Treatment of intracranial rat glioma model with implant of radiosensitizer and biomodulator drug combined with external beam radiotherapy.
OBJECTIVE
To evaluate an intracranial polymer implant containing bromodeoxyuridine (BrdUrd) and N-(phosphonacetyl)-L-aspartic acid (PALA) in combination with external beam radiotherapy (EBRT) in the treatment of a rat glioma.


METHODS
Combinations of the biomodulators 5-fluorouracil, methotrexate, or PALA with BrdUrd were evaluated as radiosensitizers in vitro by clonogenic assay. In in vivo experiments, BrdUrd and PALA were incorporated into a polyanhydride-based polymer, bis(p-carboxyphenoxy)propane sebacic acid, and implanted in the C6 rat glioma growing intracranially. The effectiveness of treatment was evaluated on the basis of survival. EBRT was given as 10-MV X-rays.


RESULTS
In tissue culture experiments, C6 cells were refractory to radiosensitization by BrdUrd even when the thymidine analog was combined with a biomodulator intended to reduce de novo thymidine synthesis. The most effective compound in vitro was PALA. When PALA and BrdUrd in a polymer formulation were implanted intracranially and combined with 10-Gy EBRT, the treatment was highly effective, with 83% of treated rats surviving 180 days.


CONCLUSIONS
Although the in vitro results were not encouraging, the combination of intratumoral BrdUrd and PAL with 10-Gy EBRT was highly effective in treating a rat glioma. These results indicate the clinical potential of combined and mixed modality treatments involving intratumoral sustained-release drug delivery.
Li
Yongbiao
Y
Department of Radiation Oncology, McGill University, Montreal General Hospital, 1650 Cedar Avenue, Montreal, Québec H3G 1A4, Canada.
Owusu
Abraham
A
Lehnert
Shirley
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D001973:Bromodeoxyuridine / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004338:Drug Combinations; D004343:Drug Implants; D005472:Fluorouracil / Q000008:administration & dosage; D005910:Glioma / Q000188:drug therapy* / Q000532:radiotherapy*; D007155:Immunologic Factors / Q000627:therapeutic use*; D008727:Methotrexate / Q000008:administration & dosage; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D051381:Rats
D004338:Drug Combinations; D004343:Drug Implants; D007155:Immunologic Factors; D011838:Radiation-Sensitizing Agents; D001224:Aspartic Acid; C013195:sparfosic acid; D001973:Bromodeoxyuridine; D010746:Phosphonoacetic Acid; D005472:Fluorouracil; D008727:Methotrexate