Abstract 3529: Evaluation of PRI vitamin D analogues, alone or with enhancers, as antileukemia agents Academic Article uri icon

abstract

  • The physiological form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D) has well established anti-cancer activity, but its potential use in the clinic is limited by the danger of life-threatening hypercalcemia. Efforts to overcome this difficulty include structural modifications of 1,25D, as well as enhancement of its activity by other compounds. In this study we have combined these two approaches by comparison of the efficacy of the induction of differentiation in AML using analogs synthesized in the Warsaw Pharmaceutical Research Institute(PRI), alone or with its enhancers carnosic acid (CA), a plant antioxidant, and SB202190 (SB), an inhibitor of p38MAPK α, β. The PRI analogs have previously been shown to have low calcemic activity in animals, and while the analogs PRI-1906 (24-ene-1,25-dihydroxy vitamin D2) and PRI-2191([24R]-1,24-dihydroxyvitamin D3) had greater activity on established AML cell lines than their congeners, their relative potency on AML blasts was not entirely clear. We therefore studied an additional cohort of 20 patients with AML, and when sufficient cell numbers were available the analogs were supplemented with CA and SB to form a “differentiation cocktail” for study ex vivo. In this series we found that there was variability in the differentiation responses between individual patients, but the majority (∼90 %) of the blast samples responded to 1,25D and to both analogs. The intensity of the response was greatly increased when the “differentiation cocktail” was used rather than the analog alone, and while there was a similarity between the potencies of PRI-1906 and PRI-2191, the most robust responses in this series were seen when PRI-1906, alone or with CA and SB, was used. The strength of responses correlated with the enhancement of VDR expression in treated cells studied by Western blots. We conclude that PRI analogs 1906 and 2191 supplemented with CA and SB merit further scrutiny as candidates for chemoprevention/ differentiation therapy of AML. (Supported by USAPH NIH grant RO1 CA 44722-20 from NCI to GPS, the ISF grant 778/07 to MD, by Wroclaw Research Center EIT+ Operational Programme Innovative Economy, 1.1.2; POIG 01.01.02-02-003/08-00 to EM, and by the Foundation for Polish Science to EG). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3529. doi:10.1158/1538-7445.AM2011-3529

publication date

  • July 12, 2011