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Diethyldithiocarbamate Inhibition of Murine Bone Marrow Toxicity Caused by cis-Diamminedichloroplatinum(II) or Diammine-(1,1-cyclobutanedicarboxylato)platinum(II)¹

Departments of Pharmacology [A. G., R. F. B.] and Radiation Oncology [P. C. K.] and the Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642

We report here the effects of diethyldithiocarbamate (DDTC) rescue on myelotoxicity caused by carboplatin (CBDCA) and cisplatin (DDP) in C57BL/6 x DBA/2 F₁ mice. All drugs were administered by injection into the tail vein. Myelotoxicity was assessed by WBC, bone marrow cellularity, and assays for pluripotent bone marrow stem cells (spleen colony forming unit) and granulocyte/macrophage progenitor cells (granulocyte/macrophage colony forming unit in culture). The most significant protection occurred in stem cells, where a single dose of DDTC (300 mg/kg) produced a platinum-drug dose modification factor of 3.3; i.e., the addition of DDTC reduced stem cell toxicity to the level produced by approximately one-third the dose of platinum drug alone. On a molar basis, DDP was 2.4 times as toxic to stem cells as CBDCA. The response of the stem cells to CBDCA and DDP was linear both with and without rescue, and the dose modification factor remained constant for doses of CBDCA up to 120 mg/kg and doses of DDP up to 15 mg/kg. Moreover, stem cell rescue appeared to be independent of DDTC dose (100–750 mg/kg) and time of administration (1.5 h before to 5 h after platinum drug). DDTC protection was less impressive for more mature hematological cells (granulocyte/macrophage colony forming units in culture). In studies of bone marrow cellularity, addition of DDTC (300 mg/kg) to DDP treatment (10 mg/kg) produced a 50% increase in the granulocytepredominant cell population but had no effect on the lymphocyte population. Peripheral WBC showed no significant difference between rescued and unrescued groups and did not reflect the toxicity observed directly in the bone marrow.

¹ This work was supported in part by Grants CA 34620 and CA 11198 from The National Cancer Institute.

² To whom requests for reprints should be addressed.

Received 4/29/88. Revised 7/12/88. Accepted 7/15/88.