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Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase
A S Morgan1, P E Sanderson, R F Borch
1Terrapin Technologies, Inc., South San Francisco, California 94080, USA.
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.
Insights
TER286, a novel drug, shows potent anti-cancer activity by activating into a nitrogen mustard alkylating agent. Its efficacy is linked to glutathione S-transferase P1-1 (GSTP1-1) levels, demonstrating promise as a clinical candidate.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- TER286 is a prodrug requiring activation by specific glutathione S-transferase (GST) enzymes.
- Cancer cell lines can develop resistance to conventional chemotherapies like doxorubicin and cyclophosphamide.
Purpose of the Study:
- To evaluate the anti-cancer efficacy of TER286.
- To investigate the correlation between GST P1-1 expression and TER286 sensitivity.
- To assess TER286's activity in various preclinical cancer models.
Main Methods:
- TER286 activation by human GST P1-1 and A1-1 to form an alkylating agent.
- Testing TER286 sensitivity in drug-resistant human colon (M7609) and breast (MCF-7) carcinoma cell lines.
- Evaluating TER286 cytotoxicity in primary human tumor clonogenic assays.
- Assessing TER286 efficacy in murine xenograft models with varying GST P1-1 expression.
- Administering TER286 to MX-1 human breast carcinoma xenografts.
Main Results:
- TER286 demonstrated increased sensitivity in M7609 and MCF-7 cells with higher GST P1-1 expression.
- TER286 exhibited a broad and distinct spectrum of cytotoxic activity in tumor clonogenic assays.
- Responses in M7609 xenografts correlated positively with GST P1-1 levels.
- Significant tumor growth inhibition and regression were observed in MX-1 xenografts.
- An aggressive dosing schedule showed manageable bone marrow toxicity.
Conclusions:
- TER286's efficacy is dependent on GST P1-1 expression.
- TER286 exhibits broad anti-tumor activity and a favorable toxicity profile.
- These findings support TER286's advancement as a clinical candidate for cancer treatment.