Irofulven or 6-hydroxymethylacylfulvene (also known as HMAF of MGI-114) is an experimental antitumor agent. It belongs to the family of

drugs A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via inhalat ...

called

alkylating agent Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting al ...

s. It inhibits the replication of DNA in cell culture. Irofulven is an analogue of illudin S, a

sesquiterpene Sesquiterpenes are a class of terpenes that consist of three isoprene units and often have the molecular formula C15H24. Like monoterpenes, sesquiterpenes may be cyclic or contain rings, including many unique combinations. Biochemical modificatio ...

toxin found in the Jack 'o' Lantern mushroom (''

Omphalotus illudens ''Omphalotus illudens'', commonly known as the eastern jack-o'lantern mushroom, is a large, orange mushroom that is often found in clumps on decaying stumps, buried roots, or at the base of hardwood trees in eastern North America. Its gills of ...

''). The compound was originally synthesized by Dr. Trevor McMorris and found to have anticancer properties in mice by Dr. Michael J Kelner. __TOC__

Licensing and Clinical development

The drug was created and patented by the

University of California The University of California (UC) is a public land-grant research university system in the U.S. state of California. The system is composed of the campuses at Berkeley, Davis, Irvine, Los Angeles, Merced, Riverside, San Diego, San Francisco, ...

, San Diego (UCSD), and subsequently licensed to the US biotech company MGI Pharma.

Eisai was a Japanese Buddhist priest, credited with founding the Rinzai school, the Japanese line of the Linji school of Zen Buddhism. In 1191, he introduced this Zen approach to Japan, following his trip to China from 1187 to 1191, during which he w ...

acquired MGI in 2007, and the license was returned to UCSD, which then re-licensed the potential cancer drug to Lantern Pharma in 2015. Soon after, the drug was again sub-licensed to Oncology Venture. The drug has undergone a number of clinical trials, mostly for late-stage tumors as well as ovarian and prostate cancers, usually preceded by treatment with

carboplatin Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used b ...

and

paclitaxel Paclitaxel (PTX), sold under the brand name Taxol among others, is a chemotherapy medication used to treat a number of types of cancer. This includes ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer ...

. A multi-center phase 2 trial involving patients with Recurrent or Persistent Ovarian Epithelial or Primary Peritoneal Cancer was well tolerated but irofluven demonstrated modest activity as a single agent. Previously, a European Phase I study in combination with

cisplatin Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, br ...

showed substantial evidence for anti-tumor activity. In that study, irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. Despite modest successes demonstrating limited efficacy for late stage tumors that were statistically not significant enough to support broader clinical trials, Oncology Venture has decided to stratify patient populations with companion diagnostic tools (

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

) to predict outcomes, and thus select that sub-set of patients through DRP (Drug Response Predictors), for whom treatment with irofulven would be most effective. Oncology Venture Sweden AB has initiated two Phase 2 drug-screening studies at two Danish University Hospitals for late-stage prostate cancers, wherein 300 patients have been included to be screened, of which only 15 are to be selected for the Phase 2 trial.

Synthesis

A synthesis of irofulven has been reported. :

References

{{reflist Experimental cancer drugs Cyclopropanes Diols Ketones Spiro compounds Terpenes and terpenoids