| InChI | InChI=1S/C21H20ClNO5.ClH/c1-23-7-6-12(17(27)10-23)19-14(24)8-15(25)20-16(26)9-18(28-21(19)20)11-4-2-3-5-13(11)22;/h2-5,8-9,12,17,24-25,27H,6-7,10H2,1H3;1H/t12-,17+;/m0./s1 |
| Reference | 1. Semin Oncol. 2002 Jun;29(3 Suppl 11):77-85. <br />
Review of flavopiridol, a cyclin-dependent kinase inhibitor, as breast cancer
therapy. <br />
Tan AR(1), Swain SM. <br />
Author information: <br />
(1)Cancer Therapeutics Branch, Center for Cancer Research, National Cancer
Institute, Bethesda, MD20889, USA. <br />
Disrupting the cell cycle through the inhibition of cyclin-dependent kinases
(CDKs) is an important therapeutic strategy in the treatment of cancer.
Flavopiridol is the first CDK inhibitor to be tested in clinical trials. It has
been shown to cause cell cycle arrest, induce apoptosis, inhibit angiogenesis,
and potentiate the effects of chemotherapy. In this review, the rationale for
using a CDK inhibitor as therapy for breast cancer is described and the
preclinical studies performed with flavopiridol in breast cancer cell lines are
highlighted. Flavopiridol is currently undergoing phase II testing as monotherapy
and phase I and/or II evaluation in combination with traditional chemotherapy
agents. The assessment of CDK inhibition as evidence of flavopiridol/’s targeted
effect in serial biopsies of tumor and surrogate tissues is also under
investigation in these protocols. The interruption of the cell cycle through
modulation of CDKs with an agent such as flavopiridol has potential therapeutic
efficacy, especially in combination with chemotherapy. <br />
2. Invest New Drugs. 1999;17(3):313-20. <br />
Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical
trials. <br />
Senderowicz AM(1). <br />
Author information: <br />
(1)DTP Clinical Trials Unit, Developmental Therapeutics Program, Division of
Cancer Treatment and Diagnosis. National Cancer Institute, Bethesda, MD 20892,
USA. [email protected] <br />
The discovery and cloning of the cyclin-dependent kinases (cdks), main regulators
of cell cycle progression, allowed several investigators to design novel
modulators of cdk activity. Flavopiridol (HMR 1275, L86-8275), a flavonoid
derived from an indigenous plant from India, demonstrated potent and specific in
vitro inhibition of all cdks tested (cdks 1, 2, 4 and 7) with clear block in cell
cycle progression at the G1/S and G2/M boundaries. Moreover, preclinical studies
demonstrated the capacity of flavopiridol to induce programmed cell death,
promote differentiation, inhibit angiogenic processes and modulate
transcriptional events. The relationship between the latter effects and cdk
inhibition is still unclear. Initial testing in early clinical human trials with
infusional flavopiridol showed activity in some patients with non-Hodgkin/’s
lymphoma, renal, prostate, colon and gastric carcinomas. Main side effects were
secretory diarrhea and a pro-inflammatory syndrome associated with hypotension.
Biologically active plasma concentrations of flavopiridol (approximately 300-500
nM) are easily achievable in patients receiving infusional flavopiridol. Phase 2
trials with infusional flavopiridol in several tumor types, other schedules and
combination with standard chemotherapies are being assessed. In conclusion,
flavopiridol is the first cdk inhibitor to be tested in clinical trials. Although
important questions remain to be answered, this positive experience will
stimulate the development of novel cdk modulators for cancer therapy. <br />
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