Differential cytotoxicity and induction of apoptosis in tumor and normal cells by hydroxymethylacylfulvene (HMAF)∗

Woynarowska, Barbara; Woynarowski, Jan M.; Herzig, Maryanne C.; Roberts, K. B.; Higdon, Arlene L.; MacDonald, John R.

doi:10.1016/s0006-2952(00)00254-9

Cited by 54 publications

(50 citation statements)

References 29 publications

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“…Previous reports suggest that for the precursor illudins preferential killing of tumor cells could result from increased cellular transport (Kelner et al, 1990); however, for HMAF preferential accumulation did not significantly account for enhanced toxicity in PC-3 and HT-29 cells (Woynarowska et al, 2000). Furthermore, microarray studies regarding cellular responses to D3T or resveratrol have failed to implicate alterations in membrane transport (Kwak et al, 2003;Whyte et al, 2007).…”

Section: Human Ptgr1 Activates Acylfulvenes and Improves Efficacy 431mentioning

confidence: 93%

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Xiang

Erzinger

Pietsch

et al. 2012

J Pharmacol Exp Ther

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Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. Previous studies demonstrated the role of rat PTGR1 in the activation of acylfulvene analogs, a class of antitumor natural product derivatives. Of these, hydroxymethylacylfulvene (HMAF) was in advanced clinical development for the treatment of advanced solid tumors, including prostate, ovarian, and pancreatic cancers. However, the efficiency of human PTGR1 in activating acylfulvenes and its potential to enhance therapeutic efficacy have remained uncharacterized. In this study, human PTGR1 was polymerase chain reaction-cloned and purified. Conversion of HMAF to its cellular metabolite by the purified enzyme proceeded at a 20-fold higher rate than with the rat variant of the enzyme. The K m was 4.9 M, which was 40-fold lower than for the rat variant and similar to the therapeutic dose. Human cell lines, including colon cancer lines, were transfected with a vector containing rat PTGR1 or human PTGR1, and cell viability was examined after dosing with HMAF. New data obtained in this study suggest that transfection with human PTGR1, or its induction in colon and liver cancer cell lines with 1,2-dithiol-3-thione, enhances susceptibility to the cytotoxic influences of HMAF by 2-to 10-fold. Furthermore, similar or enhanced enzyme induction and HMAF toxicity results from preconditioning cancer cells with the bioactive food components curcumin and resveratrol. The functional impact of PTGR1 induction in human cells and chemical-based strategies for its activation can provide important knowledge for the design of clinical strategies involving reductively activated cytotoxic chemotherapeutics.

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Section: Human Ptgr1 Activates Acylfulvenes and Improves Efficacy 431mentioning

confidence: 93%

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Xiang

Erzinger

Pietsch

et al. 2012

J Pharmacol Exp Ther

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“…Categorical variables were compared using the 2 or Fisher exact test, as appropriate. The correlation between continuous variables was determined using Spearman's .…”

Section: Methodsmentioning

confidence: 99%

“…Irofulven (6-hydroxymethylacylfulvene, MGI-114, HMAF; MGI PHARMA, Inc., Bloomington, MN) is a novel semisynthetic derivative of illudin S. Irofulven binds covalently to DNA and other macromolecules, resulting in the inhibition of DNA synthesis and eventual apoptosis (1)(2)(3)(4). In addition to direct effects on DNA, irofulven also induces protein oxidation and mitochondrial dysfunction (2,5).…”

Section: Introductionmentioning

confidence: 99%

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Characterization and Multiparameter Analysis of Visual Adverse Events in Irofulven Single-Agent Phase I and II Trials

Raymond

Kahatt²,

Rigolet

et al. 2004

Clinical Cancer Research

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Purpose: Irofulven (6-hydroxymethylacylfulvene) is a novel agent, derived from illudin S, with potent apoptotic effects in preclinical models. In the Phase I trial evaluating intermittent weekly schedules, visual symptoms were dose limiting. The aim of this analysis was to better characterize the visual adverse events of irofulven and provide treatment guidelines.Experimental Design: Clinical data from 277 patients entered in single-agent Phase I to II clinical trials who received irofulven on days 1 and 15 every 4 weeks; days 1, 8, and 15 every 4 weeks; or days 1 and 8 every 3 weeks were included in this multiparameter analysis.Results: Overall, 74 patients (27%) experienced visual symptoms. The most frequently reported symptoms were flashing lights (12% of patients), blurred vision (9%), and photosensitivity (8%). Grade 3 toxicity was observed in 12 patients (4%). The incidence and severity of visual events were dose dependent, with no grade 3 visual events occurring at doses <0.50 mg/kg and grade 1 to 2 events in only 12% and 8% of patients, at doses of <0.50 mg/kg and <20 mg/m 2 , respectively. Grade 1 to 2 toxicity was reversible in most patients. Abnormal electroretinogram and abnormal visual fields were noted after irofulven treatment in 24 of 39 patients (62%) and 15 of 26 patients (58%), respectively. All but 1 patient who had electroretinogram assessment received doses >0.50 mg/kg. Clinical examination and visual field assessment were found to be better correlated with symptoms and appear to be more appropriate for surveillance of irofulven retinal symptoms than electroretinograms. Conclusions: On the basis of retained antitumor activity and reversibility of grade 1 and 2 visual symptoms at lower doses, it appears that an irofulven dose of <0.50 mg/kg or <20 mg/m 2 , not to exceed 50 mg in a single dose, given as a 30-minute infusion on days 1 and 8 every 3 weeks or days 1 and 15 every 4 weeks minimizes the frequency and severity of visual symptoms.

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“…This cytotoxic agent is a potent inhibitor of DNA synthesis; its mechanism of action involves rapid uptake by sensitive tumor cell types, cell cycle arrest in S phase and induction of caspase-mediated apoptosis [1][2][3][4]. In addition to direct effects on DNA, irofulven also induces protein oxidation and mitochondrial dysfunction [4,5]. Potent growth inhibition is observed against a wide variety of human solid tumor cell lines and primary tumor cell types, and activity is retained in tumor types which have multidrug resistance to conventional therapies [1,[6][7][8].…”

Section: Introductionmentioning

confidence: 99%

A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors

Alexandre

Kahatt²,

Bertheault-Cvitkovic

et al. 2007

Invest New Drugs

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Differential cytotoxicity and induction of apoptosis in tumor and normal cells by hydroxymethylacylfulvene (HMAF)∗

Cited by 54 publications

References 29 publications

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Characterization and Multiparameter Analysis of Visual Adverse Events in Irofulven Single-Agent Phase I and II Trials

A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors

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