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Titolo:
Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA)
Autore:
Zhao, LL; Kestell, P; Philpott, M; Ching, LM; Zhuang, L; Baguley, BC;
Indirizzi:
Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc, Res Ctr, Auckland 1,New Zealand Univ Auckland Auckland New Zealand 1 oc, Res Ctr, Auckland 1,New Zealand
Titolo Testata:
CANCER CHEMOTHERAPY AND PHARMACOLOGY
fascicolo: 6, volume: 47, anno: 2001,
pagine: 491 - 497
SICI:
0344-5704(200106)47:6<491:EOTSRA>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
TUMOR-NECROSIS-FACTOR; FLAVONE ACETIC-ACID; FACTOR-ALPHA; FLAVONE-8-ACETIC ACID; MULTIDRUG-RESISTANCE; ANTITUMOR-ACTIVITY; COLON-38 TUMORS; MICE; AGENTS; VINBLASTINE;
Keywords:
colon 38; bile; glucuronide; serotonin; TNF;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Baguley, BC Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc, Res Ctr,Private Bag92019, Auckland 1, New Zealand Univ Auckland Private Bag 92019 Auckland New Zealand 1 ealand
Citazione:
L.L. Zhao et al., "Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA)", CANC CHEMOT, 47(6), 2001, pp. 491-497

Abstract

Background: DMXAA (5,6-dimethylxanthenone-4-acetic acid) is a new drug synthesized in this laboratory and currently in phase I clinical trial. In mice it acts as an antivascular drug, selectively inhibiting tumour blood flowand inducing tumour haemorrhagic necrosis with resultant tumour regression. It also induces the synthesis of tumour necrosis factor (TNF), nitric oxide and serotonin. Cyproheptadine, a type 2 serotonin receptor antagonist, is known to reduce the degree of tumour necrosis-induced TNF in mice. We investigated the pharmacological interaction between a suboptimal dose of DMXAA (20 mg/kg) and cyproheptadine (20 mg/ kg) using mice with Colon 38 tumours that are sensitive to DMXAA. Methods: Mice with or without tumours were treated with DMXAA and/or cyproheptadine. Concentrations of plasma and tissue DMXAA and the serotonin metabolite 5-hydroxyindoleacetic acid were measured by high performance liquid chromatography. TNF concentrations were measured by ELISA. Results: While DMXAA alone (20 mg/kg) showed little or no antitumour activity, coadministration with cyproheptadine was curative in fourof five mice. DMXAA half-lives in plasma and tumour tissue were increased 5.1- and 5.6-fold, respectively, and the appearance of DMXAA glucuronides in bile was almost completely inhibited for up to 4 h. Serum TNF was low andunchanged by cyproheptadine, and plasma concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were also not substantially changed. Conclusion: The augmentation by cyproheptadine of the induction of tumour response to DMXAA reflects a pharmacological interaction, leading to increasedplasma and tumour half-lives, and to reduced excretion. However, serum TNFconcentrations were not increased, suggesting that the increased antitumour effects are mediated by an increased local tumour response, arising from the extended tumour DMXAA concentrations.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 14/07/20 alle ore 08:32:32