A human
medulloblastoma (BN-2) and a
glioblastoma (BN-3) which were previously established in nude mice were used to determine the effect of
combined modality therapy with gamma-radiation, and three chemotherapeutic agents,
procarbazine, 1,4-cyclohexadiene-1,4-dicarbamic
acid, 2,5-bis(1-aziridinyl)-3,6-dioxo diethylester (
AZQ), and
1,3-bis(2-chloroethyl)-1-nitrosourea (
BCNU). The
tumor cells were grown in tissue culture and implanted intracranially in the right cerebral hemisphere of NIH Swiss nude mice to a depth of 3 mm. The mice were randomized, and treatment was started 3 days after
tumor implantation.
Procarbazine and
AZQ were injected i.p. every 5 days for three treatments.
BCNU was injected one time for a single treatment. Radiation was localized to the head. A 60Co unit was used for irradiation at the rate of 125 rads/min 3 days after
tumor implantation. Ten experiments were performed using six to nine mice per group and different
drug-radiation dose combinations. The
drug dose ranged from 400 to 500 mg/kg/injection for
procarbazine, 7.5 mg/kg/injection for
AZQ, and 10 to 20 mg/kg/injection for
BCNU. The radiation dose ranged from 320 to 1050 rads/mouse (whole head). The day of death was recorded for each animal, and the mean of each treatment group was used to calculate the percentage increase in life span (ILS) compared to the untreated control group.
Chemotherapy alone produced a minimal effect, while radiation alone produced minimal effects at 320 to 640 rads with progressively positive effects at 800 and 1050 rads. When the combination treatment of the human
medulloblastoma xenograft with
procarbazine was used, the ILS was significantly increased in all four experiments, ranging from 25 to 41%, and was superior to single-modality treatment in all but the 1050-rad treatment, where it showed an equal effect. The combination treatment using
AZQ and
BCNU showed no ILS for the
medulloblastoma tumor. Combination treatment of the human
glioblastoma xenograft using
BCNU produced significant ILSs of 105 and 119% and was superior to single-modality treatment with a
drug dose of 10 mg/kg and radiation doses of 540 and 800 rads, respectively. The nude mouse-human
tumor xenograft model was found to be useful for combined modality studies and should give valuable information for the experimental design of pilot Phase III clinical studies against a variety of
brain tumors.