Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan

Kelner, Michael J.; McMorris, Trevor C.; Estes, Leita A.; Samson, Kyra M.; Trani, Nicole A.; MacDonald, John R.

doi:10.1038/sj.leu.2401611

Cited by 21 publications

(13 citation statements)

References 19 publications

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“…All three of these RNR inhibiting agents did display additive interaction, suggesting that RNR inhibition may contribute to the phenomena, but would not solely explain the beneficial interaction noted with these other agents. Instead, the synergistic interaction noted with cytidine-derived agents (such as gemcitabine) may be related to their associated ability to induce topoisomerase I cleavage complexes [63,64], as previous studies have demonstrated a strong synergistic interaction in vitro and in vivo between irofulven and topoisomerase I inhibiting agents [31][32][33]38].…”

Section: Discussionmentioning

confidence: 99%

“…The MV522 lung carcinoma xenograft model was chosen to allow comparison to previous in vitro and xenograft studies [33][34][35][36]44], and because this model is resistant to treatment with a variety of conventional and experimental agents [45]. Here we present evidence that irofulven interacts synergistically both in vitro and in vivo with a variety of other anticancer agents.…”

Section: Introductionmentioning

confidence: 86%

“…While irofulven has displayed impressive single-agent activity in recent clinical trials, notably against hepatocellular and taxotere-refractory prostate cancer [28][29][30], a number of preclinical studies have described enhanced antitumor activity when the drug was combined with other agents. A strong synergistic activity is noted between irofulven and topoisomerase I inhibitors, taxanes, platinum-derived agents, and 5-fluorouracil (5FU) [31][32][33][34][35][36][37][38][39]. Preliminary reports of clinical studies administering irofulven in combination with other agents suggest that this approach can result in clinical responses with acceptable toxicity in the majority of patients [40][41][42][43].…”

Section: Introductionmentioning

confidence: 99%

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Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil

et al. 2008

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The novel agent Irofulven (HMAF, NSC 683863) has demonstrated significant antitumor activity against solid tumors in various xenograft models and human clinical trials. The antitumor potential of combining irofulven with 72 different anti-metabolite, enzyme inhibiting, and miscellaneous agents was investigated in this study. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with these different agents. Irofulven in combination with select anti-metabolites, notably cytidine or adenine-derived agents, displayed strong synergistic activity in both in vitro and in vivo studies. Agents demonstrating strong synergistic interaction with irofulven included gemcitabine, cyclocytidine, cytarabine, fludarabine phosphate, cladribine, and 5-fluorouracil. Other anti-metabolites, enzyme inhibitors, and a variety of miscellaneous agents failed to interact beneficially when administered in combination with irofulven. The therapeutic activity of irofulven is enhanced considerably when irofulven is combined with select anti-metabolite agents, and further clinical evaluation of these combinations is warranted. The synergistic interaction with these combinations may stem from a variety of actions including inhibition of the nucleotide excision repair (NER) pathway, topoisomerase I activity, and caspase-dependent and independent induction of apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

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Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil

et al. 2008

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“…Sesquiterpenes from basidiomycetes produce a rich variation of activities as well. It is worthy to point out that HMAF based on illudane sesquiterpenes from the basidiomycete Clitocybe illudens is now in the clinical trial II phase and promises to become an antitumor drug [1]. Inspired by the potential biological activities of different sesquiterpenes from basiodiomycetes, our group focused on sesquiterpene metabolites from higher fungi, and also reported numerous novel sesquiterpenes.…”

Section: Introductionmentioning

confidence: 99%

New triquinane and gymnomitrane sesquiterpenes from fermentation of the basidiomycete Antrodiella albocinnamomea

Chen

Wang

et al. 2015

Fitoterapia

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“…Thiol attack appears to be rate-determining and is directed by substitute-dents present at C (11). Specifically, the facial selectivity of thiol attack on 1 is controlled thus.…”

mentioning

confidence: 99%

Ab Initio Structure/Reactivity Investigations of Illudin‐Based Antitumor Agents: A Model for Reaction in vivo

Gregerson¹,

McMorris²,

Siegel³

et al. 2003

Helvetica Chimica Acta

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This and the companion paper are dedicated to Professor Duilio Arigoni on the occasion of his 75th birthday.His work on the structures of natural products and the mechanisms and stereochemistry of biochemical processes strongly influences our course of study. Non scholae sed vitae discumus.(Hydroxymethyl)acylfulvene (HMAF, irofulven; 4), a third-generation derivative of a natural product extracted from the mushroom Omphalotus illudens, is selectively toxic towards certain forms of malignant tumors. Conversion of HMAF and cognates to stable aromatic derivatives is triggered by thiol attack in vitro and in vivo. Quantum-chemical methods predict well the structure for several functionalized derivatives of irofulven as compared to known X-ray crystallographic structures. Computational reaction profiles for thiol attack and aromatic rearrangement of irofulven and illudin S, a toxin from which irofulven is derived, provide insight into HMAF×s selectivity and toxicity. Methods used include hybrid density-functional theory (HDFT), HartreeÀFock (HF), and M˘llerÀPlesset second-order perturbation theory (MP2). Solvent effects have been explored by means of the new continuum-solvation method, COSab, presented in an accompanying paper.

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Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with topotecan

Cited by 21 publications

References 19 publications

Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil

Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil

New triquinane and gymnomitrane sesquiterpenes from fermentation of the basidiomycete Antrodiella albocinnamomea

Ab Initio Structure/Reactivity Investigations of Illudin‐Based Antitumor Agents: A Model for Reaction in vivo

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