In vitro and in vivo chemotherapy screening of the divalent cation chelator 1,10-orthophenanthroline.
1,10-Orthophenanthroline (OP) is a divalent cation chelating agent with known cytotoxicity to human normal and malignant T-lymphocytes. To determine whether OP might be a useful anticancer agent with specific T cell toxicity, OP's effect on cell growth was determined on colony-forming cells. The assay used supported growth of both malignant lymphoid and normal myeloid colony-forming cells (CFU-C) and thus a direct comparison of OP's antilymphoid and antimyeloid toxicity was obtained. The malignant lymphoid cells tested were established from patients at relapse and were resistant to conventional chemotherapeutic agents in vitro. While OP was found to be toxic to all cells tested, some selective kill of malignant cells over CFU-C occurred. OP's cytotoxicity was time-dependent and a three-log enhanced kill occurred when the drug exposure time was increased from 1 to 24 h. When test cells were continously exposed to OP, the ID50 was less than 1 micrograms/ml for malignant lymphoid cells and the sensitivity index (SI = x ID50 CFU-C divided by x ID50 cell line) ranged from 1.5 to 3.0. The National Cancer Institute currently screens new compounds for antitumor activity by determining whether the test drug is toxic to a mouse lymphocytic leukemia cell line (P388). While the mouse P388 cells were sensitive to OP in vitro, no effect was seen when OP was administered in vivo, even when schedules designed to take advantage of OP's time-dependent toxicity were used. Since malignant cells were sensitive to OP (ID50 less than 1 micrograms/ml), and some selectivity over CFU-C occurred (SI greater than 1), OP may be a useful agent for control of leukemic cell growth in vitro. However, since OP did not control the growth of P388 cells in vivo, additional studies designed to enhance the therapeutic index of OP in vivo are needed.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D010618:Phenanthrolines / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects; D013997:Time Factors; D015032:Zinc / Q000378:metabolism
D010618:Phenanthrolines; C001635:ferroin; D008274:Magnesium; D015032:Zinc