By Dr. D.S. Bautista, Ph.D.

Upon start of clinical investigations on the potential use of adenovirus-mediated wild-type p53 gene transfer to treat various forms of cancer, the concept of combining gene therapy with standard chemotherapy and radiation therapy also emerged, and had since quickly received considerable attention. Thus, a number of relevant studies ranging from in vitro studies of tumor cell lines, to xenograft models in mice, and finally to investigations on human subjects, have shown the utility of this concept as an effective modality to managing advanced forms of tumors. 

 Recent clinical evidence including those reported at the 2011 American Society of Clinical Oncologists Annual Meeting indeed shows a growing interest in translational medicine to integrate p53 gene therapy with radiotherapy in treating cervical cancer (REFS 1,2), unresectable hepatocellular carcinoma (REF 3), and advanced nasopharyngeal cancer (REF 4).

Similarly, p53 gene therapy combined with chemotherapy to treat advanced colorectal cancer (REF 5), and in particular, hepatocellular carcinoma (REFS 6,7,8) are few examples of this new paradigm for cancer treatment.

Patients with advanced recurrent cancer are among those who should benefit from such a combinational p53 gene therapy. Clinical recurrence or relapse is characterized by emergence of cancer cells from a state of tumor dormancy in what is now recognized as a clinical phenomenon in a number of cancer types (reviewed in REF 9). Dormant tumor cells are those that are lying in wait for a period of time following treatment of the primary tumor, then subsequently re-grow and contribute to clinical recurrence. Such dormant tumor cells may remain in the original tumor bed site or may form micrometastases and even appear later at a distant site.

The properties of the dormant tumor cells which remain following treatment of the primary tumor can  vary over a wide range and are likely determined by various factors, including cell and tissue type of primary tumor, treatment that was used to remove the primary tumor, degree of progression and heterogeneity of the tumor population, among others. Specifically, tumor cells that recur following intensive chemotherapy are most likely to have become resistant via selection not only to the anticancer agents initially used but also to others that share the same mechanism of resistance. The resistance may be due to overexpression of the multi-drug resistance gene 1, or MDR1, whose product is the P-gp, and/or abrogation of apoptotic pathways that mediate cytotoxicity of many anticancer drugs.

Cross-resistance of tumor cells to various structurally unrelated anti-cancer drugs such as anthracyclines, epipodsophyllotoxins, vinca alkaloids, actinomycin D and paclitaxel is attributed to P-gp expression (REF 10), which is suppressed by the normal p53 gene product. In tumor cells that have defective p53, the suppression of P-gp is absent leading to over-expression of P-gp, thus causing resistance to anticancer drugs. In fact, some p53 mutations may yet activate the promoter of MDR1 as an acquired function of the mutant p53.

Equally important is the phenomenon of loss of apoptosis in tumor cells, which also leads to resistance to drugs. Most anti-cancer drugs induce ‘stress’ on tumor cells that ideally causes activation of apoptotic pathway leading to tumor cell death. In this manner, a normal p53 is required for apoptotic tumor cell death much like p53 functions orchestrate a whole array of molecular events through transcriptional activation and suppression in response to threats to the genome of normal cells. In advanced tumor cells the p53 gene is most likely mutated, or part of its p53 pathway is damaged such that the response to induce apoptosis is no longer available. In this manner, the cytotoxic activity of anticancer drugs is negated.

Chemo-resistance in tumor cells is achieved when selective pressure from treatment of the primary tumor is exerted, resulting in apparently dormant or quiescent cells to remain, but only to reappear at a later time to form the population of what would be refractory tumor cells. Chemo-resistance from activated MDR1 may result from a defective p53 or its pathway, or some other means. In advanced tumor cells, chemo-resistance may be manifested by abrogation of the apoptotic pathways, which are important for most anticancer drugs to kill tumor cells. Restoration of p53 functions using adenovirus-mediated p53 transduction in tumor cells has been shown at the clinical level to reverse chemo-resistance and synergistically enhance cytotoxicity of anti-cancer agents.     （2011-12）

References:
1. Zhang, S.W. (2011). Recombinant adenovirus-p53 (rAd-p53) in combination with radiotherapy for treating cervical cancer. J. Clin. Oncol. 29 (suppl; abstr 5096).
2. Pan, J.J. (2011). A phase II study of recombinant adenoviral human p53 gene combined with radiotherapy in treatment of patients with locally advanced cervical carcinoma. J. Clin. Oncol 29 (suppl; abstr 5097).
3. Zhang, Y.W. (2011). Transcatheter arterial embolization (TAE) combined with recombinant adenoviral human p53 gene in treatment of patients with unresectable hepatocellular carcinoma (HCC). J. Clin. Oncol. 29 (suppl; abstr e14521).
4. Pan, J.J., Zhang, S.W., Chen, C.B., Xiao, S.W., Sun, Y., et al. (2009). Effect of recombinant adenovirus-p53 combined with radiotherapy on long-term prognosis of advanced nasopharyngeal carcinoma. J. Clin. Oncol. 27: 799-804.
5. Zhang, Z.G. (2011). Recombinant adenoviral human p53 gene combined with FOLFOX4 in treatment of advanced colorectal cancer. J. Clin. Oncol. 29 (suppl; abstr e14133).
6. Tian, G., Liu, J., and Sui, J. (2009). A patient with huge hepatocellular carcinoma who had a complete clinical response to p53 gene combined with chemotherapy and transcatheter arterial embolization. Anti-Cancer Drugs 20:403-407.
7. Tian, G., Liu, J., Sui, J., Zhou, R., and Chen, W. (2009). Multiple hepatic arterial injections of recombinant adenovirus p53 and 5-fluorouracil after transcatheter arterial chemmoembolization for unresectable hepatocellular carcinoma: a pilot phase II trial. Anti-cancer Drugs 20:389-395.
8. Guan, Y.S., Liu, Y., Sun, L., Li, Xiao, and He, Q. (2005). Successful management of post-operative recurrence of the hepatocellular carcinoma with p53 gene therapy combining transcatheter arterial chemoembolization. World J. Gastroenterol. 11:3803-3805.
9. Goss, P.E. and Chambers, A.F. (2010). Does tumor dormancy offer a therapeutic target? Nature Reviews 10:871-877.
10. Van Kalken, C.K., Pinedo, H.M., and Giaccone, G. (1991). Multidrug resistance from the clinical point of view. E

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