title: Activity of pivaloyloxymethyl butyrate, a novel anticancer agent, on primary human tumor colony-forming units.
abstract: The anti-proliferative effects of pivaloyloxymethyl butyrate (AN-9), a butyric acid (BA) derivative with potent tumor-differentiating properties both in vitro and in vivo, was evaluated against colorectal, breast, lung, ovarian, renal cell, bladder, and other types of tumor colony-forming units in a human tumor cloning assay. A total of 76 evaluable specimens were exposed to AN-9 continuously, 48 of these were also exposed to BA continuously for direct comparison of the two agents, and 20 specimens were exposed to AN-9 for two hours. An in vitro inhibitory response was defined as a > or = 50% decrease in tumor colony formation in treated cells compared to untreated controls. Superior anti-tumor activity was observed with the continuous exposure to AN-9 (39% in vitro response at 100 microM and 70% at 200 microM) than with the two-hour exposure (20% at 100 microM and 25% at 200 microM). At a continuous concentration of 200 microM, AN-9 demonstrated greater tumor-specific activity than BA against melanoma (100% vs. 67%), ovarian (67% vs. 40%), breast (63% vs. 0%), non-small cell lung (60% vs. 10%), and colorectal tumor colony-forming units (62% vs. 20%). AN-9 is a novel differentiating agent with activity against colony-forming units derived from a variety of primary human tumors, including those that are considered relatively chemoresistant, and may thus provide a therapeutic alternative or addition to standard cytotoxic agents, if appropriate drug concentrations can be achieved in patients.
authors.affiliation: Cancer Therapy Research Center, San Antonio, Texas 78229, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Siu
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: A
authors.initials: A
authors.lastname: Rephaeli
authors.forename: E
authors.initials: E
authors.lastname: Izbicka
authors.forename: C
authors.initials: C
authors.lastname: Cerna
authors.forename: L
authors.initials: L
authors.lastname: Gomez
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002087:Butyrates / Q000008:administration & dosage / Q000494:pharmacology*; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015507:Drugs, Investigational / Q000494:pharmacology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D015507:Drugs, Investigational; C070441:pivalyloxymethyl butyrate