Novel Therapeutic Agents 31 Agents With Novel Targets

3.1.1. Flavopiridol

A semisynthetic flavonoid derived from rohitukine, flavopiridol is an alkaloid isolated from a plant indigenous to India. Initial studies showed that this agent could induce cell cycle arrest either in G1 by cdk2 inhibition or in G2/M by cdk1 inhibition. Various studies utilizing purified CDKs showed that flavopiridol inhibits cdks-1, -2, and -4 in a competitive manner through the ATP binding pocket (Fig. 2 and Table 1). A potentially important action of flavopiridol is the inhibition of cyclin D1, an oncogene that is overexpressed in mantle cell lymphoma. In vitro studies by Byrd et al. (23) in B-CLL demonstrated that flavopiridol can directly induce apoptosis independent of the BCL-2 and p53 pathways, suggesting that it may be active in lymphomas

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Table 1

Drugs With Novel Mechanisms of Action

Agent

Potential mechanisms of action

Flavopiridol

Inhibits cyclin D1, CDK1, -2, -4

Cell cycle arrest in G1 or G2 phase of cell cycle

Induces apoptosis by caspase 3 activation

Downregulates BCL-2 and Mcl-1

Potential anti-angiogenesis

Depsipeptide

Inhibits DNA histone deactylase enzyme

Inhibits cell cycle progression in G0-G1

Induces apoptosis through effects on BCL-2/Bax ratio

Bryostatin 1

Induces differentiation of CLL cells to hairy cell phenotype

Inhibits protein kinase C

Induces apoptosis

UCN-01 (7 hydroxy-staurosporine) Nonspecific protein kinase C inhibitor

Inhibits CDK and induces Gi and G2 cell cycle arrest

Synergistic effects with purine analogs (e.g., fludarabine)

PS-341

Inhibits degradation of proteins important in cell cycle progression

such as cyclin A, B, D, E, and CDKIs

Inhibits NF-kB activation

Genasense

Reduces BCL-2 and its inhibition on apoptosis

Arsenic trioxide

Inhibits tumor proliferation and induces apoptosis

Inhibits NF-kB through inhibition of IkB kinase

CDK, cyclin-dependent kinase; CDKI, CDK inhibitor; NF-kB, nuclear factor-KB.

CDK, cyclin-dependent kinase; CDKI, CDK inhibitor; NF-kB, nuclear factor-KB.

that harbor these potential pathways of resistance. Others have suggested that flavopiridol-induced apoptosis in CLL cells is associated with early activation of the MAP kinase family [MEK, p38, c-Jun-N-terminal kinase (JNK)], which may lead to caspase activation, whereas studies by Byrd et al. (23) suggest direct activation of caspase 3. Melillo et al. (24) demonstrated anti-angiogenic properties of flavopiridol in in vitro studies. Thus far, flavopiridol administered as a continuous infusion has not shown significant clinical activity in lymphoid malignancies, but pharmacokinetic studies indicate that suboptimal concentrations of free drug are achieved owing to high protein binding. Based on this observation, new studies are under way using a short bolus schedule followed by a 4-h infusion, which is expected to provide higher target concentration of this drug in humans.

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