This study is part of an effort to evaluate efficacy of the novel agent
MGI 114 (HMAF) against
tumors resistant to conventional chemotherapeutic agents.
MGI 114 is a novel semisynthetic
anticancer agent currently in chemotherapeutic phase II trials to evaluate activity against various solid
tumors. Previous studies indicate
MGI 114 was active against human MDR1/gp170+ solid
tumor xenografts. Recent evidence suggests overexpression of the MRP
protein may also be clinically relevant to development of drug resistance in solid
tumors. We evaluated the efficacy of
MGI 114 against a human MRP+ lung
carcinoma xenograft. Parent MV522 lung
carcinoma cells were transfected with a MRP
cDNA expression vector and resistant cells selected by exposure to
vinblastine (30-fold resistance). Analysis of resistant clones indicated 20- to 40-fold increases in expression of both MRP
mRNA and MRP
protein. Administration of
MGI 114 at the maximum tolerated dose (7 mg/kg, 5 x/week for 3 weeks) to MRP
tumor-bearing mice demonstrated this novel agent was active 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 multidrug-resistant
tumors.