Background

Recent ideas related to the anticancer treatment are mostly focused on the connection of different signaling pathway modulators in the cell. Imatinib (STI571, Glivec),a cell cycle inhibitor is one of them. Its anticancer activity relays mainly on the specifical inhibition of a number of tyrosine kinases. Imatinib can suppress the phosphorylation and decrease the activity of c-kit tyrosine kinase and also restrains cell proliferation and tumor growth in human NSCLC model A549 acting through the inhibition of PDGFR-α phosphorylation and decreasing the VEGFR expression. The hormonally active form of vitamin D, calcitriol, is known to reveal a therapeutic effect against many type of cancers, including lung cancer, mainly by regulation of many signaling pathways in the cell. Calcitriol influences the activity of protein kinase C, ras, MAPK, prostaglandins, cyclic AMP and many others, what can lead in consequence to cell proliferation inhibition, differentiation or apoptosis. Low-calcemic vitamin D3 analogs; PRI-2191 and PRI-2205 were previously tested for their antiproliferative activity against different cancer cell lines. In our latest studies, the influence of vitamin D analogs PRI-2191 and PRI-2205 on the activity of imatinib mesylate against NSCLC has been evaluated.

Materials and methods

Cell line: The human lung cancer A549 cell line was purchased from American Type Culture Collection (ATCC, USA).

Compounds: The vitamin D analogs: PRI-2191 (tacalcitol) and PRI-2205 (5,6-trans- calcipotriol), and imanitib mesylate are certified synthetic materials provided by the Pharmaceutical Research Institute, Warsaw, Poland.

In vivo studies

Two in vivo experiments were performed. NOD/SCID female mice were subcutaneously (s.c.) inoculated in the right flank of the abdomen with 5x106 viable A549 tumor cells per mouse in 0.2 ml of Hanks buffer (day 0) and then randomly divided into groups receiving different treatment agents used alone or in combination. In both experiments the treatment was started from day 7 after tumor cells inoculation (when tumors were palpable). Imatinib was administered intraperitoneally (i.p.) in the dose of 50 or 75 mg/kg/day. In the first experiment the vitamin D analogs PRI-2191 and PRI-2205 were administered subcutaneously (s.c.) in the doses 1 or 10 mg/kg/day respectively, 3 times a week. The second experiment was performed to evaluate the correlation of the administration route and the activity of compound PRI-2191 used alone or combined with imatinib. Analog PRI-2191 was administered in the dose of 2 mg/kg/day subcutaneously or orally, 3 times a week.

Evaluation of the therapeutic effect. Tumor volume was calculated using the formula (a2 x b)/2, where a = shorter tumor diameter in mm and b = longer tumor diameter in mm. Inhibition of tumor growth is calculated from the following formula: TGI [%] (tumor growth inhibition) = (WT/WC) x 100 – 100%, where WT is the median tumor weight of treated mice and WC – that of untreated control animals. The minimal expected inhibition used to estimate the effect of combination of two compounds is calculated using the formula: %H=100-[(100-TGI for cytostatic) x (100-TGI for vitamin D analog) /100]. Statistical analysis using the Kruskal-Wallis was performed. Animal weight and tumor volume were measured three times weekly.

Results: In the first experiment mice receiving imatinib (GV) in combination with vitamin D analogs had lower tumor volume than animals from the control group or from the group treated with imatinib alone. Tumor growth inhibition (TGI) at 26th day of the experiment was 30% for GV administered alone, 69 and 55% for GV administered in combination with PRI-2191 and PRI-2205 respectively. This difference for analog PRI-2191, as compared to GV alone, was statistically significant. Moreover, in almost all days of experiment, the tumor volume of mice treated with GV combined with PRI-2191 or PRI-2205 was statistically significant as compared to control mice. The second experiment showed, that the antitumor effect of PRI-2191 used alone or in combined treatment with imatinib depends on the route of administration. In the case of oral administration, PRI-2191 used alone exhibits better effect than after s.c. injections. However, in combined treatment with GV, synergistic interaction was observed when PRI-2191 was administered subcutaneously. Comparing two days of experiment: 14 and 21, when both schedules of treatment lead to statistically significant tumor growth inhibition as compared to control or imatinib administered alone, analysis of interactions showed synergistic effect only in the case of s.c. administration. At day 14th the tumor growth inhibition index TGI for groups receiving combined treatment achieved 51 and 38% for GV+PRI-2191 s.c. and GV+PRI-2191 p.o. respectively. Imatinib administered alone in the dose and schedule used (75mg/kg/day) didn’t affect tumor growth.

Conclusions

These findings suggest that therapeutic agents that can augment the activity of imatinib without additional toxicity, like vitamin D analogs, may be of potential use in anticancer therapy - to improve the activity and overcome resistance and relapse.

Patent application no P-397662, 30.12.2011, Combined therapy in non-small cell lung cancer therapy; J. Wietrzyk, B. Filip-Psurska, A. Kutner, W. Szelejewski, M. Chodyński, 30.12.2011 This work was supported by Ministry of Science and Higher Education Grant No PBZ-MNiI-1/1/2005,"New drugs with specific therapeutic and social values" Task: "Vitamin D Analog (PRI-2191) in combination with anticancer agents. In vitro and in vivo" period of 09.11.2006-08.11.2009.

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