Isolation, physicochemical characterization and preclinical efficacy evaluation of soluble scleroglucan.
Herein we describe the isolation, physicochemical characterization and preclinical evaluation of a water-soluble biologic response modifier extracted from Sclerotium glucanicum. Alkaline extraction of insoluble S. glucanicum exopolymers produced a soluble scleroglucan composed of a triple-helical beta-1,3-linked glucopyranose backbone with single beta-1,6-linked glucopyranosyl branches every third subunit. Scleroglucan has a weight average molecular mass of 1.56 x 10(6) Da, a weight average root mean square distance from the center of gravity of the molecule to its farthest elements of 51.8 nm, a polydispersity (weight-average molecular mass/number average molecular mass) of 1.83 and intrinsic viscosity of 3.081 dl/g. Scleroglucan (250 mg/kg, intravenously) stimulated in vivo murine macrophage phagocytic activity (66%, P less than .001) and increased in vitro macrophage tumor cytotoxicity against syngeneic tumor targets by 124% (P less than .05). Scleroglucan enhanced (P less than .001) murine bone marrow proliferation in a biphasic manner by up to 328%. Scleroglucan therapy increased survival of mice challenged with syngeneic lymphoma, melanoma or adenocarcinoma. AKR/J mice bearing syngeneic lymphoma (1 x 10(3) cells, intraperitoneally) demonstrated increased (P less than .001) long-term survival (100% vs. 0%, greater than 64 days). C57Bl/6J mice bearing syngeneic melanoma B16 (5 x 10(5) cells, subcutaneously) demonstrated increased long-term survival (64% vs. 0%, P less than .05). C57Bl/6J mice bearing syngeneic adenocarcinoma BW10232 (1 x 10(5) cells, subcutaneously) demonstrated increased (P less than .05) median survival time. In addition, scleroglucan prophylaxis increased resistance of mice to challenge with Staphylococcus aureus, Candida albicans and mouse hepatitis virus A-59. Scleroglucan did not induce toxicity or hepatomegaly. We conclude that: 1) a branched, water-soluble beta-1,3-linked scleroglucan biologic response modifier can be extracted from S. glucanicum; 2) scleroglucan will stimulate immunity, modify experimental neoplastic disease and increase resistance to microbial challenge; and 3) scleroglucan shows promise as an immunopotentiating drug.
Pretus
H A
HA
Glucan Research Laboratory, Tulane University School of Medicine, New Orleans, LA 70112.
Ensley
H E
HE
McNamee
R B
RB
Jones
E L
EL
Browder
I W
IW
Williams
D L
DL
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000473:pathology; D005936:Glucans / Q000737:chemistry / Q000302:isolation & purification* / Q000627:therapeutic use; D007155:Immunologic Factors / Q000737:chemistry / Q000302:isolation & purification* / Q000627:therapeutic use; D017053:Infection Control; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D008970:Molecular Weight; D009374:Neoplasms, Experimental / Q000188:drug therapy; D010587:Phagocytosis / Q000187:drug effects; D014783:Viscosity
D005936:Glucans; D007155:Immunologic Factors; C045938:scleroglucan