title: Injection of chemotherapeutic microspheres and glioma. IV: Eradicating tumors in rats.
abstract: Polymer microspheres can be easily injected into the brain to provide a local and sustained delivery of chemotherapeutics to a tumor or surrounding tissue subject to high rates of tumor recurrence following surgery. Building on previous studies that established the clear advantage of local, peritumoral injections of sustained release microspheres, the following experiments utilized two different approaches for maximizing the survival benefit in glioma-bearing rats. In the first experiment, a previously grown cortical tumor was debulked and animals received either one or two treatments with carboplatin-loaded microspheres (either 200 or 800 microg total carboplatin per treatment). In each case, the microspheres were injected along the perimeter of the resection cavity with each treatment separated by 20 days. Survival studies clearly demonstrated that two, temporally spaced injections were superior to a single series of injections. At the lowest dose tested (200 microg), median survival was increased an additional 40% over that in animals receiving one treatment. At the higher dose (800 microg), one third of the animals receiving two separate treatments were long-term survivors (> 150 days) and showed complete eradication of the tumor on histological examination. In the second experiment, we directly compared the efficacy produced by sustained release carboplatin or 1,3-bis[2-chloroethyl]-1-nitrourea (BCNU) alone versus injecting carboplatin and BCNU-loaded microspheres blended together as a single suspension. Carboplatin and BCNU both enhanced survival, with BCNU being significantly less effective than carboplatin. However, the greatest improvements in survival were seen when a blended suspension of carboplatin and BCNU microspheres was injected around the surgical cavity. In contrast, spatially alternating injections of BCNU and carboplatin microspheres was significantly less effective and the increase in survival was no greater than that achieved with BCNU alone. These data offer further support for the potential utility of local, sustained release chemotherapeutic microspheres for treating glioma. Moreover, they suggest that injectable chemotherapeutic microspheres may offer important advantages by (a) permitting multiple, temporally spaced injections to be made, as needed, and (b) providing the opportunity to deliver combinations of several different efficacious drugs directly to the tumor site to enhance survival beyond what can be achieved with delivery of any single chemotherapeutic agent.
authors.affiliation: Alkermes, Inc., Cambridge, MA 02139, USA.
authors.forename: Dwaine F
authors.initials: DF
authors.lastname: Emerich
authors.forename: Shelley R
authors.initials: SR
authors.lastname: Winn
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Bartus
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D016190:Carboplatin / Q000008:administration & dosage*; D002330:Carmustine / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D003131:Combined Modality Therapy; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D007267:Injections; D008297:Male; D008863:Microspheres; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D003692:Delayed-Action Preparations; D016190:Carboplatin; D002330:Carmustine