Colorectal cancer is the second most common cause of mortality due to cancer among men and women [1]. Epidemiological studies strongly suggest a protective effect of calcitriol (1,25-dihydroxyvitamin D3) against this type of cancer. Moreover, the experimental research reveals its anticancer properties but only in hyper-physiological doses, which can lead to hypercalcemia. For this reason the synthesis of vitamin D analogs has been started in order to obtain compounds with better therapeutic activity. On the basis of previous studies we selected two analogs coded: PRI-2191 (tacalcitol, 1,24-dihydroxyvitamin D₃) and PRI-2205 (5,6-trans-isomer of calcipotriol), which reveal higher antitumor and lower calcemic activity as well as lower toxicity than calcitriol [2, 3].

One of the anticancer research directions is the development of novel combined treatment strategies. The benefit from such an approach is a possibility of enhancing the therapeutic effect of a drug, which is the basis of a standard therapy [4]. In the current work, it is presented the influence of vitamin D analogs on antitumor activity of irinotecan in mice bearing transplantable murine colon cancer MC38. The antitumor effect of combined treatment was evaluated as tumor growth inhibition and increase in life span of treated mice over control. The monitored parameters were body weight and tumor volume, which was calculated using the formula (a² x b)/2, where a = shorter tumor diameter in mm and b = longer tumor diameter in mm.

It was observed that both vitamin D analogs improve antitumor activity of irinotecan in murine MC38 colon cancer model. Tumor growth  inhibition by irinotecan and PRI-2191 or PRI-2205 was observed starting from the eight day of the experiment till the last day (in comparison to the group treated with cytostatic alone). At the first stage of experiment the additive effect was observed which than changed to synergy. Moreover, the combined application of irinotecan and PRI-2191 caused the increase of life span of mice in 47% in relation to control group, whereas cytostatic applied alone only in 5%. In case of combined treatment with PRI-2205 - 11% increase of life span was observed. Both analogs in combination with irinotecan indicated synergistic interactions in the increase of life span of mice [5].

Obtained data suggest that vitamin D analogs combined with irinotecan could be promising agents supporting the standard treatment against colon cancer.

This work was supported by Ministry of Science and Higher Education Grants: No. N N401 014535, „Supporting anticancer therapy of colon cancer by using new vitamin D analogs”, period of 2008–2011.

References:

1. Winawer S. et al. World Gastroenterology Organisation. 2007; 2. Wietrzyk J. et al; Steroids 69/10: 629-635, 2004; 3. Wietrzyk J. et al; Anticancer Drugs, 18(4):447-57, 2007; 4. Wietrzyk J., Milczarek M., Kutner A., Chodyński M.: Combined therapy of colorectal carcinoma. Inter. Pat. Appl. PCT/PL2010/000044, 2010; 5. Wietrzyk J., Milczarek M., Kutner A., Chodyński M.: Combined therapy of colorectal carcinoma with the use of vitamin D analogs and oxaliplatin and irinotecan. Pat. Appl. P-397661, 2011;

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