Local administration of 7 beta-hydroxycholesteryl-3-oleate inhibits growth of experimental rat C6 glioblastoma.
The effect of 7 beta-hydroxycholesteryl-3-oleate on rat brain C6 glioblastoma cells was studied. Three days after the inoculation of 2 x 10(5) C6 cells into the frontal cortex of 6-day-old Wistar rats, two types of liposomes [consisting of either phosphatidylcholine and monosialoganglioside (PG:GM1, 10:1 mol/mol) only, or containing 7 beta-hydroxycholesterol, 7 beta-hydroxycholesteryl-3-oleate, 7 alpha-hydroxycholesteryl-3-oleate, or 7-ketocholesteryl-3-oleate] were injected into the xenograft. Ten days later, the animals were sacrificed, the tumors were stained with cresyl violet or hematoxylin/eosin, their volumes determined by image analysis, and their development followed by magnetic resonance imaging. The mean (+/- SE) tumor volume was 4.4 +/- 1.0 mm3. The injection of liposomes without oxysterol had no effect on tumor growth, whereas injection of liposomes containing 7 beta-hydroxycholesteryl-3-oleate (36 nmol) gave rise to a marked decrease in tumor volume (from 4.4 +/- 1.0 to 0.7 +/- 0.4 mm3). Seven nmol had no effect on tumor growth, 72 nmol were as efficient as 36 nmol, and 144 nmol attenuated the tumor volume by 50% only. Liposomes containing 72 nmol of oleic acid enhanced the tumor volume 4-fold. These findings were confirmed by magnetic resonance imaging. Thus, following induction of tumors in both the right and left sides of the cortex and treatment of the right side, magnetic resonance imaging indicated a significant decrease in tumor volume on the right side only. When C6 cells and 7 beta-hydroxycholesteryl-3-oleate were simultaneously injected, tumors did not develop in 80% of the animals. The clearance of [3H]7 beta-hydroxycholesteryl-3-oleate, of which 75% was converted to cholesterol, reached 99% after 48 h. Other oxysterols did not affect the tumor volume except that 7-keto-cholesteryl-3-oleate decreased the tumor volume by 50%. Thus, the 3-fatty acyl ester and 7 beta-hydroxyl groups are apparently required for the antitumor growth effect. Taken together, these data suggest that 7 beta-hydroxycholesteryl-3-oleate might be useful for local glioblastoma chemotherapy.
Werthle
M
M
Laboratoire de Neurobiologie Moléculaire des Interactions Cellulaires, UPR 416 CNRS, Strasbourg, France.
Bochelen
D
D
Adamczyk
M
M
Kupferberg
A
A
Poulet
P
P
Chambron
J
J
Lutz
P
P
Privat
A
A
Mersel
M
M
D000287:Administration, Topical; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006888:Hydroxycholesterols / Q000378:metabolism / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D009368:Neoplasm Transplantation; D019301:Oleic Acid; D009829:Oleic Acids / Q000378:metabolism / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D006888:Hydroxycholesterols; D009829:Oleic Acids; C085947:7-hydroxycholesteryl-3-oleate; D019301:Oleic Acid