Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase.
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.
Morgan
A S
AS
Terrapin Technologies, Inc., South San Francisco, California 94080, USA.
Sanderson
P E
PE
Borch
R F
RF
Tew
K D
KD
Niitsu
Y
Y
Takayama
T
T
Von Hoff
D D
DD
Izbicka
E
E
Mangold
G
G
Paul
C
C
Broberg
U
U
Mannervik
B
B
Henner
W D
WD
Kauvar
L M
LM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D005982:Glutathione Transferase / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000401:mortality; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013370:Subrenal Capsule Assay; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D018906:Antineoplastic Agents, Alkylating; D003603:Cytotoxins; D011355:Prodrugs; C107479:TER 286; D005982:Glutathione Transferase; D005978:Glutathione