Chemical and clinical development of darinaparsin, a novel organic arsenic derivative.
The inorganic arsenic derivative arsenic trioxide (ATO) has proven to be highly efficacious in patients with acute promyelocytic leukemia (APL) and has been associated with complete cytogenetic response in most treated patients diagnosed with this disease. This is due to ATO's direct effect on PML-RARalpha oncoprotein patognomonic for APL. ATO has shown moderate activity against certain other hematologic and solid organ malignancies but is also associated with significant toxicities, especially when used at higher doses. The development of orally bioavailable organic arsenic derivatives (OAD) offering improved toxicity profiles and better efficacy may expand the use of arsenic derivatives in hematologic malignancies and solid tumors. The favorable in vivo carcinostatic activity of S-dimethylarsino-thioglucose, the first OAD synthesized in murine leukemia models by our group in 1975, set the stage for our efforts to develop OADs. Unfortunately, the program remained dormant for almost two decades. The success of ATO in APL in the late 1990s re-ignited the interest in the use of OADs in cancer chemotherapy. This review describes the chemical development of OADs and summarizes the clinical development of a promising lead compound, Darinaparsin (ZIO-101; SGLU; S-dimethylarsino-glutathione), for the treatment of a variety of cancers.
Quintás-Cardama
Alfonso
A
Department of Chemistry, Texas A&M University, College Station, TX 77842-3012, USA.
Verstovsek
Srdan
S
Freireich
Emil
E
Kantarjian
Hagop
H
Chen
Yi Wen
YW
Zingaro
Ralph
R
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001152:Arsenicals / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D005978:Glutathione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D051379:Mice
D000970:Antineoplastic Agents; D001152:Arsenicals; C515055:darinaparsin; D005978:Glutathione