. In a variety of tumor types, docetaxel and irinotecan are efficacious drugs with a new mode of action: prevention of depolymerization of tubulin and inhibition of specific DNA topoisomerase I, respectively. But we cannot obtain responses from all tumors, and in some tumors the efficacy, although established, diminished with time. In these cases of resistant tumors or recurrences and relapses, combined treatment with adenop53 and chemotherapeutic agents may be an attractive
Acknowledgments We would like to thank Aventis Pharma Finland for supporting this work.
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