title: Tumor efficacy and bone marrow-sparing properties of TER286, a cytotoxin activated by glutathione S-transferase.
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.
authors.affiliation: Terrapin Technologies, Inc., South San Francisco, California 94080, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Morgan
authors.forename: P E
authors.initials: PE
authors.lastname: Sanderson
authors.forename: R F
authors.initials: RF
authors.lastname: Borch
authors.forename: K D
authors.initials: KD
authors.lastname: Tew
authors.forename: Y
authors.initials: Y
authors.lastname: Niitsu
authors.forename: T
authors.initials: T
authors.lastname: Takayama
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: E
authors.initials: E
authors.lastname: Izbicka
authors.forename: G
authors.initials: G
authors.lastname: Mangold
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.forename: U
authors.initials: U
authors.lastname: Broberg
authors.forename: B
authors.initials: B
authors.lastname: Mannervik
authors.forename: W D
authors.initials: WD
authors.lastname: Henner
authors.forename: L M
authors.initials: LM
authors.lastname: Kauvar
mesh_terms: 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
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003603:Cytotoxins; D011355:Prodrugs; C107479:TER 286; D005982:Glutathione Transferase; D005978:Glutathione