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Keywords:

  • tryptophan hydroxylase;
  • 7-hydroxytryptophan;
  • carcinoid tumor;
  • small-cell lung carcinoma;
  • suicide prodrug

Abstract

BACKGROUND

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.

METHODS

The authors synthesized 7-hydroxytryptophan to test its chemotherapeutic value in cell culture, using a system consisting of serotonin-producing and nonproducing cell lines.

RESULTS

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.

CONCLUSIONS

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.

DOI 10.1002/cncr.10592