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Titolo:
FLAVOPIRIDOL (L86-8275,NSC-649890), A NEW KINASE INHIBITOR FOR TUMOR-THERAPY
Autore:
SEDLACEK HH; CZECH J; NAIK R; KAUR G; WORLAND P; LOSIEWICZ M; PARKER B; CARLSON B; SMITH A; SENDEROWICZ A; SAUSVILLE E;
Indirizzi:
BEHRINGWERKE AG D-35041 MARBURG GERMANY HOECHST MARION ROUSSEL LTD,CTR BASIC RES MUMBAI 400080 INDIA NCI,DIV CANC TREATMENT DIAG & CTR BETHESDA MD 00000
Titolo Testata:
International journal of oncology
fascicolo: 6, volume: 9, anno: 1996,
pagine: 1143 - 1168
SICI:
1019-6439(1996)9:6<1143:F(ANKI>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
FLAVONE ACETIC-ACID; CELL-CYCLE PROGRESSION; HAMSTER OVARY CELLS; MURINE RENAL-CANCER; PROTEIN-KINASES; CDC2 KINASE; ANTITUMOR-ACTIVITY; MAMMALIAN-CELLS; P34CDC2 KINASE; FLAVONE-8-ACETIC ACID;
Keywords:
CYCLIN-DEPENDENT KINASE; INHIBITOR; TUMOR THERAPY; PRECLINICAL ACTIVITY; TOXICITY; PHARMACOKINETIC; FLAVOPIRIDOL;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
135
Recensione:
Indirizzi per estratti:
Citazione:
H.H. Sedlacek et al., "FLAVOPIRIDOL (L86-8275,NSC-649890), A NEW KINASE INHIBITOR FOR TUMOR-THERAPY", International journal of oncology, 9(6), 1996, pp. 1143-1168

Abstract

Flavopiridol is a new synthetic flavone, structurally related to a natural alkaloid, originally purified from Dysoxylum binectariferum, a plant indigenous to India and used in Indian folk medicine. Flavopiridol was detected by a tandem screening system consisting in inhibition of the EGF-receptor Tyrosine phosphokinase and cytotoxicity. As a cytostatic mechanism, however, Flavopiridol strongly inhibits the cyclin-dependent kinases (cdk1, cdk2, cdk4, cdk7), with the potential to cause inhibition of cell cycle progression in G(1) and G(2) by multiple mechanisms relatable to cdk inhibition. In certain cell types, Flavopiridol induces apoptosis. The antitumor activity of that compound on human xenograft tumors is similar to standard cytostatic drugs and superior to them at least in prostate carcinoma. The dose limiting toxicity is diarrhea. Compared with other flavonoids or other kinase inhibitors Flavopiridol can be regarded as unique as no other compound is yet knownthat as specifically and potently inhibits nearly all the main cyclindependent kinases and by that mechanisms can arrest cell cycle progression in G(1) as well as in G(2) and no other specific kinase inhibitor is known, which after i.v. or oral application reduces the growth ofsubcutaneous or subrenal xenografts of human tumors of different types. Initial results of a phase I study at the National Cancer Institute(NCI), USA, (Investigational New Drug Application no. 46211) providedsome clinical and laboratory evidence for antineoplastic effect at nontoxic doses (no grade IV toxicities encountered). Thus, Flavopiridol is clearly in need of further clinical evaluation of its tumor therapeutic potential. In this review the chemical profile, tumorpharmacology(in vitro activity, inhibition of cdk's and preclinical in vivo activity), preclinical toxicology and pharmacokinetic of Flavopiridol are reviewed to provide a comprehensive source to aid further developmentalefforts.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/12/20 alle ore 03:43:46