Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice

The present treatment of colon cancer is based on 5-fluorouracil (5-FU). De spite promising results of combining leucovorin or levamisole with 5-FU, th e 5-year survival rate of patients with advanced colon cancer has not incre ased significantly. Colon tumors in vitro have been shown previously to hav e an elevated requirement for methionine, suggesting a new therapeutic targ et, In this study, targeting the methionine dependence of colon tumors is e ffected by recombinant methioninase (rMETase), alone and in combination wit h cisplatin (CDDP), In vitro results demonstrated that CDDP and rMETase act synergistically on the human colon cancer cell line SW 620, with a combina tion index (CI) of 0.45, as well as on the human colon cancer cell line Col o 205 with a CI of 0.7. Human colon cancer lines HCT 15, HT 29, Colo 205, a nd SW 620 growing in nude mice were treated with rMETase to determine an ef fective dose for depletion of tumor methionine, rMETase at 15 units/g/day f or 5 days depleted tumor methionine in all four tumor types to similar to-3 0% of untreated control. rMETase alone arrested growth of HCT 15 and HT29 i n nude mice for 1 week after treatment termination. Colo 205 and SW 620 wer e partially arrested by rMETase. However, CDDP in combination with rMETase resulted in tumor regression of Colo 205 and growth arrest of SW 620 in nud e mice. The ratio of the treated:control group (T:C) tumor weights for Colo 205 was 8% when CDDP was given on day-5, followed by treatment on days 5-9 with rMETase, This treatment schedule resulted in two of the six animals h aving no detectable tumor when the experiment was terminated on day 16, SW6 20 was resistant to CDDP alone and only partially sensitive to rMETase alon e. However, when SW 620 was treated with rMETase from days-5 to -9 and CDDP on day-5, tumor growth was arrested. The results demonstrate that rMETase used simultaneously in combination with CDDP had significant antitumor effi cacy in colon cancer in vitro and in vivo, The data suggest a novel and pro mising therapeutic approach by targeting the elevated methionine dependence of colon cancer.