Potent antitumour activity of (-)-(R)-2-aminomethylpyrrolidine (1,1-cyclobutanedicarboxylato)platinum(II) monohydrate (DWA2114R) against advanced L1210 leukaemia in mice.

K Akamatsu,K Koizumi,K Morikawa,M Koizumi,K Kamisango,K Endo,T Matsumoto

doi:10.1038/bjc.1992.368

Abstract

The time dependency of the antitumour activity of (-)-(R)-2-aminomethylpyrrolidine(1,1-cyclobutanedicarboxylato++ +)platinum(II) monohydrate (DWA2114R) was examined in mice inoculated i.p. with 10(5) mouse L1210 leukaemia cells. The increase in life span was greater in mice treated with 72 mg kg-1 DWA2114R on the 6th day following tumour inoculation than in mice treated at earlier times. Such superior effects against advanced L1210 were also seen with cis-diammine (1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA) but not seen with the parent compound, cis-diamminedichloroplatinum(II) (CDDP) or other antitumour agents devoid of platinum. After the injection of DWA2114R on day 6, most of the ascites tumour cells accumulated in the S and G2/M phases of the cell cycle and the total cell number markedly decreased from 10(8) to less than 10(6). On the other hand, only a temporary G1 arrest and a less than 50% reduction of the cell number were induced after a similar treatment on day 3. Interestingly, the superiority of DWA2114R for advanced L1210 was lost in athymic nude mice and mice depleted of T cells by anti-thymocyte antisera. In addition, mice cured of advanced L1210 specifically rejected re-inoculated L1210 cells. These results indicate that the superior antitumour activity against advanced L1210 is unique to DWA2114R among the agents tested (except for CBDCA) and is caused by both an increased drug susceptibility of tumour cells and a drug-induced antitumour effect mediated by T cells of the host mice.

Highlights

DWA2114R and CBDCA were synthesised in our laboratories by the method described previously (Morikawa et al, 1990) and CDDP was purchased from Aldrich Chemical Co. 5-fluorouracil and doxorubicin were purchased from Kyowa Hakkou Co
The median survival time of the mice injected with 72 mg kg- ' DWA21 14R on day 6 was about 2-times greater than that on day 1 in both experiments
A similar enhanced activity against advanced L1210 was shown by equitoxic dose of CBDCA but not shown by CDDP (Table II)

Summary

Methods

DrugsDWA2114R and CBDCA were synthesised in our laboratories by the method described previously (Morikawa et al, 1990) and CDDP was purchased from Aldrich Chemical Co. 5-fluorouracil and doxorubicin were purchased from Kyowa Hakkou Co. (Tokyo), cyclophosphamide was from Shionogi Pharmaceutical Inc. (Osaka), etoposide was from Nihon Kayaku (Tokyo) and vincristine sulfate was from Sigma Chemical Co. Rabbit anti-mouse thymocyte, anti-asialo GMI antisera and normal rabbit IgG were purchased from Wako Pure Chemical Industries Ltd. Murine L1210 leukaemia cells were passaged in male 6-weekold DBA/2 mice once a week by intraperitoneal (i.p.) inoculation of 106 cells and used to evaluate the drug effects in male 7-week-old (BALB/c x DBA/2)F1 (CDFI) mice. Both strains were supplied by Charles River, Japan. All mice were housed in an air conditioned room with a 12 h light- 12 h dark cycle and given food (CE-2: Japan Clea Inc.) and tap water ad libitum

Results

Discussion

Conclusion