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Morgan AS , Sanderson PE , Borch RF , Tew KD , Niitsu Y , Takayama T , Von Hoff DD , Izbicka E , Mangold G , Paul C , Broberg U , Mannervik B , Henner WD , Kauvar LM
Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase
Cancer Research. 1998 Jun 15;58(12) :2568-2575
PMID: ISI:000074178300016   
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Abstract
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.
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Times Cited: 8 English Article ZU255 CANCER RES