GEM 231, a second-generation antisense agent complementary to protein kinase A RIα subunit, potentiates antitumor activity of irinotecan in human colon, pancreas, prostate and lung cancer xenografts

Abstract

GEM 231, a second-generation antisense oligonucleotide targeted against the RIalpha subunit of protein kinase A (PKA) was co-administered with the chemotherapeutic agent irinotecan, a topoisomerase-I inhibitor, to study the antitumor efficacy of the combination in nude mice bearing various human tumor xenografts. The combination treatment of GEM 231 and irinotecan produced enhanced and prolonged tumor-growth inhibition, compared with irinotecan monotherapy, against human colon (HCT-116), pancreas (Panc-1), prostate (PC3) and lung (SKMES) tumors in mice. The extent of tumor-growth inhibition, however, varied among the different tumor models studied. The tumor-growth inhibition depended on the dose of GEM 231 co-administered with irinotecan. The combination of GEM 231 (20 mg/kg, i.p., 5 days on 2 days off x 7) and irinotecan (50 mg/kg, i.v., qwk x 3) produced significantly longer tumor-growth delay than did irinotecan administered alone. Importantly, the co-administration of irinotecan and GEM 231 did not result in higher toxicity compared with monotherapies in the several tumor models tested. These results suggest that the use of irinotecan in combination with GEM 231 may increase the therapeutic index of irinotecan in cancer patients.