Activity of TER286 against human tumor colony-forming units.
Glutathione S-transferase (GST) isozymes have been shown to be elevated in many human cancer types as compared to normal tissues. TER286, one in a class of glutathione-based GST-activated cytotoxins, was tested in a soft agar cloning assay to determine its in vitro activity against primary human tumor colony-forming units. Breast and lung specimens from patients who had received prior therapy and those who were previously untreated were exposed to TER286 at concentrations of 1, 10 and 50 microM using both 1 h and continuous exposures. Overall in vitro responses (50% or less survival compared to untreated controls) were observed in 0% (0/14), 14% (2/14) and 29% (4/14), respectively, in specimens exposed to TER286 for 1 h, and in 5% (2/41), 10% (4/41) and 61% (25/41), respectively, in specimens exposed to TER286 continuously. TER286 has cytotoxic activity against both breast and lung cancer colony-forming units, and demonstrates a concentration-response effect. At 50 microM, there is a significant difference between 1 h and continuous exposures in head-to-head comparisons. These data suggest that TER286 can be activated in human tumor colony-forming units and should be pursued as a treatment candidate for patients whose tumors are resistant to drug treatment based on up-regulation of GST.
Izbicka
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E
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78245, USA.
Lawrence
R
R
Cerna
C
C
Von Hoff
D D
DD
Sanderson
P E
PE
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003603:Cytotoxins / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D003603:Cytotoxins; C107479:TER 286; D005978:Glutathione