Brain distribution and efficacy as chemosensitizer of an oral formulation of PARP-1 inhibitor GPI 15427 in experimental models of CNS tumors.
We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors. Since the oral route has a number of advantages in terms of safety and convenience with respect to intravenous injection, in this study we tested whether administration per os of the novel PARP-1 inhibitor GPI 15427 allows sufficient absorption of the compound and achievement of brain concentrations capable of enhancing the efficacy of TMZ against tumors growing at the CNS. Pharmacokinetics analysis of GPI 15427 levels in plasma and brain was assessed in Sprague-Dawley rats after oral dosing, by liquid chromatography and tandem mass spectrometry. Antitumor activity of oral GPI 15427 in association with TMZ was evaluated in BD2F1 mice injected intracranially with B16 melanoma or L5178Y lymphoma. Pharmacokinetics studies revealed that GPI 15427 possesses a substantial oral bioavailability (plasma Cmax after a single dose of 40 mg/kg: 1041+/-516 ng/ml). Moreover, the brain levels and brain/plasma ratios of GPI 15427 (3.37 at 0.5 h and 3.19 at 1 h) indicated that the compound readily penetrates the blood-brain barrier. GPI 15427 (10 or 40 mg/kg/per os) was then administered for five days, 1 h before TMZ (100 mg/kg/i.p.), to tumor-bearing mice. The results indicated that GPI 15427+TMZ was well tolerated and significantly increased life-span of the animals with respect to TMZ. In conclusion, PARP-1 inhibitor GPI 15427 is efficacious as chemosensitizer for the treatment of tumors located at the CNS site when it is administered by oral route.
Tentori
Lucio
L
Department of Neuroscience, University of Rome 'Tor Vergata', I-00133 Rome, Italy. tentori@uniroma2.it
Leonetti
Carlo
C
Scarsella
Marco
M
Vergati
Matteo
M
Xu
Weizheng
W
Calvin
David
D
Morgan
Lisa
L
Tang
Zhaocheng
Z
Woznizk
Krystyna
K
Alemu
Christina
C
Hoover
Randall
R
Lapidus
Rena
R
Zhang
Jie
J
Graziani
Grazia
G
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002853:Chromatography, Liquid; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D016195:G2 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D013058:Mass Spectrometry; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009930:Organic Chemicals / Q000493:pharmacokinetics*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077204:Temozolomide; D013997:Time Factors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009930:Organic Chemicals; C502278:GPI 15427; D003606:Dacarbazine; D011065:Poly(ADP-ribose) Polymerases; D000077204:Temozolomide