Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. 1124 75

Dysregulation of the cyclin dependent kinase pathway in luminal breast cancer creates a new therapeutic opportunity for estrogen receptor positive breast cancer. Initial pan-CDK inhibitors were associated with extensive toxicities but in recent years, the development of potent specific CDK inhibitors with favorable tolerability has driven renewed interests in this class of targeted therapies. Palbociclib, ribociclib and abemaciclib are specific CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration for use in combination with endocrine therapy for women with advanced hormone receptor positive breast cancer. These three anticancer therapeutics were approved based on progression free survival benefit seen on phase III trials with the most common grade 3 treatment-related side effects being neutropenia, fatigue, nausea and diarrhea. Except for estrogen receptor positivity, no biomarkers predictive of response to CDK4/6 inhibitors have been identified to date. Based on mechanistic insights here described, CDK4/6 inhibitors are currently being explored in combination with other agents, including targeted therapies, immunotherapy and chemotherapy.
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PMID:CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. 2993 34