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Ability of the and ß Anomers of Chlorozotocin to Kill Rat 9L Tumor Cells in Vitro¹

Experimental Radiation Oncology, Department of Radiology, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103

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 and ß anomers at the D-glucose moiety should be expected, particularly when CLZ is placed in aqueous solution. In this study, the and ß 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°C, CLZ decomposed with a t of 82 min; at 37°C with serum, CLZ decomposed with a t of < 10 min. In these two cases, the ß: ratio reached 1 in 48 min and < 5 min, respectively. The maximum ß: 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 and ß anomers. These experiments demonstrated that the ß 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.

¹ Supported in part by Grant CA-44106 from the National Cancer Institute, NIH, and in part by Biomedical Research Support Grant RR-05404 awarded to the Bowman Gray School of Medicine from the NIH. The NMR, MS, and some of the pharmacology analyses were performed in the Core Facilities of the Cancer Center of Wake Forest University, supported by Grant CA-12197 from the NIH.

² To whom requests for reprints should be addressed.

Received 4/11/89. Revised 7/13/89. Accepted 8/17/89.