Ability of the alpha and beta anomers of chlorozotocin to kill rat 9L tumor cells in vitro.

Abstract

Chlorozotocin (CLZ), a nitrosourea synthesized in the hope that it would have little bone marrow toxicity, has been shown to be effective against animal tumors and tumor cells in culture. However, the clinical results with CLZ have been disappointing. The original report on the synthesis of CLZ indicated that alpha and beta anomers at the D-glucose moiety should be expected, particularly when CLZ is placed in aqueous solution. In this study, the alpha and beta anomers have been separated by high-performance liquid chromatography and characterized by UV spectroscopy, mass spectroscopy, and nuclear magnetic resonance. The equilibration and decomposition of the anomers in various physiological solutions were determined as a function of temperature, pH, and serum concentration. In Eagle's basal medium (pH 7.2) held at 25 degrees C, CLZ decomposed with a t1/2 of approximately 82 min; at 37 degrees C with serum, CLZ decomposed with a t1/2 of less than 10 min. In these two cases, the beta:alpha ratio reached 1 in approximately 48 min and less than 5 min, respectively. The maximum beta:alpha ratio obtained in all cases ranged from 1.25 to 1.5. After holding CLZ in tissue culture medium and compensating for its decomposition, 9L rat brain tumor cells were treated in vitro with CLZ having different ratios of the alpha and beta anomers. These experiments demonstrated that the beta anomer has little, if any, ability to kill 9L cells. Thus, this anomerization phenomenon may have been responsible for the disappointing clinical results with CLZ. Our data suggest that appropriate preparation, handling, and drug delivery procedures might be devised to minimize this problem in both experimental and clinical situations.

• Authors: K H Wong, K T Wheeler
• Journal: Cancer research (Cancer Res) Vol. 49 Issue 22 Pg. 6169-73 (Nov 15 1989) ISSN: 0008-5472 [Print] United States
• PMID: 2529961 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• chlorozotocin
• Streptozocin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms
• Cell Line
• Cell Survival (drug effects)
• Chromatography, High Pressure Liquid
• Drug Screening Assays, Antitumor
• Drug Stability
• Kinetics
• Rats
• Stereoisomerism
• Streptozocin (pharmacology)
• Tumor Cells, Cultured (drug effects)