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


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.


CONCLUSIONS
TLK58747 is a promising new alkylating agent with broad antitumor activity and superior safety that warrants further development.
Xu
Hua
H
Telik, Inc., Palo Alto, CA 94304, USA.
Wang
Zhuo
Z
Donaldson
John C
JC
Yao
Hong
H
Zhou
Siqun
S
Kelson
Andrew B
AB
Ma
Wenli
W
Weber
Kevin T
KT
Laborde
Edgardo
E
Cheng
Mingshan
M
Sambucetti
Lidia
L
Keck
James G
JG
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D011355:Prodrugs / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D009943:Organophosphorus Compounds; D011355:Prodrugs; C545095:TLK58747