(-)-Irofulven

(-)-Irofulven (MGI 114), an Illudin S analog, is a DNA alkylating agent. (-)-Irofulven inhibits the replication of DNA, induces tumor cells apoptosis, and has potent antitumor activity[1][2].

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA Alkylator/Crosslinker

(-)-Irofulven (2.8 μM; 1 hour) induces p53-dependent cell cycle arrest[1]. (-)-Irofulven (0.8 μM, 0.9 μM and 2.8 μM; 1 hour) induces CHK2 activation is related to p53 status in cells[1]. (-)-Irofulven inhibits DNA replication and induces chromosome aberrations (breaks and radials)[1]. Cell Cycle Analysis[1] Cell Line: A2780, CAOV3 and HCT116 cells Concentration: 2.8 μM Incubation Time: 1 hour Result: p53 wild-type cells mainly arrested at G1/S phases, while p53-mutated or p53-null cells arrested at S and G2/M phases. Western Blot Analysis[1] Cell Line: A2780, CAOV3 and HCT116 cells Concentration: 0.8 μM, 0.9 μM and 2.8 μM Incubation Time: 1 hour Result: Induced the Thr 68 phosphorylation of CHK2 kinase in cells.

(-)-Irofulven (7 mg/kg; i.p; on days 1-5 and 8-12) produces a statistically significant increase in the median survival of mice bearing tumor cells[2]. Animal Model: Male and female athymic BALB/c mice (nu/nu genotype, 6 weeks old or older) injected with human glioblastoma multiforme[2]. Dosage: 7 mg/kg Administration: i.p; on days 1-5 and 8-12 Result: Was active against all tumor lines.

[1]. Yutian Wang, et al. Irofulven induces replication-dependent CHK2 activation related to p53 status. Biochem Pharmacol. 2007 Feb 15;73(4):469-80.

[2]. H S Friedman, et al. Activity of irofulven (6-hydroxymethylacylfulvene) in the treatment of glioblastoma multiforme-derived xenografts in athymic mice. Cancer Chemother Pharmacol. 2001 Nov;48(5):413-6.

MOLECULAR FORMULA :

C15-H18-O3

MOLECULAR WEIGHT :

246.33

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD - Lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

>6610 ug/kg

TOXIC EFFECTS :

Cardiac - other changes Blood - changes in bone marrow (not otherwise specified) Blood - changes in other cell count (unspecified)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 36(1, Pt 2),180,1997

TYPE OF TEST :

LDLo - Lowest published lethal dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

2 mg/kg

TOXIC EFFECTS :

Blood - thrombocytopenia Blood - changes in bone marrow (not otherwise specified) Blood - changes in other cell count (unspecified)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 36(1, Pt 2),180,1997 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

20339 ug/kg/5D-I

TOXIC EFFECTS :

Cardiac - other changes Blood - changes in bone marrow (not otherwise specified) Blood - changes in other cell count (unspecified)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 36(1, Pt 2),180,1997

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

3 mg/kg/5D-I

TOXIC EFFECTS :

Blood - thrombocytopenia Blood - changes in bone marrow (not otherwise specified) Blood - changes in other cell count (unspecified)

REFERENCE :

FAATDF Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1981- Volume(issue)/page/year: 36(1, Pt 2),180,1997