Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors.
Structurally diverse histone deacetylase inhibitors (HDACI) have emerged as chemotherapeutic agents. Here, we report the first mercaptoacetamide HDACIs (coded 6MAQH and 5MABMA) for use in treatment against prostate cancer cells in vitro and in vivo and correlate their plasma pharmacokinetics and tissue-pharmacodynamics with tumor sensitivity. HDACIs were assessed for in vitro microsomal stability and growth inhibition against prostate cancer and nonmalignant cells. Antitumor activity was determined following i.p. administration of 6MAQH and 5MABMA (0.5 and 5 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). The plasma pharmacokinetics of 6MAQH and 5MABMA and their effects on the acetylation of histone H4 in tissues were determined in athymic mice. Both HDACIs significantly inhibited the growth of cancer cells while exerting limited effect on nonmalignant cells. They exhibited stability in human, dog, and rat microsomes [t(1/2 (min)) = 83, 72, and 66 for 6MAQH and 68, 43, and 70 for 5MABMA, respectively]. Both HDACIs (0.5 mg/Kg) led to tumor regression (P < 0.01), which was sustained for at least 60 days. In vivo data show favorable plasma pharmacokinetics with the area under the curve of 4.97 +/- 0.6 micromol/L x h for 6MAQH and 4.23 +/- 0.43 micromol/L x h for 5MABMA. The clearance rates for 6MAQH and 5MABMA were 4.05 +/- 0.15 and 4.87 +/- 0.2 L/h, whereas the half-lives were 2.2 +/- 0.33 and 1.98 +/- 0.21 h, respectively. Both HDACIs markedly enhanced the acetylation of histone H4 within 30 minutes in tissues, including the brain, liver, and spleen. Taken together, the results provide a rationale for further investigation of these mercaptoacetamide HDACIs as potent anticancer agents.
Division of Radiation Biology, Department of Radiation Medicine, The Research Building, Room E-211, Georgetown University School of Medicine, Box 571482, 3970 Reservoir Road, Northwest, Washington, DC 20057-1482, USA.
Zacharoula
Z
Konsoula
Hong
H
Cao
Alfredo
A
Velena
Mira
M
Jung
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D011471:Prostatic Neoplasms / Q000473:pathology; D051381:Rats; D013864:Thioglycolates / Q000494:pharmacology*; D013997:Time Factors
D000081:Acetamides; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D013864:Thioglycolates