Local delivery of mitoxantrone for the treatment of malignant brain tumors in rats.
OBJECTIVE
Mitoxantrone is a drug with potent in vitro activity against malignant brain tumor cell lines; however, its effectiveness as a systemic agent has been hampered by poor central nervous system penetration and dose-limiting myelosuppression. To avoid these problems, we incorporated mitoxantrone into biodegradable polymeric wafers to be used for intracranial implantation, a strategy that has been shown to be safe and successful in the treatment of malignant gliomas. The authors investigated the release kinetics, toxicity, distribution, and efficacy of mitoxantrone delivered from intracranially implanted biodegradable wafers in the treatment of 9L gliosarcoma in Fischer 344 rats.


METHODS
Mitoxantrone released from the biodegradable wafer matrix reached therapeutic drug concentrations in the brain for at least 35 days. Only animals with implanted wafers of the highest drug loading dose (20% mitoxantrone by weight) showed signs of significant toxicity. In three separate efficacy experiments, animals treated with mitoxantrone-loaded biodegradable wafers had significantly improved survival compared with control animals. The combined median survival for each treatment group was the following: 0% mitoxantrone wafers, 19 days; 1%, 30 days, p < 0.0001; 5%, 34 days, p < 0.0001; and 10%, 50 days, p < 0.0001.


CONCLUSIONS
These findings establish that mitoxantrone delivered from intracranially implanted biodegradable wafers is effective in the treatment of malignant gliomas in rodents and should be considered for future clinical application in humans.
DiMeco
Francesco
F
Department of Neurosurgery, Istituto Nazionale Neurologico C. Besta, Milan, Italy.
Li
Khan W
KW
Tyler
Berry M
BM
Wolf
Ariel S
AS
Brem
Henry
H
Olivi
Alessandro
A
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D003270:Contraceptive Agents; D018316:Gliosarcoma / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007700:Kinetics; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011108:Polymers / Q000737:chemistry; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003270:Contraceptive Agents; D011108:Polymers; D008942:Mitoxantrone