Lactacystin exhibits potent anti-tumor activity in an animal model of malignant glioma when administered via controlled-release polymers.
Lactacystin, a proteasome-inhibitor, has been shown to induce apoptosis of experimental gliomas in vitro. However, its systemic toxicity prevents further clinical use. To circumvent this problem, lactacystin can be delivered intratumorally. We tested the efficacy of lactacystin incorporated into controlled-release polymers for treating experimental gliomas. 9L-gliosarcoma and F98-glioma cell lines were treated with lactacystin (10-100 microg/ml) for 72 h in vitro. Cell-viability was measured with MTT-assays. Toxicity of lactacystin/polycarboxyphenoxypropane-sebacic-acid (pCPP : SA) polymers was tested in vivo using Fischer-344 rats intracranially implanted with lactacystin polymers loaded from 0.1 to 2% lactacystin by weight. The efficacy of 1, 1.3, 1.5 and 1.7% lactacystin/pCPP : SA polymers was determined in Fischer-344 rats intracranially challenged with 9L and treated either simultaneously or 5 days after tumor implantation. Lactacystin was cytotoxic in 9L cells, causing a 16 +/- 8% growth inhibition at 10-microg/ml that increased to 78 +/- 4% at 100-microg/ml. Similarly, lactacystin inhibited growth of F98 by 18 +/- 8% at 10-microg/ml and 74 +/- 2% at 100-microg/ml in vitro. Polymers released lactacystin for 21 days and intracranial implantation in rats neither generate local nor systemic toxicity at doses lower than 2%. Treatment with lactacystin/pCPP : SA polymers with loading concentrations of 1.0, 1.3, and 1.5% prolonged survival of animals intracranially challenged with 9L when polymers where inserted in the day of tumor implantation. In conclusion, lactacystin exhibits potent cytotoxic-activity against 9L and F98 in vitro, it can be efficiently incorporated and delivered using controlled-release polymers, and at the proposed concentrations lactacystin polymers are safe for CNS delivery and prolong survival in the 9L model.
Legnani
Federico G
FG
Department of Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
Pradilla
Gustavo
G
Thai
Quoc-Anh
QA
Fiorindi
Alessandro
A
Recinos
Pablo F
PF
Tyler
Betty M
BM
Gaini
Sergio M
SM
DiMeco
Francesco
F
Brem
Henry
H
Olivi
Alessandro
A
D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D018316:Gliosarcoma / Q000188:drug therapy; D036502:Infusions, Intralesional / Q000379:methods; D009374:Neoplasms, Experimental; D011108:Polymers / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D003692:Delayed-Action Preparations; D004343:Drug Implants; D011108:Polymers; C045869:polybis(carbophenoxypropane); C067713:lactacystin; D000111:Acetylcysteine