Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 nM—necessary to inhibit CDK—were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m² per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5–3.5 μM. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G₂ checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m² per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.