RT Journal Article
SR Electronic
T1 The effect of misonidazole on the cytotoxicity and DNA cross-linking activity of an activated sulfidocyclophosphamide in hypoxic mouse leukemia cells.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 175
OP 181
VO 22
IS 1
A1 L M Ramonas
A1 L C Erickson
A1 M E McManus
YR 1982
UL http://molpharm.aspetjournals.org/content/22/1/175.abstract
AB The effect of misonidazole on the cytotoxicity of 4-S-(propionic acid)-sulfidocyclophosphamide (C-2) was assessed by measuring the colony-forming ability of mouse L1210 leukemia cells. C-2 under physiological conditions spontaneously hydrolyzes to 4-hydroxycyclophosphamide. Misonidazole alone at a concentration of 2.5 mM was only slightly toxic to hypoxic L1210 cells and allowed a greater than 90% survival following a 2-hr exposure. Combined treatment of C-2 and 2.5 mM misonidazole resulted in a cell kill that was greater than the additive toxicities of C-2 and misonidazole. The synergistic toxicity of the C-2 and misonidazole (2.5 mM) combination increased with increasing C-2 concentration, and at 0.01 survival the dose-modification ratio of C-2 alone versus the combination was approximately 1.5. Similarly, when the concentration of C-2 was held constant (10 microM) and the concentration of misonidazole varied from 2.5 to 25 mM, a cell kill greater than the additive toxicities of misonidazole and C-2 alone was observed. The kinetic patterns of formation and removal of DNA interstrand cross-links following a 2-hr treatment of 10 microM C-2 or 10 microM C-2 plus 2.5 mM misonidazole were similar. However, with the exception of the 0-hr time point, cells treated with the C-2 plus misonidazole combination showed consistently greater cross-linking of DNA than did cells treated with C-2 alone. The interstrand cross-link ratio closely correlated with the cytotoxic dose-modification ratio of the combination compared with C-2 alone.