Ketoconazole Therapy for Advanced Prostatic Cancer: Feasibility and Treatment Results

Vanuytsel, L.; Ang, Kie-Kian; Vantongelen, K.; Drochmans, A; Baert, Luc; Schueren, E. van der

doi:10.1016/s0022-5347(17)44291-1

Cited by 27 publications

(5 citation statements)

References 9 publications

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“…There have been multiple reports evaluating ketoconazole as a single agent in patients with hormone‐refractory prostate carcinoma 21–23. The standard dose used in those studies was 400 mg 3 times per day, and the most common toxicities observed were gastrointestinal intolerance, fatigue, and liver function abnormalities.…”

Section: Discussionmentioning

confidence: 99%

“…The standard dose used in those studies was 400 mg 3 times per day, and the most common toxicities observed were gastrointestinal intolerance, fatigue, and liver function abnormalities. These single‐agent toxicities can be significant, however, with as many as 32% of patients discontinuing treatment 23. There are limited data available for evaluating the efficacy of ketoconazole at doses lower than 1200 mg per day.…”

Section: Discussionmentioning

confidence: 99%

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Docetaxel and ketoconazole in advanced hormone‐refractory prostate carcinoma

Veldhuizen

Reed

Aggarwal

et al. 2003

Cancer

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BACKGROUND Docetaxel has significant single‐agent activity in patients with prostate carcinoma, and ketoconazole has activity as a second‐line hormonal agent. In vitro, ketoconazole exhibits synergy with several chemotherapeutic agents. A potential drug interaction exists, however, because both docetaxel and ketoconazole are metabolized hepatically by the cytochrome p450 system (CYP3A4). The authors performed a Phase I study and a pharmacokinetic study evaluating the both tolerability of a docetaxel/ketoconazole combination as well as this potential drug interaction. METHODS For all initial patients, docetaxel was administered intravenously at a dose of 55 mg/m2 over 1 hour every 21 days. Starting on Day 8 after their first docetaxel dose, cohorts of at least 3–5 new patients were enrolled to receive escalating doses of ketoconazole. When the maximally tolerated dose (MTD) of ketoconazole was reached, the subsequent cohort of patients received an escalating dose of docetaxel. Pharmacokinetic studies were performed after docetaxel infusions on Day 1 (prior to ketoconazole) and Day 22 (after starting ketoconazole). RESULTS Twenty‐six patients were enrolled and completed at least 2 cycles of treatment. The MTD was ketoconazole 400 mg twice daily and docetaxel 55 mg/m2. Dose‐limiting toxicities included neutropenia and fatigue. Ketoconazole did not cause a consistent effect on docetaxel pharmacokinetics, although there was significant intrapatient and interpatient variability in serum levels. CONCLUSIONS The recommended Phase II dose for this combination is ketoconazole 400 mg twice daily and docetaxel 55 mg/m2 every 21 days. Cancer 2003. Published 2003 by the American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Docetaxel and ketoconazole in advanced hormone‐refractory prostate carcinoma

Veldhuizen

Reed

Aggarwal

et al. 2003

Cancer

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“…It has been reported that hydralazine, a DNA demethylating agent, was approved by FDA and used in the therapeutic treatment of cancer patient by the combination with a therapeutic dose of valproic acid to mediate the epigenetic modification in tumor cells [186]. Ketoconazole can block the dysregulated cellular metabolism to inhibit the progression of prostate cancer and may be a useful adjunct in treating lung cancer and breast cancer [187, 188]. Besides, promethazine may also be used in treating cancer by modulating energy metabolism in malignant cells [189].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have been reported that procainamide may be potentially used in preventing the development of lung cancer by changing the epigenetic modification [202]. Moreover, ketoconazole can inhibit the progression of prostate cancer and may have potential use in treatment of lung cancer and breast cancer [187, 188]. Through the therapeutic treatment using the proposed genetic and epigenetic multiple-molecule drug, the proteins with significant higher expression in the middle stage (COL1A1, JAG1, IGF1, IGF1R, TRAF4, SUSD4, and PARG) can be repressed, and proteins with significant lower expression in the middle stage (TNS1, ACTA2, CCL21, CCR7, MYLK, ITGB1, TSC2, GATA2, JUN, ETS1, and JUNB) can be activated to facilitate the restoration of middle stage LSCC to normal lung cells.…”

Section: Discussionmentioning

confidence: 99%

Comparing progression molecular mechanisms between lung adenocarcinoma and lung squamous cell carcinoma based on genetic and epigenetic networks: big data mining and genome-wide systems identification

Yeh

Chang

et al. 2019

Oncotarget

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Non-small-cell lung cancer (NSCLC) is the predominant type of lung cancer in the world. Lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC) are subtypes of NSCLC. We usually regard them as different disease due to their unique molecular characteristics, distinct cells of origin and dissimilar clinical response. However, the differences of genetic and epigenetic progression mechanism between LADC and LSCC are complicated to analyze. Therefore, we applied systems biology approaches and big databases mining to construct genetic and epigenetic networks (GENs) with next-generation sequencing data of LADC and LSCC. In order to obtain the real GENs, system identification and system order detection are conducted on gene regulatory networks (GRNs) and protein-protein interaction networks (PPINs) for each stage of LADC and LSCC. The core GENs were extracted via principal network projection (PNP). Based on the ranking of projection values, we got the core pathways in respect of KEGG pathway. Compared with the core pathways, we found significant differences between microenvironments, dysregulations of miRNAs, epigenetic modifications on certain signaling transduction proteins and target genes in each stage of LADC and LSCC. Finally, we proposed six genetic and epigenetic multiple-molecule drugs to target essential biomarkers in each progression stage of LADC and LSCC, respectively.

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“…Ketoconazole and omeprazole have been shown to cause a blunted response to adrenocorticotropin hormone administration (3,10,16,18), and there have been several reports of patients who have experienced adrenal insufficiency while receiving ketoconazole (2,14). These effects on steroidogenesis have resulted in the clinical use of ketoconazole in diseases such as prostatic cancer, precocious puberty, hirsutism, and Cushing's disease (9,11,13,21,22). Metyrapone is a potent inhibitor of cortisol production, and as a result, its primary indication is to assess hypothalamic-pituitary function.…”

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confidence: 99%

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males

Waite

Edwards

Arnott

et al. 1989

Antimicrob Agents Chemother

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Several inhibitors of oxidative drug metabolism inhibit the synthesis of endogenous compounds such as testosterone and cortisol. Since ciprofloxacin is a potent inhibitor of the metabolism of a number of drugs, we studied its effect on serum testosterone and cortisol concentrations in eight healthy male subjects. Blood samples were collected over a 12-h period under baseline conditions and following the first and final doses of ciprofloxacin (500 mg orally every 12 h for 4 days). No significant differences in concentrations or area under the concentration-time curve were found when baseline values were compared with those observed for either testosterone or cortisol after ciprofloxacin administration. These results suggest that ciprofloxacin is unlikely to have either antiandrogenic side effects or clinical utility in lowering testosterone or cortisol concentration.Ciprofloxacin is a member of a promising new class of antimicrobial agents known as the fluoroquinolones. These drugs are expected to be widely used because of their broad spectra of activity and favorable pharmacokinetic profiles, which allow for oral administration and prolonged dosing intervals. While clinical experience with these drugs has shown them to be relatively well tolerated, with a 3 to 10% incidence of adverse effects (20), numerous studies have documented their abilities to inhibit oxidative drug metabolism (6). Ciprofloxacin appears to be comparable to cimetidine in its ability to inhibit the metabolism of classical substrates such as antipyrine and theophylline (12,19), while the related quinolones enoxacin and pipemidic acid have even greater effects.Oxidative biotransformation is important not only for the metabolism of drugs but also for the activation and degradation of a number of endogenous substances. Several compounds such as ketoconazole, metyrapone, and omeprazole (1,4,7,8)

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Ketoconazole Therapy for Advanced Prostatic Cancer: Feasibility and Treatment Results

Cited by 27 publications

References 9 publications

Docetaxel and ketoconazole in advanced hormone‐refractory prostate carcinoma

Docetaxel and ketoconazole in advanced hormone‐refractory prostate carcinoma

Comparing progression molecular mechanisms between lung adenocarcinoma and lung squamous cell carcinoma based on genetic and epigenetic networks: big data mining and genome-wide systems identification

Effects of ciprofloxacin on testosterone and cortisol concentrations in healthy males

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