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Correlation between Drug Uptake and Selective Toxicity of Porfiromycin to Hypoxic EMT6 Cells¹

Departments of Pharmacology [S. R. K., A. C. S.] and Therapeutic Radiology [S. R.], Developmental Therapeutics Program, Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06510

Mitomycin C and its methylated analogue porfiromycin (Por) have significant potential as adjuncts to regimens presently used for treating solid tumors because of their preferential toxicity to cells existing in an hypoxic environment. An understanding of the factors producing the differential activity of these drugs under aerobic and hypoxic conditions would facilitate the development of new agents of this class. Previous studies have focused on the enzymes that reductively activate the mitomycins and on the interaction of these drugs with DNA; none of these studies has fully explained the differences in cytotoxicity observed under hypoxic and aerobic conditions. The present investigation demonstrates that the rate of Por uptake is directly correlated with cytotoxicity under both aerobic and hypoxic conditions. Uptake of Por into hypoxic cells is more rapid than into aerobic cells at equal drug concentrations. Hypoxic cells also accumulate drug in concentrations well in excess of those in the extracellular medium; this is apparently a reflection of drug sequestration in these cells. This sequestration of Por, which affects the rate and extent of uptake in hypoxic cells, does not take place in aerobic cells. The failure of aerobic cells to sequester drug is evidenced by the very rapid efflux of Por from these cells upon removal of extracellular Por and by the fact that aerobic cells attain a state of equilibrium between the intracellular and extracellular drug concentrations. The findings demonstrate that differences in the uptake and retention of Por are associated with the preferential toxicity of Por to hypoxic cells.

¹ This research was supported in part by Grants CH-211 and PDT-145 from the American Cancer Society and USPHS CA-43659 from the National Cancer Institute. A preliminary report of these data was presented at the 1985 ASPET meeting (15).

² Recipient of an Argall L. and Anna G. Hull Cancer Research Award. To whom requests for reprints should be addressed.

Received 11/10/86. Revised 7/27/87. Accepted 8/ 7/87.