Phase I clinical and pharmacokinetic trial of irofulven

Thomas, James P.; Arzoomanian, Rhoda Z.; Alberti, Dona; Feierabend, Chris; Binger, Kimberly; Tutsch, Kendra D.; Steele, Thomas E.; Marnocha, Rebecca; Smith, Christopher B.; Smith, Sheri L.; MacDonald, John R.; Wilding, George; Bailey, Howard

doi:10.1007/s002800100365

Cited by 17 publications

(9 citation statements)

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“…Thus, the recommended dose for the phase II clinical trials was 6 mg/m 2 . 28 HMAF was taken into phase I clinical studies in patients with primary refractory or relapsed acute myeloid leukemia, acute lymphocytic leukemia, or myelodysplastic syndromes, and the toxicity profile and activity of the drug were investigated. 274 It was given as a 5 min intravenous infusion daily for 5 days with the starting dose of 10 mg/m 2 /day (50 mg/m 2 /course).…”

Section: Population Pharmacokinetics and Phase I Clinical Trialsmentioning

confidence: 99%

Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Tanasova

Sturla

2012

Chem. Rev.

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Section: Population Pharmacokinetics and Phase I Clinical Trialsmentioning

confidence: 99%

Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Tanasova

Sturla

2012

Chem. Rev.

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“…Although many illudins are highly effective against various drug-resistant tumours both in vivo and in vitro, the extreme cytotoxicity of these compounds in the nanomolar range has severely restricted their practical use in cancer therapy [2,3]. Recently semisynthetic derivatives have been reported [4] with a strongly improved therapeutic index [2,5,6] of which hydroxymethylacylfulvene (HMAF, Irofulven) is currently under clinical trial [7,8]. The tissue specificity and tumour selectivity of the illudins has been attributed to the presence of an energy-dependent system mediating transport into the cells [9] and subsequent metabolic activation to an unknown reactive intermediate [10].…”

Section: Introductionmentioning

confidence: 99%

Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways

et al. 2002

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Illudin S is a natural sesquiterpene drug with strong anti-tumour activity. Inside cells, unstable active metabolites of illudin cause the formation of as yet poorly characterised DNA lesions. In order to identify factors involved in their repair, we have performed a detailed genetic survey of repair-defective mutants for responses to the drug. We show that 90% of illudin's lethal effects in human fibroblasts can be prevented by an active nucleotide excision repair (NER) system. Core NER enzymes XPA, XPF, XPG, and TFIIH are essential for recovery. However, the presence of global NER initiators XPC, HR23A/HR23B and XPE is not required, whereas survival, repair and recovery from transcription inhibition critically depend on CSA, CSB and UVS, the factors specific for transcription-coupled NER. Base excision repair and non-homologous end-joining of DNA breaks do not play a major role in the processing of illudin lesions. However, active RAD18 is required for optimal cell survival, indicating that the lesions also block replication forks, eliciting post-replication-repair-like responses. However, the translesion-polymerase DNA pol eta is not involved. We conclude that illudin-induced lesions are exceptional in that they appear to be ignored by all of the known global repair systems, and can only be repaired when trapped in stalled replication or transcription complexes. We show that the semisynthetic illudin derivative hydroxymethylacylfulvene (HMAF, Irofulven), currently under clinical trial for anti-tumour therapy, acts via the same mechanism.

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“…Additionally, primary colony formation was inhibited 68 and 62% in cultures at 0.1 µg/ml irofulven exposures for 1 h or continuously for 14 days, respectively. These results may be clinically relevant, as irofulven plasma concentrations ranging from 0.01 and 0.1 µg/ml have been shown to be achievable in cancer patients ( 48 ) . Irofulven also indicated superior activity in comparison with paclitaxel when tested using 1‐h exposure times against the same tumor specimens, 91 versus 45% responses, respectively.…”

Section: Discussionmentioning

confidence: 92%

Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts

Laar¹,

Izbicka

Weitman

et al. 2004

Int J Gynecol Cancer

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The objective of this study was to investigate the cytotoxic activity of irofulven (HMAF, MGI 114), a unique chemotherapeutic agent currently under clinical investigation, in various preclinical models of ovarian cancer. Antiproliferative effects of irofulven in ovarian cancer cell lines and ovarian tumor specimens were characterized in vitro using sulforhodamine B and human tumor colony-forming assays, respectively. Irofulven demonstrated marked activity against a panel of ovarian tumor cell lines, including IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, and SK-OV-3, all of which exhibit various drug resistance mechanisms. In human tumor cloning assays, irofulven inhibited colony formation in surgically derived ovarian tumors at concentrations as low as 0.001 micro g /ml and indicated superior activity in comparison with paclitaxel when tested against the same tumor specimens. The antitumor activity of irofulven compared to that of paclitaxel was also examined using the SK-OV-3 xenograft model. In mice bearing subcutaneously implanted SK-OV-3 tumors, treatment with paclitaxel failed to inhibit tumor growth; whereas mice treated with maximum tolerated doses of irofulven had a 25% partial shrinkage rate, and the remaining animals had a mean tumor growth inhibition of 82%. The potent activity of irofulven against ovarian tumors in vitro and in vivo supports the evaluation of its clinical activity in ovarian cancer.

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Phase I clinical and pharmacokinetic trial of irofulven

Abstract: The recommended phase II dose on this schedule is 6 mg/m2.

Cited by 17 publications

References 0 publications

Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Anti-tumour compounds illudin S and Irofulven induce DNA lesions ignored by global repair and exclusively processed by transcription- and replication-coupled repair pathways

Antitumor activity of irofulven against human ovarian cancer cell lines, human tumor colony-forming units, and xenografts

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