A novel hydroxamic acid compound, BMD188, demonstrates anti-prostate cancer effects by inducing apoptosis. II: In vivo efficacy and pharmacokinetic studies.
BACKGROUND
In the preceding paper, we demonstrated that, BMD188 [cis-1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one], a newly synthesized cyclic hydroxamic acid compound, induces potent apoptotic death of prostate cancer cells in vitro. In this project, we studied the in vivo pharmacokinetic behavior and anti-tumor efficacy of this novel compound.


METHODS
A bioavailability/elimination study was first performed using radiolabeled BMD188 administered to rats through intraperitoneal (i.p.), intravenous (i.v). or oral (p.o.) routes. Based on these pharmacokinetic data as well as pilot experiments on in vivo toxicity, two sets of efficacy studies, with i.p. administered BMD188, were performed in SCID mice or athymic nude mice which had been orthotopically transplanted with Du145 human prostate cancer cells. Tumor growth rate was measured and the final tumor weights and sizes determined. Subsequently, histopathological data were obtained and tumor tissue sections were used for apoptosis (i.e., TUNEL) staining.


RESULTS
The pharmacokinetic studies revealed low (approximately 8%) absorption through the p.o. route and high (approximately 70%) absorption through the i.p. route. The average plasma half life (T1/2) of BMD188 was approximately 50 h. Post-absorption, plasma elimination of radioactivity was similar to that in animals given [3H]-188 intravenously. The in vivo efficacy results indicate that i.p. administered BMD188 significantly inhibited the primary growth and local invasion of Du145 prostate cancer cells orthotopically implanted into SCID or athymic nude mice. The tumor-inhibitory effect of BMD188 was due to apoptosis induction in vivo, as revealed by histological analysis as well as TUNEL staining of the tumor tissue sections.


CONCLUSIONS
Collectively, the preceding in vitro and the current in vivo studies suggest that BMD188 and its analogs may find clinical applications in the treatment of prostate cancer patients by inducing apoptotic death of prostate cancer cells.
Li
L
L
Biomide Laboratories, Wayne State University, Detroit, MI 48202, USA.
Zhu
Z
Z
Joshi
B
B
Zhang
C
C
Johnson
C R
CR
Marnett
L J
LJ
Honn
K V
KV
Crissman
J D
JD
Porter
A T
AT
Tang
D G
DG
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010881:Piperidones / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014407:Tumor Cells, Cultured
C117140:1-hydroxy-4-(1-naphthyl)-6-octylpiperidine-2-one; D000970:Antineoplastic Agents; D006877:Hydroxamic Acids; D010881:Piperidones