title: Antitumor activity of delimotecan against human metastatic melanoma: pharmacokinetics and molecular determinants.
abstract: Delimotecan (MEN 4901/T-0128) is a new cytotoxic prodrug constituted by a camptothecin analog (T-2513) bound to carboxymethyl dextran through a triglycine linker. A significant antitumor activity of delimotecan against human metastatic melanoma xenograft model Me15392 is reported. Dacarbazine, the drug approved for the treatment of metastatic melanoma, was ineffective in this melanoma model. Pharmacokinetic studies, together with the expression analysis of mRNA for enzymes involved in delimotecan metabolism, showed that T-2513 and other cytotoxic metabolites of delimotecan (SN 38 and T-0055) are generated in greater quantities in the tumor tissue than in toxicity target tissues, such as liver, thus accounting for the antitumoral activity. Moreover, we demonstrated that human metastatic melanoma cells are able to phagocytose delimotecan and cleave it to release the cytotoxic moieties T-2513 in the tumoral environment. Further flow cytometric analysis showed a higher recruitment of macrophages in xenografted human metastatic melanoma, when compared with other human tumors. Thus, the antitumoral activity of delimotecan exerted on metastatic melanoma is due to several factors: (i) the ability of melanoma cells to phagocytose and metabolise delimotecan; (ii) the accumulation of delimotecan in tumoral mass; (iii) the recruitment of macrophage cells to the melanoma nodule and (iv) the expression in melanoma cells of a pattern of enzymes that converts delimotecan into cytotoxic metabolites. Based on these results, delimotecan might be exploited as a new anticancer agent for the therapy of metastatic melanoma because of its high efficacy and good selectivity, and therefore clinical trials for this indication are warranted.
authors.affiliation: Pharmacology Department of Menarini Ricerche SpA, Pomezia, Rome, Italy. mbigioni@menarini-ricerche.it
authors.forename: Mario
authors.initials: M
authors.lastname: Bigioni
authors.forename: Massimo
authors.initials: M
authors.lastname: Parlani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bressan
authors.forename: Daniela
authors.initials: D
authors.lastname: Bellarosa
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Fabio
authors.initials: F
authors.lastname: Animati
authors.forename: Attilio
authors.initials: A
authors.lastname: Crea
authors.forename: Rossana
authors.initials: R
authors.lastname: Bugianesi
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Maggi
authors.forename: Stefano
authors.initials: S
authors.lastname: Manzini
authors.forename: Monica
authors.initials: M
authors.lastname: Binaschi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003911:Dextrans / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D014018:Tissue Distribution; D019772:Topotecan / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D019772:Topotecan; C410031:T 0128