Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50 mg per day. Gossypol plasma levels were measured (n = 8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies (n = 4). Grade I-II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50 mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with > 50% decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40 mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds.
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PMID:Oral gossypol in the treatment of patients with refractory metastatic breast cancer: a phase I/II clinical trial. 1151 Jun 95

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 n M-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/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. 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 G(2) 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/m(2) 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.
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PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

Seliciclib is an inhibitor of cyclin-dependent kinases 2, 7 and 9. Its primary mechanism of action is the inhibition of transcription, resulting in the selective downregulation of rapidly cycling mRNA transcripts, including Mcl-1 and cyclin D1. It possesses antitumour activity as a single agent and also synergises with a wide range of cytotoxic and targeted drugs. Seliciclib has high oral bioavailability and is in clinical development in a capsule formulation. The clinical dose has been determined in Phase I clinical trials for schedules of 3 - 10 consecutive days per cycle of 2 or 3 weeks duration. Its major clinical toxicities include nausea, vomiting, asthenia, hypokalaemia, elevation of creatinine levels and liver function tests, which are reversible after cessation of dosing. Seliciclib is non-myelosuppressive and does not cause intestinal toxicity. Phase II trials have commenced in non-small cell lung cancer and will be initiated shortly in nasopharyngeal carcinoma.
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PMID:Seliciclib, a cell-cycle modulator that acts through the inhibition of cyclin-dependent kinases. 2348 Jan 44

Diffuse Large B-Cell Lymphoma (DLBCL) is the most common histological subtype of Non-Hodgkin's Lymphoma (NHL). Primary retroperitoneal DLBCL is uncommon and has seldom been reported. Extrinsic compression of the duodenum due to lesions originating from the retroperitoneum is also rare. We present a case of a 39-year-old man who presented with inability to tolerate oral intake, abdominal pain, an upper abdominal mass and postprandial bilious vomiting caused by a large DLBCL arising from the retroperitoneum causing extrinsic compression of the duodenum. The cause of compression was initially presumed to be a neoplasm arising from the uncinate process of the pancreas or duodenum because of its proximity to the uncinate process and apparent widening of the C loop of duodenum. Repeat Computed Tomography (CT) scans were obtained because of the rapid increase in the size of the mass, normal levels of tumour markers such as Cancer Antigen (CA) 19-9, Carcinoembryonic Antigen (CEA) and no evidence of jaundice in spite of the large size of the mass. It revealed encasement of the uncinate process of pancreas with no involvement of parenchyma of the pancreas, thereby mimicking a pancreatic tumour. The neoplastic lymphoid cells were positive for Leukocyte Common Antigen (LCA), Cluster of Differentiation (CD)20, CD10, B-cell Lymphoma 2 (Bcl-2) and were negative for Creatine Kinase (CK), CD23, CD30, Anaplastic Lymphoma Kinase (ALK) and cyclin D1, D3 and D5. The Ki67 proliferative index was greater than 95%. Retroperitoneal DLBCL although rare should be considered in cases of duodenal obstruction.
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PMID:An Aggressive Primary Retroperitoneal Diffuse Large B-Cell Lymphoma Mimicking a Pancreatic Neoplasm, Presenting as Duodenal Stenosis. 2920 77