Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine: relation to vascular effects.
A number of antitumor agents are known to cause selective reduction in tumor blood flow, leading in some cases to tumor necrosis and growth delay. These agents include flavone acetic acid (FAA), an antitumor agent with high experimental but no clinical antitumor activity, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a highly active analogue of FAA, endotoxin, vinblastine, and colchicine. We find here that plasma concentrations of serotonin (5-hydroxytryptamine) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) are increased following administration of these agents. Mice were injected with each at the maximum tolerated dose and, at various times later, blood samples were taken, cells and platelets removed by centrifugation, and serotonin and 5-HIAA concentrations were measured by high performance liquid chromatography. FAA and DMXAA induced six- and sevenfold increases in serotonin and 5-HIAA, respectively, with maximal levels 4 h after drug administration. 8-Methylxanthenone-4-acetic acid, an inactive analogue of DMXAA, failed to increase serotonin and caused only a small increase in 5-HIAA. Endotoxin, vinblastine, and colchicine each caused increases in serotonin and 5-HIAA between 2 and 6 h after drug administration. The mitotic poison paclitaxel, despite inducing growth delays of Colon 38 tumors, did not induce tumor necrosis and caused no increase in serotonin or 5-HIAA up to 6 h. The effect of the presence of subcutaneous Colon 38 tumors was tested and found not to affect the induction of increases in serotonin and 5-HIAA by DMXAA and colchicine. We suggest that the increases in plasma serotonin and its metabolite are a result of drug-induced vascular effects in host tissues, and that measurement of these compounds provides a potential means of monitoring drugs exerting vascular effects.
Baguley
B C
BC
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand. b.baguley@auckland.ac.nz
Zhuang
L
L
Kestell
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003078:Colchicine / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000097:blood / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D012701:Serotonin / Q000097:blood*; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology*; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones
D000970:Antineoplastic Agents; D005419:Flavonoids; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D014747:Vinblastine; C049328:flavone acetic acid; D003078:Colchicine