The majority of
hematopoietic malignancies have aberrancies in the
retinoblastoma (Rb) pathway. Loss in Rb function is, in most cases, a result of the phosphorylation and inactivation of Rb by the
cyclin-dependent kinases (cdks), main regulators of cell cycle progression.
Flavopiridol, the first cdk modulator tested in clinical trials, is a
flavonoid that inhibits several cdks with evidence of cell cycle block. Other interesting preclinical features are the induction of apoptosis, promotion of differentiation, inhibition of angiogenic processes and modulation of transcriptional events. Initial clinical trials with infusional
flavopiridol demonstrated 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. Phase 2 trials with infusional
flavopiridol in CLL and
mantle cell lymphoma, other schedules and combination with standard
chemotherapies are ongoing. The second cdk modulator tested in clinical trials,
UCN-01, is a potent
protein kinase C inhibitor that inhibits cdk activity in vitro as well.
UCN-01 blocks cell cycle progression and promotes apoptosis in hematopoietic models. Moreover,
UCN-01 is able to abrogate checkpoints induced by genotoxic stress due to modulation in
chk1 kinase. The first clinical trial of
UCN-01 demonstrated very prolonged half-life (approximately 600 h), 100 times longer than the half-life observed in preclinical models. This effect is due to high binding affinity of
UCN-01 to the human
plasma protein alpha-1-acid
glycoprotein. Main side-effects in this trial were
headaches,
nausea/
vomiting,
hypoxemia and
hyperglycemia. Clinical activity was observed in patients with
melanoma,
non-Hodgkin's lymphoma and
leiomyosarcoma. Of interest, a patient with
anaplastic large cell lymphoma refractory to high-dose
chemotherapy showed no evidence of disease after 3 years of
UCN-01 therapy. Trials of infusional
UCN-01 in combination with
Ara-C or
gemcitabine in patients with acute
leukemia and CLL, respectively, have commenced. In conclusion,
flavopiridol and
UCN-01 are cdk modulators that reach biologically active concentrations effective in modulating CDK in vitro, and show encouraging results in early clinical trials in patients with refractory
hematopoietic malignancies. Although important questions remain to be answered, these positive experiences will hopefully increase the therapeutic modalities in
hematological malignancies.