Jm. Schuster et al., INTRAARTERIAL THERAPY OF HUMAN GLIOMA XENOGRAFTS IN ATHYMIC RATS USING 4-HYDROPEROXYCYCLOPHOSPHAMIDE, Cancer research, 53(10), 1993, pp. 2338-2343
The addition of chemotherapy, notably using nitrosoureas, in the treat
ment of patients with glioblastoma multiforme has resulted in only mod
est improvements in long-term patient survival over the use of surgica
l intervention and irradiation alone. Intraarterial (i.a.) chemotherap
y offers the potential benefit of increasing tumor drug delivery becau
se of first-pass drug uptake, while minimizing systemic drug levels an
d toxicity. We have now investigated the i.a. therapy of intracerebral
human glioma xenografts in athymic rats with 4-hydroperoxycyclophosph
amide (4-HC), a preactivated derivative of cyclophosphamide. Athymic m
ale rats were given intracerebral injections of the human glioma line
D-54 MG. On Day 5 after injection, the rats were randomized (n = 8-10)
by body weight (mean weight. approximately 300 g). In one set of expe
riments, each group received either i.v. saline, i.a. saline, 6 mg i.a
. 4-HC, 6 mg i.v. 4-HC (6 mg), or 12 mg i.v. 4-HC. Intraarterial 4-HC
produced significant increases in median survival (Day 24) compared wi
th i.a. saline controls (140% increase), equivalent doses given i.v. (
71% increase), and twice the equivalent dose given i.v. (50% increase)
(by Wilcoxon rank sum analysis, P < 0.05 is statistically significant
). The i.a. maximum tolerated dose was subsequently determined to be a
pproximately 12.5 mg in non-tumor-bearing rats. Further experiments de
monstrated a dose-response increase in survival for i.a. dosages of 6,
9, and 12.5 mg with significant improvement when compared with saline
controls and 12.5 mg i.v. Pharmacokinetic experiments also demonstrat
ed a significant first-pass uptake advantage for i.a. (versus i.v.) ad
ministered 4-HC. The short plasma half-life and marked antiglioma acti
vity of 4-HC, without the need for hepatic activation, suggest a thera
peutic application of this drug in the i.a. treatment of brain tumors.