GTMB 7 - Gene Therapy & Molecular Biology

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Jekunen et al: Strategy of sensitizing tumor cells with adenovirus-p53 transfectionV. ConclusionSeveral subsequent studies have confirmed thatvarious malignant cell lines and tumors expressing mutantor deleted p53 are chemoresistant to a wide range ofanticancer agents. However, other studies disagreesuggesting that cells with impaired p53 function canbecome sensitized to various anticancer agents. Thus, therelationship between p53 status and chemosensitivity iscomplex and presumably depends on a number of factors,including the specific cytotoxic stimuli, tissue-specificdifferences, and the specific cellular context thatincorporates the overall genetic machinery and the variousintracellular signaling pathways (Chu and DeVita 2001).The relationship between p53 and chemotherapy dependson the chemotherapeutic agents used, the target and thecritical tissues, and the intracellular signal transductionpathways affected.The theoretical basis of the sensitizing effect ofchemotherapeutic agents in combination with adenovirusp53 has been presented and so have a number ofsupportive data. As adenovirus p53 has its own activity,there seems to be a possibility that the cytotoxicity may beenhanced at least in some cell lines by transfer of the geneinto the tumor cells. This concept has reached the level ofproof in some, although not all, experimental conditions.This leaves a room for doubt, as all spontaneous solidtumors are heterogeneous and there may always remaincell clones that fail to obey the sensitizing principle. It isclear that more evidence is needed to support thisprinciple, especially clonogenic assays and classicalinteraction studies. Although the in vivo experiments areconvincing and strongly positive, it may not be altogethercorrect to extrapolate these results into clinical practice.There is a relative lack of pharmacokinetic studies andpharmacokinetic interaction studies in adenovirus p53gene therapy.Several strategies may be used to develop p53-basedanticancer therapies, with the goal of resensitizing tumorcells to conventional chemotherapy (Chang 2000). Theseinclude reintroduction of the gene encoding wild-type p53and methods for restoring normal p53 function to mutantp53. In addition, methods are being developed that targetthe p53-mdm-2 interaction of using lack of wild-type p53in tumors to protect normal tissue from the adverse effectsof chemotherapy. Replacement of the wild-type p53 byintratumoral transfection has already reached the phase IIIstage of clinical trials. Transfection of p53 can becombined with radioimmunotherapy as part of a tumormanipulation scheme (Kairemo, Jekunen et al, 1999).Increasing suppressor gene p53 expression in tumor cellsimproves the sensitivity of the tumor cells to routinechemotherapy. In a variety of tumor types, docetaxel andirinotecan are efficacious drugs with a new mode ofaction: prevention of depolymerization of tubulin andinhibition of specific DNA topoisomerase I, respectively.But we cannot obtain responses from all tumors, and insome tumors the efficacy, although established,diminished with time. In these cases of resistant tumors orrecurrences and relapses, combined treatment with adenop53and chemotherapeutic agents may be an attractivestrategy for inhibiting progression of local cancers. It isclear that even a modest change in drug sensitivity maybring some refractory tumors within a range that istreatable with conventional chemotherapy. Future therapymight couple standard cytotoxic agents with new biologicagents that attack specific molecular targets to reregulatethe cell-cycle checkpoint.Human data supporting the effect of sensitizingchemotherapy with adenovirus p53 is still maturing,although we have not found a way to use systemicadministration. We know that is s safe to performintratumoral gene therapy with adenovirus either with areplication non-competent or replication competent vector.As yet, there is no clinical evidence to support a definiteconclusion that adenovirus p53 provides a clinicallymeaningful improvement on conventional chemotherapy.However, it is clear that in some trial set ups it has beenpossible to demonstrate encouraging results and thepossibility of a clinical sensitizing effect of p53 genetherapy on the chemotherapy used when specificallyindicated. Intratumoral expression of transgenes andtumor-selective tissue destruction have been documentedin phase I and phase II clinical trials of adenovirus p53mediated gene therapy. However, durable responses andthe clinical benefit seen have been limited, with of 10-15%response rates.The rationale of combining p53 gene therapy with achemotherapeutic agent in the clinical setting has beennoted to be as follows: combinations of agents withdifferent toxicologic profiles can result in increasedefficacy without increased overall toxicity, they maythwart the development of resistance to the single agents,they may offer a solution to the problem of heterogeneoustumor cell populations with different drug sensitivityprofiles and they allow the physician to take advantage ofpossible synergies between drugs, resulting in increasedanticancer efficacy in patients (Nielsen, Lipari et al, 1998).Several phase III clinical trials with adenovirus p53therapy in head and neck cancer, NSCLC, and ovariancancer, will be completed in the near future, and the roleof gene therapy may become routine a part of treatmentregimens.AcknowledgmentsWe would like to thank Aventis Pharma Finland forsupporting this work.ReferencesBadie B, Kramar MH, Lau R, Boothman DA, Economou JS,Black KL. 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Gene Therapy and Molecular Biology Vol 7, page 33Brown, M. J. and B. G. Wouters (1999). “Apoptosis, p53, andtumor cell sensitivity to anticancer agents.” Cancer Res 59:1391-1399.Bunz, F. (1999). “Disruption of p53 in human cancer cells altersthe responses of chemotherapeutic agents.” J Clin Invest104: 263-269.Calvert, A. H. (1999). “Carboplatin and paclitaxel, alone and incombination: dose escalation, measurement of renal function,and role of the p53 tumor supressor gene.” Semin. Oncol.29: 90-94.Carrier, F., Georgel, P.T., Pourquier, P., Blake, M., Kontny,H.U., Antinore, M.J., Gariboldi, M., Myers, T. G, Weinstein,J.N., Pommier, Y,and Fornace, A.J., Jr. (1999). “Gadd45, ap53-responsive stress protein, modifies DNA accessibility ondamaged chromatin.” Mol Cell Biol 19(3): 1673-85.Chang, E. H. (2000). “Tp53 gene therapy: akey to modulatingresistance to anticancer therapies?” Molecular MedicineToday 6: 358-364.Chu, E. and V. T. J. DeVita (2001). Apoptosis, cell-cycle control,and resistance to chemotherapy. Cancer. Principles &Practice of Oncolgy. V. T. J. DeVita, S. Hellman and S. A.Rosenberg. Philadelphia, Lippincott Williams & Wilkins. 6:289-306.Clahsen PC, van de Velde CJ, Duval C, Pallud C, Mandard AM,Delobelle-Deroide A, van den Broek L, Sahmoud TM, vande Vijver MJ. (1998). “p53 protein accumulation andresponse to adjuvant chemotherapy in premenopausal womenwith node-negative early breast cancer.” J Clin Oncol 16(2):470-3945.Clayman GL, el-Naggar AK, Lippman SM, Henderson YC,Frederick M, Merritt JA, Zumstein LA, Timmons TM, LiuTJ, Ginsberg L, Roth JA, Hong WK, Bruso P, Goepfert H.(1998). “Adenovirus-mediated p53 gene transfer in patientswith advanced recurrent head and neck squamous cellcarcionoma.” JCO 16: 2221-2232.Constenla-Figueiras M, Betticher DC, DelCampo JM, Hitt R,Rochlitz C, Dhondt V, Gautier E, Saulnier P, Yver A, BadriN. 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