Synergistic cytotoxic interaction in hormone-refractory prostate cancer with the triple combination docetaxel-erlotinib and 5-fluoro-5'-deoxyuridine.
The current reference treatment of hormone-refractory prostate cancer consists mainly of chemotherapy with docetaxel. To improve the management of advanced prostate cancer, one should examine the benefits of adding other agents to docetaxel. We examined the growth inhibitory effects of a triple combination, including the anti-epidermal growth factor receptor drug erlotinib, docetaxel and 5-fluoro-5'-deoxyuridine (the main intermediary metabolite of capecitabine), on the human prostate cancer cell lines PC3 and DU145, which are both devoid of androgen receptors. Marked synergistic cytotoxic effects were observed with the application of the double combination of erlotinib-5-fluoro-5'-deoxyuridine for both cell lines and to a lesser magnitude with the triple combination. For PC3 cells, all conditions resulted in synergistic interactions. The combination between erlotinib and docetaxel resulted in an approximately 50% reduction in thymidylate synthase activity (the molecular target of 5-fluorodeoxyuridine monophosphate, the active capecitabine anabolite) with an higher impact observed with DU145 cells than with PC3 cells. Neither erlotinib nor docetaxel alone displayed marked effects on thymidine phosphorylase activity (the enzyme that governs at the cellular level the final and crucial step in the activation cascade of capecitabine), in contrast to their combination that resulted in a strong increase in thymidine phosphorylase activity in PC3 cells. These data may serve as a rational basis for setting up clinical trials in advanced prostate cancer combining epidermal growth factor receptor-targeting agents like erlotinib together with docetaxel and capecitabine.
Fischel
Jean-Louis
JL
Centre Antoine-Lacassagne, Department of Oncopharmacology, Nice Cedex, France.
Ciccolini
Joseph
J
Formento
Patricia
P
Ferrero
Jean-Marc
JM
Milano
Gérard
G
D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D048429:Cell Size; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D005467:Floxuridine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D011799:Quinazolines / Q000627:therapeutic use*; D043823:Taxoids / Q000627:therapeutic use*; D013939:Thymidine Phosphorylase / Q000378:metabolism; D013940:Thymidylate Synthase / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D011799:Quinazolines; D043823:Taxoids; D005467:Floxuridine; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D013940:Thymidylate Synthase; D013939:Thymidine Phosphorylase