Therapeutic efficacy and bone marrow protection of the mdr1 gene and over-dose chemotherapy with doxorubicin for rabbits with VX2 hepatocarcinoma.
BACKGROUND
Malignant tumors are common diseases threatening to the health and life of human being. Clinically, the multidrug resistance of tumor cells and bone marrow depression caused by chemotherapeutic agents are the main obstacles to the treatment of tumors, and both are related to the mdr1 gene. The over expression of the mdr1 gene in tumor cells contributes to the multidrug resistance of malignant tumor cells. With little expression of the mdr1 gene, bone marrow cells particularly susceptible to multidrug resistance-sensitive agents, which cause serious toxicity in bone marrow. This study was undertaken to assess therapeutic efficacy of transplantation of bone marrow mononuclear cells transferred with the mdr1 gene and over-dose chemotherapy with doxorubicin for VX2 hepatocarcinoma of rabbits.


METHODS
The mdr1 gene was transferred into the bone marrow mononuclear cells of rabbits, which was co-cultured with retroviral vector-containing supernatant, and the cells were autotransplanted into a rabbit model with VX2 hepatocarcinoma. After chemotherapy with doxorubicin, the protective effects of the mdr1 gene and therapeutic efficacy of over-dose chemotherapy were observed.


RESULTS
The mdr1 gene was transferred successfully into the bone marrow mononuclear cells, with a transduction efficiency of 35%. After autotransplantation, the mdr1 gene was expressed functionally in bone marrow with a positive rate of 8%, indicating that the gene played an important role in bone marrow protection. The rabbits with VX2 hepatocarcinoma, which had received the mdr1 gene-transduced cells, survived after chemotherapy with a 3-fold dose of adriamycin, and their white blood cell counts were (4.26 +/- 1.03) x 10(4)/L. Since hepatocarcinoma cells were eradicated, the survival time (97.00 +/- 46.75 d) of the rabbits was extended (P<0.05) and the healing rate of the tumor was increased (P<0.05).


CONCLUSIONS
The transferring of the mdr1 gene into bone marrow mononuclear cells could confer chemoprotection to bone marrow, and over-dose chemotherapy could be prescribed for the treatment of malignant tumors.
Wang
Yi
Y
Department of General Surgery, Chongqing Children's Hospital, Chongqing University of Medical Sciences, Chongqing 400014, China.
Jin
Xian-Qing
XQ
Wang
Shan
S
Wang
Qiao
Q
Luo
Qing
Q
Luo
Xiao-Ji
XJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D015870:Gene Expression; D019450:Genes, MDR; D015316:Genetic Therapy / Q000379:methods*; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy*; D011817:Rabbits
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin