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 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.

Structural organization of the human gastrointestinal glutathione peroxidase (GPX2) promoter and 3'-nontranscribed region: transcriptional response to exogenous redox agents.

The flanking upstream and downstream regions of the human GPX270%). The human GPX2 promoter region was not G-C rich (<50% G+C) and classical TATA/CCAAT elements were not present. The ubiquitous SP1 and AP elements were present. Several GATA elements as well as liver-specific sites (HNF series) were present. Despite the unique intestinal specific expression of GPX2, classical intestine-specific sites were not detected in the flanking 5' or 3' regions. The ability of the GPX2 promoter to direct transcription was confirmed. Exogenous agents capable of producing oxidative stress, such as paraquat, could induce the transcriptional activity of the GPX2 promoter. Analysis of three previously reported polymorphism sites revealed that they represented the most common polymorphisms. Surprisingly, the human GPX2 promoter could direct transcription and respond to oxidative stress in the murine NIH3T3 fibroblast cell line, which is devoid of the ability to bind to a variety of intestinal specific elements. This finding suggests that the unique intestinal specific expression of GPX2 may be due to elements in the intron, the flanking 3'-nontranslated region, or to elements existing even farther upstream. The ability of GPX2 to respond transcriptionally to redox stress is likely to be more physiologically relevant than post-transcriptional regulation which is dependent upon selenium availability.