7-Hydroxytryptophan, a novel, specific, cytotoxic agent for carcinoids and other serotonin-producing tumors.
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.
Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany. dwalther@mdc-berlin.de
Diego J
DJ
Walther
Jens-Uwe
JU
Peter
Michael
M
Bader
D015115:5,6-Dihydroxytryptamine / Q000494:pharmacology; D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019556:COS Cells; D002276:Carcinoid Tumor / Q000188:drug therapy* / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D012701:Serotonin / Q000096:biosynthesis*; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology*; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
C461139:7-hydroxytryptophan; D000970:Antineoplastic Agents; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; D014364:Tryptophan; D014365:Tryptophan Hydroxylase; D015115:5,6-Dihydroxytryptamine