Combined treatment with temozolomide and poly(ADP-ribose) polymerase inhibitor enhances survival of mice bearing hematologic malignancy at the central nervous system site.
Temozolomide (TZM) is a DNA-methylating agent that has recently been introduced into various clinical trials for treatment of solid or hematologic neoplasias, including brain lymphomas. In the current study, we have investigated whether the antitumor activity of TZM could be selectively enhanced at the central nervous system (CNS) site by intracerebral injection of a poly(ADP-ribose) polymerase (PARP) inhibitor. Mice were injected intracranially with lymphoma cells. The PARP inhibitor NU1025 (1 mg/animal) was delivered intracerebrally, whereas TZM was given as a single or a fractionated dose of 200 mg/kg by intraperitoneal administration. Results indicated that this drug combination significantly enhanced the survival of tumor-bearing mice and that this fractionated modality of treatment was the most effective schedule. Increased survival time was related to a marked reduction of tumor growth, as evidenced by histologic studies. Treatment with TZM alone was ineffective. This is the first report exploring in vivo the combination of TZM with PARP inhibitor for intracerebral neoplasias.
Tentori
Lucio
L
Department of Neuroscience, University of Rome Tor Vergata, Via di Tor Vergata 135, 00133 Rome, Italy. tentori@uniroma2.it
Leonetti
Carlo
C
Scarsella
Marco
M
d'Amati
Giulia
G
Portarena
Ilaria
I
Zupi
Gabriella
G
Bonmassar
Enzo
E
Graziani
Grazia
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D003606:Dacarbazine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000008:administration & dosage; D016019:Survival Analysis; D015996:Survival Rate; D000077204:Temozolomide
C115774:NU 1025; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D003606:Dacarbazine; D000077204:Temozolomide