Biochemical studies on the anticancer effects of natural retinoids in human pancreatic cancer

Abstract

Despite major strides in our understanding of the factors involved in the development of pancreatic cancer, the clinician is restricted to a severely limited therapeutic armory for this disease. Local therapies, such as surgery and radiation are inevitably of limited value because pancreatic cancer is usually encountered at a stage when local invasion or metastases have already developed. Systemic chemotherapy is also ineffective in significantly extending survival in pancreatic cancer patients. Over the past 30 years cancer treatment research has focused mainly on the development of cytotoxic agents. However, despite significant progress in chemotherapy for cancers such as testicular carcinoma and lymphomas, the prognosis of the most invasive and metastatic tumors such as pancreatic cancer has remained extremely poor. Differentiating agents such as retinoids inhibit the proliferative capacity of cancer cells and

induce morphological and biochemical maturation. They may suppress or reverse evolving lesions and prevent cancer invasion and offer an attractive potential alternative to conventional cytotoxic drugs. A major advantage of retinoids is their potential to inhibit primary and secondary cancers with p53 mutation that are resistant to chemotherapy and radiotherapy, while having minimal effects on normal cells. Although resistance to retinoids may develops following prolonged treatment, agents which block retinoid metabolism could result in maintenance of higher retinoic acid concentrations within tumor cells, thus overcoming such resistance. Reported examining effects of retinoids on growth and differentiation on pancreatic cancer and other solid tumors cell lines are highly conflicting, despite frequently using the same cell lines. Moreover, the two reported clinical trials on retinoids in pancreatic cancer patients were not encouraging, although the retinoids were well tolerated. I hypothesized that retinoids under properly controlled conditions c uld regulate pancreatic cancer cells growth and that this activity would correlate with the redifferentisting effect of retinoids on these cells. Initially, individual interfering factors in the in vitro treatment conditions were investigated.