Interaction of D,L- and D-tetraplatin with hyperthermia in vitro and in vivo.

Abstract

The cytotoxicities of D,L-tetraplatin and D-tetraplatin were evaluated at 37 degrees C, 42 degrees C and 43 degrees C at normal pH, at pH 6.45 and under normally oxygenated and hypoxic conditions in EMT-6 cells in vitro. The D-isomer was also tested in FSaIIC cells in vitro. Under these various conditions the pure D-isomer was very similar in cytotoxicity with the racemic mixture. Like cisplatin, both D,L- and D-tetraplatin were selectively cytotoxic toward normally oxygenated cells under acidic pH (6.45) conditions at 37 degrees C. In both cell lines the cytotoxicity of D,L- and D-tetraplatin was markedly increased at hyperthermic temperatures. Under the same conditions platinum levels in EMT-6 cells exposed to D,L- or D-tetraplatin were higher than in cells exposed to cisplatin, and unlike cisplatin there was an increase in intracellular platinum levels when the cells were exposed to D,L- or D-tetraplatin at 42 degrees C compared with 37 degrees C. The tumour growth delay of the FSaIIC fibrosarcoma was the same for D,L- and D-tetraplatin. A dose of 10 mg/kg intraperitoneally of tetraplatin produced a tumour growth delay of about 4.3 days which was increased to about 6 days with the addition of local hyperthermia (43 degrees C, 30 min) to the drug treatment. The tumour cell survival assay also showed no difference between D,L- and D-tetraplatin and a log-linear increase in tumour cell killing with increasing drug dose which was increased 1.5-3-fold with local hyperthermia. D,L- and D-tetraplatin were relatively much more cytotoxic toward bone marrow colony forming units of granulocyte-macrophage progenitors (CFU-GM) than was cisplatin and this cytotoxicity was increased about 5-10-fold under hyperthermic conditions. There was an increase in DNA crosslink formation in tumours when hyperthermia accompanied tetraplatin treatment. Overall, D,L- and D-tetraplatin produced very similar responses under hyperthermic conditions in both tumour and normal tissues, and may be a useful agent in combination with local hyperthermia.

• Authors: R Epelbaum, B A Teicher, S A Holden, G Ara, A Varshney, T S Herman
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 28A Issue 4-5 Pg. 794-800 ( 1992) ISSN: 0959-8049 [Print] England
• PMID: 1524897 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• DNA, Neoplasm
• Organoplatinum Compounds
• Cisplatin
• Oxygen
• ormaplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Bone Marrow (drug effects)
• Bone Marrow Cells
• Cell Hypoxia (physiology)
• Cell Survival (drug effects)
• Cisplatin (pharmacology)
• Combined Modality Therapy
• DNA Damage
• DNA, Neoplasm (analysis)
• Fibrosarcoma (drug therapy, pathology, therapy)
• Granulocytes (drug effects)
• Hematopoietic Stem Cells (drug effects)
• Hydrogen-Ion Concentration
• Hyperthermia, Induced
• Macrophages (drug effects)
• Male
• Mammary Neoplasms, Experimental (drug therapy, pathology, therapy)
• Mice
• Mice, Inbred C3H
• Neoplasm Transplantation
• Organoplatinum Compounds (pharmacology, toxicity)
• Oxygen (metabolism)
• Tumor Cells, Cultured