Alkylating benzamides with melanoma cytotoxicity: experimental chemotherapy in a mouse melanoma model.
The in-vivo antineoplastic potential of the alkylating N-(2-dialkylaminoethyl)benzamides BZA1 and BZA2, novel melanoma targeted anticancer drugs, was evaluated in a mouse melanoma model with nude mice bearing subcutaneous SkMel28, B16 or WM266-4. The maximal tolerated dose (MTD) for the intraperitoneal application of both agents was found to be 24 mg/kg. Treatment was initiated with an intraperitoneal injection of 8 mg/kg of BZA1 or BZA2 on days 0, 2 and 4 in the case of B16 melanoma on days 0, 1 and 2 after the onset of the experiment, when the mean tumor diameter ranged within 4-6 mm. The experiment was terminated when the mean tumor diameter in the control group had reached a value of 12 mm. Tumor growth delay of these agents was compared with dacarbazine (3x250 mg/kg), chlorambucil (3x5 mg/kg) and an untreated control group. Significant tumor growth delay was observed under BZA1, BZA2 and dacarbazine treatment compared with the untreated control group in all three evaluated melanomas with insignificant differences among BZA1, BZA2 and dacarbazine. The insignificant effect of chlorambucil and the strong improvement on growth delay achieved with BZA1 and BZA2 demonstrated melanoma targeting characteristics of the N-(2-dialkylaminoethyl)benzamide structure element. Dacarbazine was more effective in the in-vivo antineoplastic assay compared with the in-vitro cytotoxicity studies, probably due to hepatic bioactivation. Similar side effect intensity of BZA2 and dacarbazine was observed, whereas BZA1 was more toxic. BZA2 might represent an alternative antimelanoma drug, especially in patients not responding to dacarbazine.
Wolf
Markus
M
Department of Radiopharmaceutical Chemistry, German Cancer Research Center (DKFZ), Heidelberg, Germany. markus.wolf@dkfz.de
Eskerski
Helmut
H
Bauder-Wüst
Ulrike
U
Haberkorn
Uwe
U
Eisenhut
Michael
M
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000627:therapeutic use*; D002699:Chlorambucil / Q000494:pharmacology; D003606:Dacarbazine / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D020714:Maximum Tolerated Dose; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012878:Skin Neoplasms / Q000188:drug therapy*; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D001549:Benzamides; C066918:N-(2-(diethylamino)ethyl)-4-iodobenzamide; D002699:Chlorambucil; D003606:Dacarbazine