American journal of cancer therapy and pharmacology最新文献

{"title":"The role of β-elimination for the clinical activity of hypomethylating agents and cyclophosphamide analogues.","authors":"Haritha Reddy, Alison Duffy, Noa G Holtzman, Ashkan Emadi","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>A beta-elimination reaction generally involves the cleavage of a sigma (σ) bond at the position beta (β) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (π) bond. We describe the importance of β-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by β-elimination reaction. When carbon 5 (C₅) of cytosine is substituted with a nitrogen atom (N) in 5-aza-cytosine analogues, the critical β-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. This ultimately culminates in selective cytotoxic effect of these agents against lymphocytes but not hematopoietic and other stem cells with high aldehyde dehydrogenase content.</p>","PeriodicalId":90427,"journal":{"name":"American journal of cancer therapy and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217992/pdf/nihms-989854.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36657945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA.","authors":"Jianqing Lin,&nbsp;Tingting Zhan,&nbsp;Danielle Duffy,&nbsp;Jean Hoffman-Censits,&nbsp;Deborah Kilpatrick,&nbsp;Edouard J Trabulsi,&nbsp;Costas D Lallas,&nbsp;Inna Chervoneva,&nbsp;Kimberly Limentani,&nbsp;Brooke Kennedy,&nbsp;Sarah Kessler,&nbsp;Leonard Gomella,&nbsp;Emmanuel S Antonarakis,&nbsp;Michael A Carducci,&nbsp;Thomas Force,&nbsp;Wm Kevin Kelly","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Background: </strong>Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.</p><p><strong>Methods: </strong>An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3-24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 - 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.</p><p><strong>Results: </strong>Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.</p><p><strong>Conclusions: </strong>Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.</p>","PeriodicalId":90427,"journal":{"name":"American journal of cancer therapy and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2014-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287984/pdf/nihms634526.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32968943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pilot phase II Study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA.","authors":"Jianqing Lin, Tingting Zhan, Danielle Duffy, J. Hoffman-Censits, D. Kilpatrick, E. Trabulsi, C. Lallas, I. Chervoneva, K. Limentani, B. Kennedy, S. Kessler, L. Gomella, E. Antonarakis, M. Carducci, T. Force, W. Kelly","doi":"10.1200/JCO.2013.31.15_SUPPL.5061","DOIUrl":"https://doi.org/10.1200/JCO.2013.31.15_SUPPL.5061","url":null,"abstract":"BACKGROUND\u0000Digoxin was found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1α synthesis in a mouse model. We hypothesized that a therapeutic dose of digoxin could inhibit human PCa growth and disease progression.\u0000\u0000\u0000METHODS\u0000An open label, single arm pilot study was performed. Patients (pts) with non-metastatic, biochemically relapsed PCa with prostate specific antigen doubling time (PSADT) of 3-24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone > 50 ng/dL at baseline. Digoxin was taken daily with dose titration to achieve a target therapeutic level (0.8 - 2 ng/ml); patients had routine follow-up including cardiac monitoring with 12-lead electrocardiograms (ECGs) and digoxin levels. The primary endpoint was the proportion of pts at 6 months post-treatment with a PSADT ≥ 200% from the baseline. HIF-1α downstream molecule vascular endothelial growth factor (VEGF) was measured in plasma.\u0000\u0000\u0000RESULTS\u0000Sixteen pts were enrolled and 14 pts finished the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease >25% from baseline with a medium duration of 14 months. At 6 months, 5 of 13 (38%) pts had PSADT ≥ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Two patients had durable PSA response for more than 1 year. Digoxin was well tolerated with possible relation of one grade 3 back pain. No patients had evidence of digoxin toxicity. The digoxin dose was lowered in 2 patients for significant ECGs changes (sinus bradycardia and QT prolongation), and there were probable digoxin-related ECG changes in 3 patients. Plasma VEGF was detected in 4 (25%) patients.\u0000\u0000\u0000CONCLUSIONS\u0000Digoxin was well tolerated and showed a prolongation of PSDAT in 38% of the patients. However, there was no significant difference comparing that of similar patients on placebo from historical data. Digoxin at the dose used in this study may have limited benefit for patients with biochemically relapsed prostate cancer.","PeriodicalId":90427,"journal":{"name":"American journal of cancer therapy and pharmacology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2013-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74342375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}