Antitumor effect of chondroitin sulfate-coated ternary granulocyte macrophage-colony-stimulating factor plasmid complex for ovarian cancer.
BACKGROUND
Although replication-competent viruses have been developed for treating cancers, their cytotoxic effects are insufficient as a result of infection inhibited by the generation of neutralizing antibodies, and systemic administration is difficult as a result of the life-threatening serious side-effects of virus-induced cytokine surge. To overcome these critical problems, we devised a plasmid/polycation/polyanion complex and assessed the potential of ternary plasmid complexes coated with chondroitin sulfate in gene therapy for ovarian cancer. The antitumor effects of chondroitin sulfate-coated complex as an anionic component were compared with those of hyaluronic acid on ovarian cancer.


METHODS
Plasmid harboring the gene of murine granulocyte macrophage-colony-stimulating factor (mGM-CSF) was complexed with polyethyleneimine (PEI) and hyaluronic acid or chondroitin sulfate. Murine ovarian cancer cells were injected into (C57BL/6 × C3H/He) F(1) mice to prepare a subcutaneous or intraperitoneal tumor model.


RESULTS
DNA/PEI was charged positively and DNA/PEI/chondroitin sulfate or DNA/PEI/hyaluronic acid was charged negatively. Plasmid-green fluorescent protein (GFP)/PEI coated with 10-kilodalton (kDa) chondroitin sulfate increased transfection efficiency compared to coating with chondroitin sulfate of higher-molecular-weight or hyaluronic acid. The transfection efficiency of GFP/PEI/10-kDa chondroitin sulfate in ovarian cancer cells was six-fold higher than that in normal cells. Intraperitoneal injection of mGM-CSF/PEI coated with 10-kDa chondroitin sulfate prolonged survival compared to that coated with hyaluronic acid. Intratumoral injection of mGM-CSF/PEI coated with 10-kDa chondroitin sulfate achieved mouse survival rates of 100%, although that with hyaluronic acid did not.


CONCLUSIONS
These findings suggest that GM-CSF/PEI coated with 10-kDa chondroitin sulfate has the potential for use in gene therapy of ovarian cancer.
Department of Obstetrics and Gynecology, School of Medicine, Ehime University, Shitsukawa, Toon, Ehime, Japan. hamakatu@m.ehime-u.ac.jp
Katsuyuki
K
Hamada
Chieko
C
Yoshihara
Tomoko
T
Ito
Kenzaburo
K
Tani
Masatoshi
M
Tagawa
Norio
N
Sakuragawa
Hiroshi
H
Itoh
Yoshiyuki
Y
Koyama
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002809:Chondroitin Sulfates / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics*; D049452:Green Fluorescent Proteins; D006801:Humans; D006820:Hyaluronic Acid; D053208:Kaplan-Meier Estimate; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000494:pharmacology*; D011094:Polyethyleneimine; D014162:Transfection / Q000379:methods
D000970:Antineoplastic Agents; D049452:Green Fluorescent Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; D002809:Chondroitin Sulfates