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.
BACKGROUND: DNA-damaging agents are widely used for the treatment of humanmalignancies. 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: Colin Charles Tièche; Ren-Wang Peng; Patrick Dorn; Laurène Froment; Ralph Alexander Schmid; Thomas Michael Marti Journal: BMC Cancer Date: 2016-02-19 Impact factor: 4.430
Authors: Darya Karatkevich; Haibin Deng; Yanyun Gao; Emilio Flint; Ren-Wang Peng; Ralph Alexander Schmid; Patrick Dorn; Thomas Michael Marti Journal: Int J Mol Sci Date: 2022-10-08 Impact factor: 6.208