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Terrapin Technologies, Inc., South San Francisco, California 94080 [A. S. M., P. E. S., L. M. K.]; Purdue University, West Lafayette, Indiana 47907 [R. F. B.]; Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [K. D. T.]; Sapporo Medical University, Chuo-ku, Sapporo 060, Japan [Y. N., T. T.]; Institute for Drug Development, San Antonio, Texas 78229 [D. D. V. H., E. I., G. M.]; Karolinska Institute, Stockholm, Sweden [C. P., U. B.]; Uppsala University, S-75123 Uppsala, Sweden [B. M.]; and Oregon Health Sciences University, Portland, Oregon 97201-3098 [W. D. H.]
TER286 is a latent drug activated by human glutathione S-transferase (GST) isoforms P1-1 and A1-1 to produce a nitrogen mustard alkylating agent. M7609 human colon carcinoma, selected for resistance to doxorubicin, and MCF-7 human breast carcinoma, selected for resistance to cyclophosphamide, both showed increased sensitivity to TER286 over their parental lines in parallel with increased expression of GST P1-1. In primary human tumor clonogenic assays, the spectrum of cytotoxic activity observed for TER286 was both broad and unusual when compared to a variety of current drugs. In murine xenografts of M7609 engineered to have high, medium, or low GST P1-1, responses to TER286 were positively correlated with the level of P1-1. Cytotoxicity was also observed in several other cell culture and xenograft models. In xenografts of the MX-1 human breast carcinoma, tumor growth inhibition or regression was observed in nearly all of the animals treated with an aggressive regimen of five daily doses. This schedule resulted in a 24-h posttreatment decline in bone marrow progenitors to 60% of control and was no worse than for a single dose of TER286. These studies have motivated election of TER286 as a clinical candidate.
1 To whom requests for reprints should be addressed, at 1489 Webster Street, No. 521, San Francisco, CA 94115-3769.
Received 1/26/98. Accepted 4/16/98.
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