Pharmacology and toxicology of the novel investigational agent Cantrixil (TRX-E-002-1).

Abstract

PURPOSE:

Recurrent, chemo-resistant ovarian cancer is thought to be due to a subgroup of slow-growing, drug-resistant cancer cells with stem-like properties and a high capacity for tumour repair. Cantrixil targets this sub-population of cells and is being developed as an intraperitoneal therapy to be used as first-line therapy in combination with carboplatin for epithelial ovarian cancer. The studies presented here justify further development.

METHODS:

A GLP dog CV study using a 4 × 4 Latin Square Crossover study was conducted using telemetric ECG recordings from dogs post IP administration to assess for cardiac abnormalities. Mutagenic potential was assessed using the bacterial reverse mutation assay. Clastogenicity was assessed by determining micronuclei formation in the bone marrow of SPF Arc(S) Swiss mice dosed at clinical concentrations. TRX-E-002-1 toxicology was evaluated in GLP-compliant MTD and 28-day repeat-dose studies in rats and dogs.

RESULTS:

In vitro TRX-E-002-1 has potent cytotoxic activity against human cancer cells including CD44+/MyD88+ ovarian cancer stem cells. TRX-E-002-1 increased phosphorylated c-Jun levels in these cancer cells resulting in caspase-mediated apoptosis. In vivo, Cantrixil was active in a model of disseminated ovarian cancer as a monotherapy and in combination with Cisplatin. Cantrixil was active as maintenance therapy in a model of drug-resistant, recurrent ovarian cancer and in an orthotopic model of pancreatic cancer.

CONCLUSIONS:

In animals, this clinical formulation and route of administration of Cantrixil demonstrated acceptable activity, safety pharmacology, genotoxicity and toxicology profile and constituted a successful Investigational New Drug application to the US Food and Drug Administration.

• Authors: Muhammad Wasif Saif, Andrew Heaton, Kimberley Lilischkis, James Garner, David M Brown
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 79 Issue 2 Pg. 303-314 (02 2017) ISSN: 1432-0843 [Electronic] Germany
• PMID: 28013349 (Publication Type: Journal Article, Review, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(para-hydroxyphenyl)-7,4'-dihydroxy-3',5'-dimethoxy-8-methylisoflavan
• Antineoplastic Agents
• Benzopyrans
• Flavonoids

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Benzopyrans (pharmacokinetics, pharmacology, toxicity)
• Cell Line, Tumor
• Cross-Over Studies
• Dogs
• Drug Interactions
• Flavonoids (pharmacokinetics, pharmacology, toxicity)
• Humans
• Mice
• Rats
• Species Specificity