A Phase 2 Evaluation of Irofulven as Second-line Treatment of Recurrent or Persistent Intermediately Platinum-Sensitive Ovarian or Primary Peritoneal Cancer A Gynecologic Oncology Group Trial

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
International Journal of Gynecological Cancer (Impact Factor: 1.95). 10/2010; 20(7):1137-41. DOI: 10.1111/IGC.0b013e3181e8df36
Source: PubMed


This multicenter phase 2 trial was conducted by the Gynecologic Oncology Group to evaluate the activity and the safety of irofulven in patients with recurrent epithelial ovarian cancer. Eligible patients had documented recurrent ovarian cancer 6 to 12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0 to 2, and adequate bone marrow, hepatic, and renal functions before study entry. The dose of irofulven was 0.45 mg/kg intravenously on days 1 and 8 every 21 days. Responses were defined by Response Evaluation Criteria in Solid Tumors. Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were 7 partial responses (12.7%), and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 months (1.3-37.5 months) and 22.1 months or more (2.8-57.8+ months), respectively. Patients received a median of 3 cycles (range, 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 nonhematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia. Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

Download full-text


Available from: Russell J Schilder,
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fourteen metabolites, isolated from phytopathogenic and toxigenic fungi, were evaluated for their in vitro antigrowth activity for six distinct cancer cell lines, using the MTT colorimetric assay. Bislongiquinolide (1) and dihydrotrichodimerol (5), which belong to the bisorbicillinoid structural class, displayed significant growth inhibitory activity against the six cancer cell lines studied, while the remaining compounds displayed weak or no activity. The data show that 1 and 5 have similar growth inhibitory activities with respect to those cancer cell lines that display certain levels of resistance to pro-apoptotic stimuli or those that are sensitive to apoptosis. Quantitative videomicroscopy analysis revealed that 1 and 5 exert their antiproliferative effect through cytostatic and not cytotoxic activity. The preliminary results from the current study have stimulated further structure-activity investigations with respect to the growth inhibitory activity of compounds belonging to the bisorbicillinoid group.
    Journal of Natural Products 04/2010; 73(5):969-71. DOI:10.1021/np900731p · 3.80 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Exploration of natural sources for novel bioactive compounds has been an emerging field of medicine over the past decades, providing drugs or lead compounds of considerable therapeutic potential. This research has provided exciting evidence on the isolation of microbe-derived metabolites having prospective biological activities. Mushrooms have been valued as traditional sources of natural bioactive compounds for many centuries and have been targeted as promising therapeutic agents. Many novel biologically active compounds have been reported as a result of research on medicinal mushrooms. In this review, we compile the information on bioactive structure-elucidated metabolites from macrofungi discovered over the last decade and highlight their unique chemical diversity and potential benefits to novel drug discovery. The main emphasis is on their anti-Alzheimer, antidiabetic, anti-malarial, anti-microbial, anti-oxidant, antitumor, anti-viral and hypocholesterolemic activities which are important medicinal targets in terms of drug discovery today. Moreover, the reader’s attention is brought to focus on mushroom products and food supplements available in the market with claimed biological activities and potential human health benefits. Keywords: Medicinal mushrooms. Anti-oxidant . Anti-tumor . Anti-HIV . Anti-microbial . Anti-viral . Hypocholesterolemic . Anti-diabetic . Anti-Alzheimer . Anti-malarial . Food supplements
    Fungal diversity 09/2013; 62(1):1-40. DOI:10.1007/s13225-013-0265-2 · 6.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Most oncology compounds entering clinical development have passed stringent preclinical pharmacology evaluation criteria. However, only a small fraction of experimental agents induce meaningful antitumor activities in the clinic. Low predictability of conventional preclinical pharmacology models is frequently cited as a main reason for the unusually high clinical attrition rates of therapeutic compounds in oncology. Therefore, improvement in the predictive values of preclinical efficacy models for clinical outcome holds great promise to reduce the clinical attrition rates of experimental compounds. Recent reports suggest that pharmacology studies conducted with patient derived xenograft (PDX) tumors are more predictive for clinical outcome compared to conventional, cell line derived xenograft (CDX) models, in particular when therapeutic compounds were tested at clinically relevant doses (CRDs). Moreover, the study of the most malignant cell types within tumors, the tumor initiating cells (TICs), relies on the availability of preclinical models that mimic the lineage hierarchy of cells within tumors. PDX models were shown to more closely recapitulate the heterogeneity of patient tumors and maintain the molecular, genetic, and histological complexity of human tumors during early stages of sequential passaging in mice, rendering them ideal tools to study the responses of TICs, tumor- and stromal cells to therapeutic intervention. In this commentary, we review the progress made in the development of PDX models in key areas of oncology research, including target identification and validation, tumor indication search and the development of a biomarker hypothesis that can be tested in the clinic to identify patients that will benefit most from therapeutic intervention.
    Biochemical Pharmacology 06/2014; 91(2). DOI:10.1016/j.bcp.2014.06.008 · 5.01 Impact Factor
Show more