Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinase C (PKC) is an enzyme family with serine/threonine kinase function which is involved in the transduction of signals for cell proliferation and differentiation. The important role played in processes relevant to neoplastic transformation, carcinogenesis and tumor cell invasion renders PKC a potentially suitable target for anticancer therapy. Bryostatin 1, a macrocyclic lactone isolated from Bugula nerutina, is a partial PKC agonist, and has shown potent antineoplastic properties in vitro and in vivo. Staurosporine, an alkaloid isolated from microbial sources, is ine of the most potent PKC inhibitors and has shown high antiproliferative activity in vitro, but poor selectivity. Staurosporine analogs have thus been synthesize with the aim of obtaining more selective PKC inhibition; among these, CGP 41251 has shown reduced PKC inhibitory activity, but a higher degree of selectivity when assayed for inhibition of different kinases. Several studies indicate a role for PKC in the regulation of the multidrug resistance (MDR) phenotype, since several PKC inhibitors are able to partially reverse MDR and inhibit P-glycoprotein (Pgp) phosphorylation. The MDR phenotype is also associated with variation in PKC isoenzyme content, in particular with PKC-alpha overexpression. While adequate PKC modulation might offer an attractive concept to modulate MDR, other potential mechanisms of PKC interaction with anticancer drugs exist and have been documented, such as the enhancement of chemotherapy-induced apoptosis by safingol, a specific PKC inhibitor. Three phase I clinical trials with bryostatin have been completed so far and have shown that myalgia is the dose-limiting toxicity, while some antitumor activity is evident. Safingol is presently undergoing a phase I clinical trial in combination with doxorubicin. While no definitive data are presently available, it appears that safingol plasma levels approach those associated with chemopotentiation in animals and no pharmacokinetic interaction between the two drugs exists. Drugs targeting PKC are well work considering for clinical trials, particularly for their potential as modulators of currently available cytotoxic agents.
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PMID:Protein kinase C: a worthwhile target for anticancer drugs? 914 7

This review covers the historical developments of the consideration that tryptophan may influence the induction of cancer in experimental studies. Studies relating to stimulatory effects, as well as to inhibitory effects, of tryptophan or tryptophan-related compounds are described. Also the effects of pyrolysis products of tryptophan on carcinogenesis are covered. In consideration that new L-tryptophan-related contaminants may be involved in a recently described human disease, a description is given of the eosinophilia-myalgia syndrome, which has been attributed to the ingestion of L-tryptophan-containing related contaminants. Whether these new L-tryptophan-related contaminants alone or together with L-tryptophan may prove to be carcinogenic remains to be determined. Lastly, recent developments relating to regulatory effects of L-tryptophan on liver metabolism are reviewed and then considered as possibly playing a role in carcinogenesis.
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PMID:Tryptophan and carcinogenesis: review and update on how tryptophan may act. 968 53

Retinoids have been shown to be potent inhibitors of epithelial carcinogenesis. Recent evidence has demonstrated that retinoid actions are mediated through nuclear receptors, which are proteins encoded by the retinoic acid receptor and retinoid X receptor gene families. These receptors are activated by binding to specific retinoids; of the known naturally occurring retinoids, 9-cis retinoic acid is unique in its ability to bind to both receptor families. Because of its unique receptor-binding characteristics, 9-cis retinoic acid may have biological activity not possible with other retinoids. For this reason, we conducted a Phase I trial of 9-cis retinoic acid in adult patients with solid tumors. Twenty-two patients were treated twice daily with p.o. 9-cis retinoic acid at doses ranging from 20 mg/m2/day to 150 mg/m2/day. The patients had non-small cell lung cancer (n = 8), breast cancer (n = 5), colorectal cancer (n = 3), head and neck cancer (n = 2), nonmelanoma skin cancer (n = 2), or ovarian cancer (n = 2). The dose-limiting (WHO grade III) toxic effects, which occurred at the 150-mg/m2/day dose level, were headaches and diarrhea. Less severe (grades I and II) toxic effects included cheilitis, dry skin, conjunctivitis, fatigue, hypertriglyceridemia, alkaline phosphatase elevation, myalgia/arthralgia, and hypercalcemia. Of the 15 patients evaluable for tumor response, no objective responses were observed. Pharmacokinetic analysis revealed a reduction in peak 9-cis retinoic acid plasma levels with chronic administration. Based on this study, the recommended Phase II dose of 9-cis retinoic acid in adult patients with solid tumors is 100 mg/m2/day administered in a divided dose twice daily.
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PMID:Phase I trial of 9-cis retinoic acid in adults with solid tumors. 981 71