[Inhibition of tumor neo-angiogenesis and induction of apoptosis as properties of docetaxel (taxotere)].
Paclitaxel and docetaxel are potent drugs that are effective in the treatment of malignant tumors. The cytotoxic action of these drugs is not fully understood, but it appears to be mediated mainly through mitotic arrest and subsequent apoptosis. Because no information is available on the antiangiogenesis action of docetaxel, the investigations were performed to determine whether inhibition of neoangiogenesis plays a role in docetaxel's antitumor efficacy. Four different mouse tumors, two squamous cell carcinomas (SCC-IV; SCC-VII) and two adenocarcinomas (MCA-4; MCA-29) were assayed for angiogenic activity using the in vivo i.c. angiogenesis assay. Tumor cells (5 x 10(5)) were injected i.c. into the skin flap over the abdominal wall, and the number of new blood vessels at the tumor cell injection site was determined 2, 4, 6, 8, 10 and 12 days later. The mice were treated with docetaxel (Taxotere--31.3 mg/kg i.v.) 1 or 4 days after tumor cell injection. The number of new blood vessels increased with time. Docetaxel reduced the number of newly formed blood vessels in MCAs, but not in SCCs. The reduction was associated with slower tumor growth. In a separate set of experiments we observed that docetaxel's inhibitory effect on the two MCAs was histologically associated with massive tumor cell destruction by means of both apoptosis and necrosis. This was not observed for the two SCCs. Since no reduction in blood vessels occurred in tumors unresponsive to docetaxel, the inhibition of neoangiogenesis in docetaxel-responsive tumors was likely the result of a decrease in angiogenic stimuli due to docetaxel's destruction of tumor cells.
Schimming
R
R
Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Carl Gustav Carus, Dresden.
Hunter
N R
NR
Mason
K A
KA
Milas
L
L
D000230:Adenocarcinoma / Q000098:blood supply* / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000473:pathology; D000077143:Docetaxel; D051379:Mice; D008809:Mice, Inbred C3H; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D012878:Skin Neoplasms / Q000098:blood supply* / Q000473:pathology; D043823:Taxoids; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel