Efficacy of MGI 114 (HMAF) against the MRP+ metastatic MV522 lung carcinoma xenograft

This study is part of an effort to evaluate efficacy of the novel agent MGI 114 (HMAF) against tumors resistant to conventional chemotherapeutic agent s. MGI 114 is a novel semisynthetic anticancer agent currently in chemother apeutic phase II trials to evaluate activity against various solid tumors. Previous studies indicate MGI 114 was active against human MDR1/gp170(+) so lid tumor xenografts, Recent evidence suggests overexpression of the MRP pr otein may also be clinically relevant to development of drug resistance in solid tumors. We evaluated the efficacy of MGI 114 against a human MRP+ lun g carcinoma xenograft, Parent MV522 lung carcinoma cells were transfected w ith a MRP cDNA expression vector and resistant cells selected by exposure t o vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP mRNA and MRP protein. Ad ministration of MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x /week f or 3 weeks) to MRP tumor-bearing mice demonstrated this novel agent was act ive against MRP+ tumors and significantly extended their lifespan (p<0.001) . In contrast, other cytotoxic agents had minimal activity against this MRP + xenograft, These results indicate MGI 114 should retain activity in vivo against MRP+ tumor types. The development of this MRP+ xenograft model, in conjunction with the parent MV522 and MDR1/gp170(+) xenograft models, will be useful for screening new classes of agents for activity against multidru g-resistant tumors. [(C) 2000 Lippincott Williams & Wilkins.].