T. Owa et al., Cell cycle regulation in the G1 phase: A promising target for the development of new chemotherapeutic anticancer agents, CURR MED CH, 8(12), 2001, pp. 1487-1503
As a result of substantial advances in recent cancer biology, cell cycle re
gulation in the G1 phase has attracted a great deal of attention as a promi
sing target for the research and treatment of cancer. Many of the important
genes associated with G1 regulation have been shown to play a key role in
proliferation, differentiation and oncogenic transformation and programmed
cell death (apoptosis). Currently, a variety of "cytostatic" agents that af
fects G1 progression and/or G1/S transition are being evaluated in clinical
trials. Flavopiridol is a potent inhibitor of cyclin-dependent kinases (CD
Ks). UCN-01 was originally found to be a PKC-selective protein kinase antag
onist. More recent studies have revealed that this agent can also inhibit s
everal CDKs and the checkpoint kinase CHK1. FR901228, MS-27-275 and SAHA ar
e histone deacetylase inhibitors that induce changes in the transcription o
f specific genes via the hyperacetylation of histories. The proteasome inhi
bitor PS-341 disrupts the degradation process of intracellular proteins, in
cluding cell cycle regulatory proteins such as cyclins. R115777, SCH66336 a
nd BMS-214662 are non-peptidic farnesyl transferase inhibitors that prevent
p21 ras oncogene activation. Rapamycin derivative CCI-779 downregulates si
gnals through S6 kinase and FRAP (FKBP-rapamycin associating protein), affe
cting the expression levels of mRNAs important for progression from G1 to S
phase. 17-Allylaminogeldanamycin targets the Hsp-90 (heat shock protein-90
) family of cellular chaperones regulating the function of signaling protei
ns. TNP-470 (AGM-1470), a fumagillin derivative shows antiangiogenic action
through binding to MetAP-2 (methionine aminopeptidase-2). The antitumor su
lfonamide E7070, causing a cellular accumulation in the G1 phase, has been
shown to suppress the activation of CDK2 and cyclin E expression in HCT116
colorectal cancer cell line highly sensitive to the drug. With respect to s
everal growth factor receptors such as EGFR, PDGFR, bFGFR and VEGFR, potent
and specific inhibitors of receptor tyrosine kinases have been also examin
ed as hopeful drug candidates. In this report, we review the current status
of extensive efforts directed towards the discovery and development of new
chemotherapeutic anticancer agents targeting cell cycle regulation in the
G1 phase, with particular focus on the compounds undergoing clinical invest
igations.