CYTOTOXIC AND ANTITUMOR-ACTIVITY OF MEN-10710, A NOVEL ALKYLATING DERIVATIVE OF DISTAMYCIN

MEN 10710 is a new synthetic distamycin derivative possessing four pyr role rings and a bis-(2-chloroethyl)-aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain. Its biological p roperties have been investigated in comparison with the structurally r elated compound, tallimustine (FCE24517), and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN 10710 was increase d from 10- to 100-fold, as compared to tallimustine or L-PAM in murine L1210, human LoVo and MCF7 tumor cell lines. MEN 10710 was still acti ve against L1210/L-PAM leukemic cells, while a partial cross-resistanc e was observed in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and expressing a MDR phenotype. Treatment with verapam il (VRP) reduced the resistance to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects reflect in vivo antitumor pot ency and toxicity in the treatment of human tumor xenografts. MEN 1071 0 was more effective in A2780/DDP, an ovarian carcinoma selected for r esistance to cisplatin. On the other hand, the IC30 for inhibiting mur ine granulocyte/macrophage colony formation was 50 times higher for ME N 10710 than for tallimustine, suggesting a lower myelotoxic potential . In conclusion, the particular biological profile of MEN 10710 charac terized by a marked cytotoxic potency, an interesting antitumor effica cy and a reduced in vitro myelosuppressive action may represent a furt her improvement in the rational design of a novel distamycin-related a lkylating compound.