Ketoconazole improved fenretinide exposures and achieved clinical responses in recurrent neuroblastoma: a NANT study
Min H. KangAraz MarachelianJulia L. Glade BenderJudith G. VillablancaSusan GroshenMeaghan GrangerBrian WeissKatherine K. MatthayC. Patrick ReynoldsBarry J. Maurer
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Fenretinide
The synthetic retinoid fenretinide induces apoptosis of neuroblastoma cells and in vitro acts synergistically with chemotherapeutic drugs used to treat neuroblastoma. The mechanisms of fenretinide-induced cell death of neuroblastoma cells are complex, involving cellular signaling pathways as yet incompletely defined but, in part, involving the generation of reactive oxygen species (ROS). In an attempt to characterize the mechanism of action of fenretinide, cDNA array filters were screened to identify apoptotic genes regulated in response to treatment of SH-SY5Y cells with fenretinide. Expression of the stress-induced transcription factor, GADD153, was up-regulated at both the protein and mRNA levels in response to fenretinide. Overexpression of GADD153 increased apoptosis in the presence and absence of fenretinide, whereas reduced expression of GADD153 by expression of antisense DNA abrogated the response to fenretinide. Although fenretinide is a partial retinoic acid receptor (RAR)-beta/gamma agonist, RARbeta/gamma antagonists did not block the induction of GADD153 by fenretinide; conversely, the induction of GADD153 was blocked by antioxidants. Enzyme inhibitors were used to identify pathways mediating the ROS-dependent effects of fenretinide: inhibitors of phospholipase A(2) and lypoxygenases (LOX), and specific inhibitors of 12-LOX, but not 5-LOX or 15-LOX, inhibited the induction of ROS, apoptosis, and GADD153 in response to fenretinide. The inhibition of ROS and apoptosis was reversed by the addition of the 12-LOX products, 12 (S)-hydroperoxyeicosatetraenoic acid (12-HpETE) and 12 (S)-hydroxyeicosatetraenoic acid (12-HETE). Fenretinide did not increase free arachidonic acid levels, but increased LOX activity without a detectable increase in 12-LOX protein. These results suggest that fenretinide induces apoptosis via RAR-dependent and -independent pathways in which the RAR-independent pathway is characterized by a fenretinide-dependent increase in 12-LOX activity, leading to the induction of GADD153. The targeting of 12-LOX and/or GADD153 in neuroblastoma cells may thus present a novel pathway for the development of drugs inducing apoptosis of neuroblastoma with improved tumor specificity.
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A 46-year-old woman had a chronic, unresponsive wrist infection that was proved to be due to the algaelike organism Prototheca wickerhamii. Treatment with ketoconazole resulted in prompt improvement and ultimate healing. Therapy was complicated by hepatitis that was ketoconazole-related. Ketoconazole may be effective and easily administered therapy for this generally unresponsive infection.
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We previously reported that concurrent ketoconazole, an oral anti‐fungal agent and P450 enzyme inhibitor, increased plasma levels of the cytotoxic retinoid, fenretinide (4‐HPR) in mice. We have now determined the effects of concurrent ketoconazole on 4‐HPR cytotoxic dose‐response in four neuroblastoma (NB) cell lines in vitro and on 4‐HPR activity against two cell line‐derived, subcutaneous NB xenografts (CDX) and three patient‐derived NB xenografts (PDX). Cytotoxicity in vitro was assessed by DIMSCAN assay. Xenografted animals were treated with 4‐HPR/LXS (240 mg/kg/day) + ketoconazole (38 mg/kg/day) in divided oral doses in cycles of five continuous days a week. In one model, intratumoral levels of 4‐HPR and metabolites were assessed by HPLC assay, and in two models intratumoral apoptosis was assessed by TUNEL assay, on Day 5 of the first cycle. Antitumor activity was assessed by Kaplan‐Meier event‐free survival (EFS). The in vitro cytotoxicity of 4‐HPR was not affected by ketoconazole ( p ≥ 0.06). Ketoconazole increased intratumoral levels of 4‐HPR ( p = 0.02), of the active 4‐oxo‐4‐HPR metabolite ( p = 0.04), and intratumoral apoptosis ( p ≤ 0.0006), compared to 4‐HPR/LXS‐alone. Concurrent ketoconazole increased EFS in both CDX models compared to 4‐HPR/LXS‐alone ( p ≤ 0.008). 4‐HPR + ketoconazole also increased EFS in PDX models compared to controls ( p ≤ 0.03). Thus, concurrent ketoconazole decreased 4‐HPR metabolism with resultant increases of plasma and intratumoral drug levels and antitumor effects in neuroblastoma murine xenografts. These results support the clinical testing of concurrent ketoconazole and oral fenretinide in neuroblastoma.
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Fenretinide (N-4-hydroxyphenyl-retinamide, or 4-HPR) is a semisynthetic retinoid that was initially developed as a low-dose chemopreventative agent.[1-3] Unlike other naturally occurring retinoids such as all-trans, 13-cis, and 9-cis retinoic acids, fenretinide does not induce systemic catabolism that interferes with the maintenance of effective plasma levels during long-term use. This characteristic, combined with the agent’s low toxicity and its ability to block aspects of carcinogenesis, provided the rationale for the development of fenretinide in lower doses as a chemoprevention agent for breast, prostate, and bladder cancer.
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This chapter provides the basic characteristics, side effects/toxicity, drug interactions, and dosage information of the ketoconazole. Ketoconazole is metabolized in the liver and excreted in the bile. Ketoconazole tablets should be used only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and para-coccidioidomycosis. Ketoconazole can be taken with or without food; however, in studies, Ketoconazole was administered with meals. It requires a low pH for absorption. If concomitant antacids, anticholinergics, and H2-blockers are needed, they should be given at least two hours after administration of Ketoconazole. Ketoconazole is an inhibitor of the cytochrome P450 3A4 enzyme system. It is available in 200 mg tablets. Ketoconazole should be started at 200 mg daily; in very serious infections or if clinical responsiveness is insufficient within the expected time, the dose may be increased to 400 mg once daily.
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评估 Ketoconazole 的发生的目的联系了 hepatotoxicity 和相关因素。方法文学检索被使用多数据库进行因为 Ketoconazole 上的元分析联系了 hepatotoxicity。数据与一种标准化形式被收集。为特定的学习类型的 hepatotoxicity 的发生的全面评价用由于在研究之中的实质的差别的一个 DerSimonian 地主随机效果的模型旁边是计算的。结果完全， 204 合格研究在分析被包括。Ketoconazole 的发生联系了 hepatotoxicity 是 3.6%-4.2% 。特定的亚群分析的剂量和持续时间没在组之中显示出任何重要差别，当时特定的亚群分析显示出的年龄在孩子和人的发生变老 > 60 年是 1.4%(95% CI：0.5%-4.2%) 并且 3.2%(95% CI：1.1%-8.7%) 分别地。另外， hepatotoxicity 的发生在在用法指令的食物以外有 ketoconazole 的口头的管理的人是更高的，并且发生是 5.7%(95% CI：4.5%-7.2%) 。结论 Ketoconazole 联系了 hepatotoxicity 是普通的。离开标签使用可能增加肝损坏的风险。设计得好的大样品研究被需要在未来识别风险因素。
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PURPOSE Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.
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