Antitumor efficacy and molecular mechanism of TLK58747, a novel DNA-alkylating prodrug.

Abstract

BACKGROUND:

DNA-damaging agents are widely used for the treatment of human malignancies. Agents containing the multifunctional alkylating moiety tetrakis(2-chloroethyl)phosphorodiamidic acid are currently under development as cancer therapeutics.

MATERIALS AND METHODS:

TLK58747, a phophorodiamidate-based prodrug, was tested in vivo for antitumor efficacy and safety. The in vitro responses of tumor cells to TLK58747 were examined by cytotoxicity assays, cell cycle analysis, immunoblots and microscopy.

RESULTS:

TLK58747 was efficacious in xenograft models of human breast, pancreas, and prostate cancer, as well as in leukemia and glioma. It caused less bone marrow suppression in rats than did cyclophosphamide. In vitro, TLK58747 inhibited the growth of a wide variety of cancer cells and activated the DNA damage-response pathway, leading to G(2)/M cell cycle arrest and subsequent premature senescence or apoptosis.

CONCLUSION:

TLK58747 is a promising new alkylating agent with broad antitumor activity and superior safety that warrants further development.

• Authors: Hua Xu, Zhuo Wang, John C Donaldson, Hong Yao, Siqun Zhou, Andrew B Kelson, Wenli Ma, Kevin T Weber, Edgardo Laborde, Mingshan Cheng, Lidia Sambucetti, James G Keck
• Journal: Anticancer research (Anticancer Res) Vol. 29 Issue 10 Pg. 3845-55 (Oct 2009) ISSN: 1791-7530 [Electronic] Greece
• PMID: 19846918 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents, Alkylating
• DNA, Neoplasm
• Organophosphorus Compounds
• Prodrugs
• TLK58747

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology, toxicity)
• Cell Division (drug effects)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• DNA Damage
• DNA, Neoplasm (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• G2 Phase (drug effects)
• HL-60 Cells
• Humans
• Male
• Mice
• Neoplasms (drug therapy, genetics, pathology)
• Organophosphorus Compounds (pharmacology, toxicity)
• Prodrugs (pharmacology, toxicity)
• Rats
• Rats, Sprague-Dawley
• Xenograft Model Antitumor Assays