In WiDr cells, MK-1775 treatment at 30 nM or 100 nM in combination with gemcitabine remarkably enhances the antigrowth effect of gemcitabine, reducing the IC50 of gemcitabine (>100 nM) to 21.5 nM and 7.1 nM, respectively. MK-1775 (300 nM) or gemcitabine (100 nM) treatment alone induces only a minimal sub-G1 population by 2.9% and 5.2%, respectively, whereas the combination treatment drastically induces sub-G1 population in a MK-1775 dose-dependent manner by 55% at 100 nM and 59% at 300 nM. MK-1775 cotreatment dramatically sensitizes TOV21G-shp53 cells but not the TOV21G-vec cells to gemcitabine, carboplatin, or cisplatin, suggesting that MK-1775 abrogates G2 DNA damage checkpoint by Wee1 inhibition, sensitizing cells to apoptosis selectively in p53-deficient cells. Gemcitabine alone only moderately inhibits tumor growth of WiDr xenografts in rats with T/C of 35%, whereas cotreatment with MK-1775 significantly enhances the antitumor effects in a dose-dependent manner with T/C of 1% and -25% at doses of 10 mg/kg and 20 mg/kg, respectively, and reduces the dose of chemotherapy required to achieve a similar or better antitumor efficacy. MK-1775 also significantly enhances the antitumor effects of carboplatin and cisplatin in the nude rat HeLa-luc and TOV21G-shp53 xenograft models models. The cotreatment does not significantly increase toxicity, which is correlated with inhibition of CDC2Y15 phosphorylation in tumor tissue and skin hair follicles.
[1] MK-1775 in combination with Chk1 inhibitor AR458323 synergistically inhibits proliferation in multiple cancer cell types, resulting in dramatic decreases in inhibitory phosphorylation of cyclin-dependent kinases, an increase in DNA damage, alterations in cell-cycle profile, and collapse of DNA synthesis, which is correlated with a synergistic induction of apoptosis.
[2] A Phase II study of MK-1775 in combination with Paclitaxel and Carboplatin versus Paclitaxel and Carboplatin alone in adult patients with platinum sensitive p53 mutant ovarian cancer is currently ongoing.
