Combined Colonic Cancer Treatment with Vitamin D Analogs and Irinotecan or Oxaliplatin

Aim: The aim of this study was the evaluation of the antitumor effect of two synthetic analogs of vitamin D, PRI-2191 and PRI-2205 in combined treatment with irinotecan or oxaliplatin on mouse (MC38) and human (HT-29) colon cancer cells. Materials and Methods: Mice bearing subcutaneous tumors were injected with vitamin D analogs and with irinotecan or oxaliplatin, according to various schedules. Results: Statistically significant inhibition of MC38 tumor growth by combined therapy was observed. When analogs were used in combined treatment with irinotecan, survival times of mice were significantly prolonged. We also observed improved antitumor effects in combined treatment with oxaliplatin in mice bearing HT-29 tumors, however, antagonism in life span prolongation was observed. Analog PRI-2191 increased the expression of vitamin D receptor (VDR), retinoic X receptor-α (RXRα) and phosphorylated extracellular signal regulated kinase 1/2 (p- ERK1/2) in HT-29 tumors when used alone. VDR and RXRα expressions were up-regulated by PRI-2191 analog, as compared to oxaliplatin alone. Conclusion: The obtained results suggest that vitamin D analogs could be used in combined colonic cancer treatment with irinotecan or oxaliplatin. However, the regulation of ERK1/2 expression by both analogs and oxaliplatin may explain the observed antagonistic interactions. Data from experimental, clinical and epidemiological studies suggest that vitamin D and calcium may reduce colorectal cancer risk via various mechanisms, including binding of bile acids and long-chain fatty acids in the small intestine and protecting colon epithelial cells from mutagens. In addition, their influence on cell proliferation, differentiation, apoptosis, angiogenesis and cell-cycle regulation is considered (1-6).