A toxicology study of
cis-diamminedichloroplatinum (II) (CDDP), aqua(1,1-bis-(aminomethyl)cyclohexane)sulfatoplatinum(II) (TNO-6), diammine(1,1-cyclobutanedicarboxylato)platinum(II) (
CBDCA), cis-dichloro-trans-dihydroxo-cis-bis(
isopropylamine)
platinum-(IV) (CHIP) and ethylenediaminemalonatoplatinum(II) (JM-40) was carried out in dogs. The main purpose of the study was to compare the results with those obtained earlier in mice and rats and with the toxicology data in humans. Each
platinum compound was tested in three dogs. Each dog received three intravenous bolus
injections at intervals of 3 weeks. The compounds were administered in dosages of 1.2, 1.0, 12, 10 (or 6) and 10 mg/kg, respectively. Toxic death occurred for two dogs (both on day 54) from haematotoxicity (10 mg/kg CHIP) and renal toxicity (TNO-6), respectively. Serum
urea nitrogen and
creatinine concentrations were variable after
TNO-6 and remained within normal values
after treatment with the other compounds. Severe
proteinuria was observed in all three dogs treated with
TNO-6. Values returned to normal within 16 days.
JM-40 did not cause significant
proteinuria. CDDP,
CBDCA and CHIP caused short-lasting and slight
proteinuria. CHIP caused a severe reduction in the number of leukocytes and platelets, while the other drugs caused acceptable reductions. Except after the high dose CHIP regimen, haematotoxicity was of a transient nature.
Vomiting in order of severity occurred after
TNO-6, CHIP, CDDP and
JM-40, while
CBDCA did not cause any
vomiting. The dogs were sacrificed 6 weeks after the last
drug dose. Organs were fixed for histopathology to complete and support clinical-toxicological parameters. On the basis of the results from the single-dose study in dogs and those obtained earlier in mice and rats it can be concluded that the gain from the use of the dog as a prognosticator for organ toxicity in man was disappointing and limited to the prediction of
vomiting.