Cancer Res 1998 Jun 15;58(12):2568-75
Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase.
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
Terrapin Technologies, Inc., South San Francisco, California 94080, USA.
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. |
