Preclinical toxicity studies of kahalalide F, a new anticancer agent: single and multiple dosing regimens in the rat.
OBJECTIVE
Kahalalide F (KF) is a new anticancer agent currently in clinical trials for solid tumors, including prostate cancer. During the preclinical development of this drug, the studies reported here were conducted to determine the acute and multiple dose toxicities of KF when administered intravenously (i.v.) to rats. This dosing route is the intended route of clinical administration.


METHODS
KF was administered i.v. to male and female CD rats using single- and multiple-dose (daily for 5 days) schedules. Animals were observed for clinical signs, and body weight, hematology, and clinical chemistry parameters determined. Animals were necropsied, gross observations and organ weights recorded, and numerous tissues were collected and examined microscopically.


RESULTS
KF produced lethality at 375 and 450 microg/kg in males and females, respectively, and the maximum tolerated dose (MTD) was estimated to be 300 microg/kg (1800 microg/m(2)). The nervous system appeared to be a potential site of action for the production of lethality. Single-dose administration of KF at 150 and 300 microg/kg produced organ toxicity in which the kidney was the primary target. Injury to distal convoluted tubules was the most toxicologically significant lesion, and was observed on day 4. However, by day 29, resolution of renal toxicity had occurred in the 150-microg/kg group, but only partial resolution was seen at 300 microg/kg. Renal injury correlated with increased serum creatinine, BUN, and kidney weights at 300 microg/kg, indicating impairment of renal function. Subacute, necrotizing inflammation of bone marrow and peritrabecular osteocyte hyperplasia of bone were seen at 300 microg/kg on day 4, with recovery thereafter. Injury to blood vessels and surrounding tissue at the injection site were produced by KF, likely due to local cytotoxicity. In general, reversibility of toxicity was seen at 150 microg/kg but not at 300 microg/kg. When KF was administered once daily for five consecutive days at a dose of 80 microg/kg per day (400 microg/kg total dose), slightly decreased body weight gain was the primary drug-related effect. Therefore, the no-adverse-effect dose was at or near 80 microg/kg per day (480 microg/m(2) per day).


CONCLUSIONS
These findings demonstrate that fractionation of a lethal or MTD dose of KF by daily administration for 5 days reduces drug-induced toxicity, and appears to be a viable option for the clinical evaluation of KF for the treatment of cancer.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D047630:Depsipeptides; D005260:Female; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D009929:Organ Size; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000737:chemistry; D051381:Rats
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010455:Peptides; C097897:kahalalide F