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7-hydroxytryptophan, a novel, specific, cytotoxic agent for carcinoids and other serotonin-producing tumors
Article first published online: 12 JUN 2002
Copyright © 2002 American Cancer Society
Volume 94, Issue 12, pages 3135–3140, 15 June 2002
How to Cite
Walther, D. J., Peter, J.-U. and Bader, M. (2002), 7-hydroxytryptophan, a novel, specific, cytotoxic agent for carcinoids and other serotonin-producing tumors. Cancer, 94: 3135–3140. doi: 10.1002/cncr.10592
- Issue published online: 12 JUN 2002
- Article first published online: 12 JUN 2002
- Manuscript Accepted: 22 JAN 2002
- Manuscript Revised: 9 JAN 2002
- Manuscript Received: 20 NOV 2001
- tryptophan hydroxylase;
- carcinoid tumor;
- small-cell lung carcinoma;
- suicide prodrug
Carcinoids and small cell lung carcinomas stimulate their growth in an autocrine manner by releasing serotonin, an effect that is blocked by selective serotonergic receptor antagonists that, unfortunately, exert undesirable side effects on serotonergic central nervous function. Moreover, conventional chemotherapeutic agents, such as streptozocin, fluorouracil, cyclophosphamide, and doxorubicin, which target tumor cells directly, have produced disappointing results in the treatment of patients with these tumors in the advanced stage. Therefore, there is still a need for more specific and potent chemotherapeutic agents in the fight against serotonin-producing tumors.
The authors synthesized 7-hydroxytryptophan to test its chemotherapeutic value in cell culture, using a system consisting of serotonin-producing and nonproducing cell lines.
The authors chose tryptophan hydroxylase, the rate-limiting enzyme of serotonin biosynthesis, which is expressed highly in small cell lung carcinomas and carcinoids, as a target for the induction of cellular suicide by chemotherapy. They found that this otherwise substrate specific enzyme was capable of metabolizing in situ a harmless tryptophan analogue, 7-hydroxytryptophan, to a potent toxin, 5,7-dihydroxytryptamine, a conversion blocked by the specific tryptophan hydroxylase inhibitor parachlorophenylalanine.
These data suggest that 7-hydroxytryptophan may be a highly specific chemotherapeutic compound against serotonin-producing tumors that also interferes with the autocrine capabilities of serotonin synthesis. Cancer 2002;94:3135–40. © 2002 American Cancer Society.