[Kamat2010]

Developments in the treatment of pancreatic cancer using gene therapy:

Among the different types of cancers, pancreatic cancer remains to be one of the most prevalent one that is difficult to treat due to its complex nature and poor prognosis. Various issues in the diagnosis of the disease in the early stages including location in the anatomy and improper symptoms; the rapid spread of the disease to the nearby crucial organs including the duct of bile, the blood vessels and nerves; the metastasis of the disease due to a minor primary focal point such as tumor; and the meagre disease response to different cancer-specific therapies, are responsible for the difficult prognosis of the disease. Since, the diagnosis of the disease in the early stages is difficult, hence in-depth research and clinical trials are necessary to discover a new method of treatment for the disease.

Gene therapy has shown great promise in the therapeutics for different diseases, especially cancer in the past few years. The main reason for the success of gene therapy lies in the fact that it targets the genes involved in the progress or development of a particular disease. In the therapy for cancer, the process mainly targets the different genes that may be responsible for the spread of cancer or those that prevent the killing of cancer cells. It may also help in the delivery of different specific devices that help in the killing of cancer cells.

The molecular abnormalities related to the pancreatic cancer is the typical occurrence of a point mutation in the K-ras gene associated with the K-ras signalling mechanism; apart from the presence of abnormal p53 gene, abnormalities leading to suppression or loss of expression in the DPC4 gene and DCC gene, different types of mutation mainly somatic in APC gene, the above-normal expression of the different fibroblast growth factors (acidic as well as basic) and the instability of the microsatellite. Since, the main role of K-ras was observed in the potent transformation of the activity of NIH3T3 cell line of mouse fibroblasts, hence was chosen as the main target for the pancreatic cancer.

The experimental studies of T.Yoshida et.al., involved the targeting of the K-ras by the transduction of the human pancreatic cancer cell lines such as AsPC-1, MIAPaCa-2, Panc-1, PSN-1 and BxPC-3 with the plasmids expressing the antisense K-ras RNA, which resulted in the tumor suppressive effect. Hence, it showed the validity of K-ras point mutation as a molecular target and the use of antisense K-ras RNA as a possible targeting tool for the same with the data from the studies showing the dependency of the pancreatic cancer cells on the K-ras protein for the growth mechanisms. However, the role of the K-ras protein may be mainly in the initiation of the cancer and not on the progression of the disease as was shown by the absence of significant difference in the number of mutations in the K-ras gene in the different stages of the disease.

They performed the targeting of the K-ras mutation in the intraperitoneal tumor nodules in the nude mice peritoneal dissemination model, as peritoneal dissemination was one of the major metastatic modes of pancreatic cancer. However, the lipofection or polyfection of the nodules with synthetic non-viral vectors using cationic lipids had low transduction efficiency. Hence, the use of viral vectors with tissue or cell specific promoters can prove to be a better method. However, the expression profiling data related to pancreatic cancer is insufficient and requires the accumulation of the data for the identification of unique tissue or cell specific promoters.

The use of immune system is another procedure for the targeting of the pancreatic cancer cell lines. The role of Interferon-α protein in the growth inhibition of cells and the presence of its antitumor activity in pancreatic cancer may help in the targeting of the immune system, although there is not much significance in the results observed. Hence, the cytokine gene therapy involving the introduction of cytokines directly to the tumor cells using vectors can be potent in the therapeutics for pancreatic cancer.

Thus, it is observed that the approach for the therapeutics for pancreatic cancer should be multidisciplinary for the development of probable protocols that may be utilised for the clinical trials associated with the disease. The significant progress observed in the studies of gene therapy, cytokine gene therapy combined with stem cell biology, vectorology, immunology, etc may help in the development of effective therapeutics for pancreatic cancer in future.