Pharmacokinetics and antitumor properties in tumor-bearing mice of an enediol analogue inhibitor of glyoxalase I.
OBJECTIVE
The enediol analogue S-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione (CHG) is a powerful, mechanism-based, competitive inhibitor of the methylglyoxal-detoxifying enzyme glyoxalase I. The [glycyl,glutamyl]diethyl ester prodrug form of this compound (CHG(Et)2) inhibits the growth of different tumor cell lines in vitro, apparently by inducing elevated levels of intracellular methylglyoxal. The purpose of this study was to evaluate the pharmacokinetic properties of CHG(Et)2 in plasma esterase-deficient C57BL/6 (Es-1e) mice after intravenous (i.v.) or intraperitoneal (i.p.) administration of bolus doses of CHG(Et)2. In addition, the in vivo antitumor properties of CHG(Et)2 were evaluated against murine B16 melanoma in these mice, and against androgen-independent human prostate PC3 tumor and human colon HT-29 adenocarcinoma in plasma esterase-deficient nude mice.


METHODS
Pharmacokinetics were evaluated after either i.v. or i.p. administration of CHG(Et)2 at the maximally tolerated dose of 120 mg/kg to both tumor-free male and female mice and male and female mice bearing subcutaneous B16 tumors. Tissue concentrations of CHG(Et)2, CHG and the [glycyl]monoethyl ester CHG(Et) were measured as a function of time by reverse-phase C18 high-performance liquid chromatography of deproteinized tissue samples. The efficacy of CHG(Et)2 in tumor-bearing mice was evaluated after i.v. bolus administration of CHG(Et)2 at 80 or 120 mg/kg for 5 days each week for 2 weeks, or after 14 days continuous infusion of CHG(Et)2 using Alzet mini-osmotic pumps. Hydroxypropyl-beta-cyclodextrin was used as a vehicle in the efficacy studies.


RESULTS
Intravenous administration of CHG(Et)2 resulted in the rapid appearance of CHG(Et)2 in the plasma of tumor-bearing mice with a peak value of 40-60 microM, followed by a first-order decrease with a half-life of about 10 min. There was a corresponding increase in the concentration of inhibitory CHG in the B16 tumors, with a maximum concentration in the range 30-60 microM occurring at 15 min, followed by a decrease to a plateau value of about 6 microM after 120 min. Neither CHG(Et)2 nor its hydrolysis products were detectable in plasma, after i.p. administration of CHG(Et)2 to tumor-free female mice. From the efficacy studies, dosing schedules were identified that resulted in antitumor effects comparable to those observed with the standard antitumor agents Adriamycin (with B16 tumors), cisplatin (with PC3 tumors), and vincristine (with HT-29 tumors).


CONCLUSIONS
This is the first demonstration that a mechanism-based competitive inhibitor of glyoxalase I effectively inhibits the growth of solid tumors in mice when delivered as the diethyl ester prodrug.
Sharkey
E M
EM
Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore 21250, USA.
O'Neill
H B
HB
Kavarana
M J
MJ
Wang
H
H
Creighton
D J
DJ
Sentz
D L
DL
Eiseman
J L
JL
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004950:Esterases / Q000097:blood / Q000172:deficiency; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007791:Lactoylglutathione Lyase / Q000037:antagonists & inhibitors; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; C119215:S-(N-4-chlorophenyl-N-hydroxycarbamoyl)glutathione; D004950:Esterases; D007791:Lactoylglutathione Lyase; D005978:Glutathione