Preclinical studies on toxicity,antitumour activity and pharmacokinetics of cisplatin and three recently developed derivatives |
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| Affiliation: | 1. Campbell Family Research Institute, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada;2. Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine;3. University of Pittsburgh School of Medicine, Pittsburgh, PA;4. VAPHS Geriatric Research, Education, and Clinical Center, Pittsburgh, PA;5. Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA;6. Columbia University and the New York State Psychiatric Institute, New York, NY;1. Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF), Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Av. Ipiranga 6681 – Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil;2. Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681 – Prédio 92A Tecnopuc, 90619-900 Porto Alegre, RS, Brazil;3. Programa de Pós-Graduação em Biologia Celular e Molecular, PUCRS, Porto Alegre, Brazil;4. Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil;5. Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil;6. Instituto de Toxicologia e Farmacologia, PUCRS, Porto Alegre, Brazil;1. Department of Infectious Disease, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan;2. Division of Reconstructive Microsurgery, Department of Plastic and Reconstructive Surgery, College of Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan;3. Department of Emergency Medicine, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan;4. Section of Epilepsy, Department of Neurology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan;5. Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, Taiwan;6. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada;7. Section of Plastic Surgery, The University of Michigan, Ann Arbor, MI, United States of America |
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| Abstract: | Preclinical studies were performed in mice, rats and dogs of cis-diamminedichloroplatinum(II) (CDDP) and its derivatives cis-l,l-di(aminomethyl) cyclohexane platinum(II) sulphate (TNO-6), cis-diammine-l,l-cyclobutanedicarboxylate platinum(II) (CBDCA) and cis-dichloro, trans-dihydroxybis-isopropylamine platinum(IV) (CHIP). In mice toxicity and antitumour activity were determined. All three derivatives were at least as toxic as CDDP for haemopoietic stem cells and were less active than CDDP against the mouse tumours leukaemia L1210 and osteosarcoma C22LR. Toxicology studies in rats revealed no renal toxicity after a single dose of TNO-6. Fractionated doses of TNO-6 and CBDCA did cause renal toxicity but less than CDDP. CHIP produced little or no kidney damage. In dogs, TNO-6 (1.5 mg/kg) produced more severe kidney damage—although this was reversible—than CDDP (2 mg/kg). Half-lives of distribution were 4.0–5.1 min for TNO-6 and 9.7 min for CDDP, while half-lives of elimination were 3.6–6.6 days and 5.9 days respectively. Plasma levels, normalized for the dose, were at least two times higher after TNO-6 than after CDDP. Twelve weeks after drug administration, plasma levels were undetectable, while tissue concentrations could still be measured. The platinum concentration in kidney cortex was higher after CDDP than after TNO-6. |
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