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Effects of Mannitol or Furosemide Diuresis on Cis-Dichlorodiammineplatinum(II) Antitumor Activity and Toxicity to Host-renewing Cell Populations in Rats¹

Department of Pharmacology, The George Washington University Medical Center, Washington, D.C. 20037 [M. F. P., H. C. H.], and Department of Pharmacology, Oral Roberts University, Tulsa, Oklahoma 74171 [H. C. H.]

Administration of mannitol (300 mg in 3.0 ml 0.45% NaCl solution as a 30-min i.v. infusion) but not furosemide (12.5 mg/kg i.p. with 6.0 ml 0.9% NaCl solution significantly reduced acute (14-day) lethality in normal male F344 rats given cis-dichlorodiammineplatinum(II) (CDDP) (8.5 mg/kg i.v.). Because both diuretics protected rats (from CDDP impairment of renal function and because a 30-min i.v. infusion of 3.0 ml 0.45% NaCl solution with CDDP (8.5 mg/kg) resulted in lower blood urea nitrogen levels but did not reduce mortality in F344 rats, it was concluded that prevention of acute lethality with mannitol was not directly related to protection of renal function. Other tissues, particularly gastrointestinal mucosa and bone marrow, were therefore studied. F344 rats given CDDP (6.0 mg/kg i.v., a sublethal dose) and rats given CDDP (8.5 mg/kg i.v.) with mannitol exhibited faster recovery of [methyl-³H]thymidine incorporation into intestinal DNA when compared to rats given CDDP (8.5 mg/kg i.v.) alone or with furosemide. Femoral nucleated cell numbers and spleen, thymus, and body weights recovered more rapidly in F344 rats given CDDP (6.0 mg/kg i.v.) with mannitol compared to animals given the same dose of CDDP alone or with furosemide.

The percentage of increase in life span of male Sprague-Dawley rats inoculated with 2.5 x 10⁶ Shay leukemia cells i.v. and treated 3 days later with CDDP (7.0 mg/kg i.v.) was unchanged by the administration of mannitol or furosemide with CDDP. When manitol was administered with CDDP (9.5 mg/kg i.v.), a dose of the platinum drug that causes substantial mortality in Sprague-Dawley rats when given alone, tumor-bearing animals given the high dose with mannitol survived longer than those given CDDP (7.0 or 9.5 mg/kg i.v.) alone. In the systems described, it appears that mannitol selectively spared rapidly proliferating host tissues as well as the kidney from CDDP toxicity and thereby improved the therapeutic index of this drug.

¹ Supported by Grant Cl-107 from the American Cancer Society and by Grant CA-02978 from the National Cancer Institute, Department of Health, Education, and Welfare. A portion of this work has been reported previously in abstract form (9).

² From a dissertation to be presented to the Graduate School of Arts and Sciences, The George Washington University in partial fulfillment of the requirements for the Ph.D. degree.

³ To whom all correspondence should be addressed, at Oral Roberts University.

Received 7/24/78. Accepted 1/ 3/79.