Cytotoxic and antitumor activity of MEN 10710, a novel alkylating derivative of distamycin.

Abstract

MEN 10710 is a new synthetic distamycin derivative possessing four pyrrole rings and a bis-(2-chloroethyl)aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain. Its biological properties have been investigated in comparison with the structurally related compound, tallimustine (FCE24517), and the classical alkylating agent, melphalan (L-PAM). Cytotoxic potency of MEN 10710 was increased 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 active against L1210/L-PAM leukemic cells, while a partial cross-resistance was observed in LoVo/DX and in MCF7/DX cells selected for resistance to doxorubicin and expressing a MDR phenotype. Treatment with verapamil (VRP) reduced the resistance to tallimustine, but not to MEN 10710, in MCF7/DX cells. The cytotoxic effects reflect in vivo antitumor potency and toxicity in the treatment of human tumor xenografts. MEN 10710 was more effective in A2780/DDP, an ovarian carcinoma selected for resistance to cisplatin. On the other hand, the IC30 for inhibiting murine granulocyte/macrophage colony formation was 50 times higher for MEN 10710 than for tallimustine, suggesting a lower myelotoxic potential. In conclusion, the particular biological profile of MEN 10710 characterized by a marked cytotoxic potency, an interesting antitumor efficacy and a reduced in vitro myelosuppressive action may represent a further improvement in the rational design of a novel distamycin-related alkylating compound.

• Authors: M Bigioni, C Salvatore, C Palma, S Manzini, F Animati, P Lombardi, G Pratesi, R Supino, F Zunino
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 8 Issue 9 Pg. 845-52 (Oct 1997) ISSN: 0959-4973 [Print] England
• PMID: 9402311 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Antineoplastic Agents, Alkylating
• Calcium Channel Blockers
• Distamycins
• MEN 10710
• Nitrogen Mustard Compounds
• tallimustine
• Verapamil
• Melphalan

Topics

• Animals
• Antineoplastic Agents (pharmacokinetics, pharmacology)
• Antineoplastic Agents, Alkylating (pharmacokinetics, pharmacology)
• Calcium Channel Blockers (pharmacology)
• Cell Survival
• Distamycins (pharmacokinetics, pharmacology, therapeutic use)
• Humans
• Leukemia L1210 (drug therapy)
• Melphalan (pharmacokinetics, pharmacology)
• Mice
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy)
• Neoplastic Stem Cells
• Nitrogen Mustard Compounds (pharmacokinetics, pharmacology, therapeutic use)
• Organ Size (drug effects)
• Tumor Cells, Cultured
• Verapamil (pharmacology)