Abstract
The toxicities and antitumor activity of a new anticancer platinum compound, (‐)‐(R)‐2‐amino‐methylpyrrolidine(l,l‐cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R), were examined in rats by single intravenous injection in comparison with those of cis‐diammine(1,1‐cyclobutanedicarboxylato)platinum(II) (CBDCA) and cis diamminedichloroplatinum(II) (CDDP). The lethal dose (LD) of DWA2114R (100 mg/kg) or CBDCA (80 mg/kg) caused a slight decrease in body weight <10%) and no significant change in the levels of blood urea nitrogen and urinary sugar and protein. In contrast, a sub‐LD level of CDDP (8 mg/kg) seriously decreased body weight (20%) and markedly elevated the levels of these nephrotoxicity parameters. Monitoring the numbers of peripheral blood cells for 3 weeks after the drug injection revealed that all three drugs showed severe thrombocytopenia, moderate leukopenia and slight anemia. However, CBDCA induced the most severe thrombocytopenia among these drugs. The number of platelets was reduced by 60% in rats injected with a half LD of CBDCA. A moderate reduction in platelet count (35–43%) was caused by an equitoxic dose of DWA2114R or CDDP, but abated about 3 days faster than that caused by CBDCA. Interestingly, only CDDP caused an irreversible anemia. Each drug showed a potent antitumor activity at weakly toxic doses against Walker 256 carcinosarcoma transplanted intramuscularly into rats. These results indicate that DWA2114R could be a promising new platinum anticancer agent with an improved toxicity profile.
Keywords: Antitumor platinum complex, Toxicity, Rat
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REFERENCES
- 1. ) Loeher , P. J. and Einhorn , L. H.Cisplatin . Ann. Int. Med. , 100 , 704 – 713 ( 1984. ). [DOI] [PubMed] [Google Scholar]
- 2. ) Bradner , W. T. , Rose , W. C. and Huftalen , J. B.Anti‐tumor activity of platinum analogs . In “ Cisplatin: Current Status and New Developments ”, ed. Prestayko A. W , Crooke S. T. and Carter S. K. , pp. 171 – 182 ( 1980. ). Academic Press; , New York . [Google Scholar]
- 3. ) Burchenal , J.H. , Kalaher , K. , Dew , K. and Lokys , L.Rationale for development of platinum analogs . Cancer Treat. Rep. , 63 , 1493 – 1498 ( 1979. ). [PubMed] [Google Scholar]
- 4. ) Connors , T. A. , Clears , M. J. and Harrap , K. R.Structure‐activity relationships of the antitumor platinum coordination complexes . Cancer Treat. Rep. , 63 , 1499 – 1502 ( 1979. ). [PubMed] [Google Scholar]
- 5. ) Harrap , K. R. , Jones , M. , Wilkinson , C. R. , Clink , H. , McD. Sparrow , S. , Mitchley , B. C. V. , Clake , S. and Veasey , A.Antitumor, toxic and biochemical properties of cisplatin and eight other platinum complexes . In “ Cisplatin: Current Status and New Developments ”, ed. Prestayko A. W. , Crooke S. T. and Carter S. K. , pp. 193 – 212 ( 1980. ). Academic Press; , New York . [Google Scholar]
- 6. ) Foster , B. J. , Harding , B. J. , Wolpert‐DeFilippes , M. K. , Rubinstein , L. Y. , Clagett‐Carr , K. and Leyland‐Jones , B. Astrategy for the development of two clinically active cisplatin analogs: CBDCA and CHIP . Cancer Chemother. Pharmacol , 25 , 395 – 404 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 7. ) Morikawa , K. , Honda , M. , Endo , K. , Matsumoto , T. , Akamatsu , K. , Mitsui , H. and Koizumi , M.Synthesis of platinum complexes of 2‐aminomethylpyrrolidine derivatives for use as carrier ligands and their antitumor activities . Chem. Pharm. Bull , 38 , 930 – 935 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Endo , K. , Akamatsu , K. , Matsumoto , Morikawa , K. , Honda , M. , Mitsui , H. , Koizumi , M. , Koizumi , K. and Matsuno , T.Antitumor activity of a new platinum complex, 2‐aminomethylpy rrolidine(1,1 ‐cyclobutanedicar‐boxylato) platinum (II) . Anticancer Res. , 9 , 987 – 992 ( 1989. ). [PubMed] [Google Scholar]
- 9. ) Koizumi , M. , Honda , M. , Morikawa , K. , Endo , K. , Matsumoto , T. , Akamatsu , K. and Mitsui , H.Antitumor activity of a new platinum cytostatic DWA2114R . In “ Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy ”, ed. Nicolini M. , pp. 695 – 699 ( 1987. ). Martinus Nijhoff Publishing; , Italy . [Google Scholar]
- 10. ) Comis , R. L.Cisplatin nephrotoxicity: the effect of dose, schedule and hydration scheme . In“Cisplatin: Current Status and New Developments ”, ed. Prestayko A. W. , Crooke S. T. and Carter S. K. , pp. 485 – 495 ( 1980. ). Academic Press; , New York . [Google Scholar]
- 11. ) Nitschke , R.Renal complications of cj's‐diamminedi‐chloroplatinum . Ann. Clin. Lab. Sci , 11 , 392 – 396 ( 1981. ). [PubMed] [Google Scholar]
- 12. ) Majima , H. and Kinoshita , H.Clinical pharmacokinetics of (R)‐( ‐)‐l, l‐cyclobutanedicarboxylato(2‐aminome‐thylpyrrolidine)platinum(II) (DWA2114R) . In “ Platinum and Other Metal Coordination Compounds in Cancer Chemotherapy ”, ed. Nicolini M. , pp. 491 – 498 ( 1987. ). Martinus Nijhoff Publishing; , Italy . [Google Scholar]
- 13. ) Calvert , A. H. , Harland , S. J. , Newell , D. R. , Siddik , H. , Jones , A. C. , McElwain , T. J. , Raju , S. , Wiltshaw , E. , Smith , I. E. , Baker , J. M. , Peckham , M. J. and Harrap , K. R.Early clinical studies with cis‐diammine‐l.l‐cyclo‐butane dicarboxylate platinum II . Cancer Chemother. Pharmaeol , 9 , 140 – 147 ( 1982. ). [DOI] [PubMed] [Google Scholar]
- 14. ) VonHoff , D. D. , Schilsky , R. , Reichert , C. M. , Reddick , R. L. , Rozencweig , M. , Young , R. C. and Muggia , F. M.Toxic effects of cw‐dichlorodiammineplatinum(II) in man . Cancer Treat. Rep. , 63 , 1527 – 1531 ( 1979. ). [PubMed] [Google Scholar]
- 15. ) Rossof , A. H. , Slayton , R. E. and Perlia , C. P.Preliminary clinical experience with c/s‐diamminedichloropla‐tinum(II) . Cancer , 30 , 1451 – 1456 ( 1972. ). [DOI] [PubMed] [Google Scholar]
- 16. ) Matsumoto , T. , Endoh , K. , Kamisango , K. , Akamatsu , K. , Koizumi , K. , Higuchi , M. , Imai , N. , Mitsui , H. and Kawaguchi , T.Effect of recombinant human erythro‐poietin on anticancer drug‐induced anemia . Br. J. Haematol , 75 , 463 – 468 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Akamatsu , K. , Mitsui , H. , Matsumoto , T. , Endo , K. , Morikawa , K. , Koizumi , M. , Tsuji , K. and Matsuno , T.Antitumor activity and toxic properties of a new platinum cytostatic, DWA2114R . Proc. 15th Int. Congr. Chemother. , 768 – 770 ( 1987. ). [Google Scholar]