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DB67 (7-tert-butyldimethylsilyl-10-hydroxycamptothecin; NSC 708298) is a camptothecin analog that has high intrinsic potency against topoisomerase I and impressive anticancer activity both in vitro and in vivo. In preparation for clinical trials, the toxicity of DB67 was investigated in groups of male and female beagle dogs (2/sex/group) and Fischer rats (10/sex/group) given single iv bolus doses of DB67 or vehicle once daily for 5 consecutive days for 2 cycles (Days 1-5 and Days 8-12). DB67 was formulated as a solution in cremophor EL:ethanol:saline (12.5:12.5:75). No mortality was observed for dogs given doses of 0.25 or 0.375 mg/kg/day (5 or 7.5 mg/m2/day) (total dose/cycle: 1.25 or 1.88 mg/kg; 25 or 37.6 mg/m2). Drug-related clinical signs of gastrointestinal toxicity included decreased food consumption and body weight loss. Drug-related clinical pathological changes observed during the dose period included neutropenia, lymphopenia, and anemia. Mean blood concentrations of DB67 at 2 minutes after dosing were similar on Days 8 and 12 and were 370 ng/mL (773 nM) and 406 ng/mL (848 nM) for dogs in the 0.25 mg/kg/day dose group, and 478 ng/mL (998 nM) and 510 ng/mL (1066 nM) for dogs in the 0.375 mg/kg/day dose group. Possible drug-related histopathological changes observed on Day 13, but not on Day 40, were limited to decreased lymphocytes in the thymus for dogs given 0.25 or 0.375 mg/kg/day. For rats given 0.5, 1, or 3 mg/kg/day (3, 6, or 18 mg/m2/day) (total dose/cycle: 5, 10, or 30 mg/kg; 30, 60, or 180 mg/m2), a no effect dose level was not observed. Mortality occurred for 2/10 rats in the vehicle control group and 1/10 rats in the 1 mg/kg/day dose group. Dose-related hematopoietic toxicity (including decreased RBC, HGB, HCT, reticulocytes, platelets, WBC, neutrophils, and/or lymphocytes) and potential drug-related decreases in BUN, creatinine, ALP, ALT, total protein, and albumin were observed. Dose-related histopathological lesions that were observed for rats necropsied on Days 10-13, but not for rats necropsied on Day 42, included lesions in the bone marrow (atrophy of blood-forming elements) and thymus (lymphocyte depletion) of animals in the 0.5, 1, and 3 mg/kg/day dose groups. Vehicle-induced lesions were also observed on Day 11 or 13 in the brain (focal malacia), spleen (cytoplasmic vacuolization of macrophages), and kidneys (eosinophilic cytoplasmic crystals in the proximal tubules); these lesions were either absent (kidney) or present in an attenuated form on Day 42. No sex-related differences in toxicity were observed for dogs or rats given DB67. The toxicity of DB67 appeared to be reversible in both dogs and rats. (Supported by NCI Contract N01-CM-42201).

[Proc Amer Assoc Cancer Res, Volume 47, 2006]