Therapeutic and pharmacological studies of tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue.

Abstract

Tetrachloro(d,l-trans)1,2-diaminocyclohexane platinum (IV) (tetraplatin), a new platinum analogue, showed greater therapeutic efficacy after i.p. administration than either cis-dichlorodiammineplatinum (II) (cisplatin) or cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (carboplatin) in mice bearing i.p. implanted L1210 leukemia. At an optimal dose of 5.7 mg/kg/injection given as a single dose on days 1, 5, and 9, tetraplatin increased the median life span over controls by more than 566% with 5 of 8 long-term (50-day) survivors. In contrast, cisplatin at the same optimal dose increased survival by 186% with 2 of 8 long-term survivors, and carboplatin at an optimal dose of 75.6 mg/kg/injection increased survival by only 120% with no long-term survivors. Tetraplatin also was more effective than cisplatin when treatment was delayed until days 3, 7, and 11 after i.p. implant. A combination of tetraplatin and Adriamycin in mice bearing i.p. implanted L1210 leukemia produced more long-term survivors over a wider range of doses than could be achieved with either drug alone. Tetraplatin at 5.7 mg/kg/injection and Adriamycin at 3 mg/kg/injection on days 1, 5, and 9 increased survival by more than 566% with 8 of 8 50-day survivors. Using the same treatment schedule, combinations of tetraplatin with either cisplatin, carboplatin, daunomycin, or 5-fluorouracil did not produce therapeutic efficacy greater than that seen with tetraplatin alone. The in vitro cellular uptake of platinum by L1210 cells at 37 degrees C was about 4-fold higher after exposure to tetraplatin compared to cisplatin following a 2-h incubation at the two concentrations examined (2.5 and 5 micrograms/ml). Comparative pharmacological studies were performed in rats at a single dose of 3 mg/kg i.v. The t1/2 beta for total platinum in plasma was 29.10 h (7.47 h for unbound platinum) after the administration of tetraplatin and 23.70 h (13.09 h for unbound platinum) after cisplatin. By 48 h the urinary excretion of platinum after tetraplatin and cisplatin was 30.1% and 41.4%, respectively. Tissue distribution of platinum was similar after either complex. Thus, tetraplatin has similar pharmacological properties to cisplatin and like cisplatin is a candidate for combination chemotherapy. However, tetraplatin may be superior to cisplatin in some therapeutic situations based on its greater efficacy against selected tumors.

• Authors: A Rahman, J K Roh, M K Wolpert-DeFilippes, A Goldin, J M Venditti, P V Woolley
• Journal: Cancer research (Cancer Res) Vol. 48 Issue 7 Pg. 1745-52 (Apr 01 1988) ISSN: 0008-5472 [Print] United States
• PMID: 3162402 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Naphthacenes
• Organoplatinum Compounds
• ormaplatin
• Fluorouracil

Topics

• Animals
• Antibiotics, Antineoplastic
• Bile (metabolism)
• Biological Transport
• Drug Therapy, Combination
• Fluorouracil (therapeutic use)
• Leukemia L1210 (drug therapy)
• Metabolic Clearance Rate
• Mice
• Naphthacenes (therapeutic use)
• Organoplatinum Compounds (pharmacokinetics, pharmacology, therapeutic use)
• Rats
• Tissue Distribution