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.