title: Evaluation of the antineoplastic activity of adozelesin alone and in combination with 5-aza-2'-deoxycytidine and cytosine arabinoside on DLD-1 human colon carcinoma cells.
abstract: Adozelesin (Ado), a CC-1065 analog, shows significant antineoplastic activity in vivo against several types of murine tumors and human tumor xenografts. Ado is a DNA alkylating agent. One objective of this study was to investigate the cytotoxic action of Ado against the human colon (HT-29, DLD-1) and the lung (SK) carcinoma cell lines. The concentrations of Ado that produced 50% cell kill for a 4 and 24 h exposure were in the range of 0.001-0.02 ng/ml for both colon and lung carcinoma cells, indicating that this analog was a very potent cytotoxic agent. Since most clinical regimens for tumor therapy consist of several drugs, we investigated the antineoplastic action of Ado in combination with 5-aza-2'-deoxycytidine (5-Aza-CdR), a potent inhibitor of DNA methylation or cytosine arabinoside (Ara-C), a potent inhibitor of DNA synthesis. The Ado plus 5-Aza-CdR combination showed a synergistic effect on cytotoxicity of DLD-1 colon carcinoma cells for both a 6 and 24 h exposure. However, combination of Ado and Ara-C for a 6 h exposure showed an antagonistic effect, whereas a 24 h exposure showed a synergistic effect. These preclinical results provide some preliminary data on possible drugs that can be selected for use in combination with Ado in future clinical trials in patients with cancer.
authors.affiliation: Département de Pharmacologie, Université de Montréal, Québec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Côté
authors.forename: R L
authors.initials: RL
authors.lastname: Momparler
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D001572:Benzofurans; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D053138:Cyclohexenes; D003561:Cytarabine / Q000008:administration & dosage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects; D000077209:Decitabine; D004354:Drug Screening Assays, Antitumor; D000080890:Duocarmycins; D006801:Humans; D007211:Indoles; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D004273:DNA, Neoplasm; D000080890:Duocarmycins; D007211:Indoles; D003561:Cytarabine; C060090:adozelesin; D000077209:Decitabine; D001374:Azacitidine