Resistance and cross-resistance of the IgM immunocytoma in the LOU/M Wsl rat for cisplatin, carboplatin, and iproplatin

We investigated the antitumor activity of cis-diammine[1,1-cyclobutanedicarboxylato]platimum(II) (CBDCA, JM8) and cis-dichloro-trans-dihydroxybis(isopropylammine)platinum(IV) (CHIP, JM9) for the cis-DDP-sensitive and-resistant IgM immunocytoma in the LOU/M Wsl rat. The optimal dose for the antitumor effect of cis-diamminedichloroplatinum (cis-DDP) in this tumor model is 1 mg/kg body weight. In order to determine the dose range for antitumor activity of JM8 and JM9, tumorbearing rats were treated i. p. (twice weekly) with 2, 4, 8, 16, or 32 mg/kg JM8 or with 2, 4, or 8 mg/kg JM9. The maximal antitumor activity of JM8 was found at a dose of 4–8 mg/kg and that of JM9, at 4 mg/kg. Doses of 16 or 32 mg/kg JM8 did not increase the antitumor activity. Recurrence of tumors was observed in JM8- and JM9-treated rats. It was demonstrated that these relapses during treatment with JM8 or JM9 involved tumor cell populations almost completely resistant against therapy with the respective durgs. The growth of cis-DDP-resistant tumors was not influenced by the analog JM9 (4 and 8 mg/kg). Only a high dose of JM8 (32 mg/kg) caused growth retardation of the cis-DDP-resistant IgM subline. The JM8-resistant tumor was resistant to treatment with cis-DDP (1 and 2 mg/kg). The JM9-resistant tumor was also resistant to this treatment (1 mg/kg); however, at a dose of 2 mg/kg cis-DDP, growth retardation of the tumor occurred. We conclude that cis-DDP, JM8, and JM9 induce resistance in the IgM immunocytoma tumor system; tumors resistant for cis-DDP were not sensitive to the treatment with JM8 or JM9. Although JM9 reacts in vitro distinctly differently with DNA than cis-DDP and JM8, no differences were found in the induction of Pt resistance. In this study tumor cells were readily made resistant, which allows us to study in more detail the induction of (cross-) resistance by cis-DDP, JM8, and JM9.