STI571 combined with vincristine greatly suppressed the tumor formation of multidrug-resistant K562 cells in a human-nude mice xenograft model.
- Author:
Lei GAO
1
;
Li CHEN
;
Xin-hong FEI
;
Hui-ying QIU
;
Hong ZHOU
;
Jian-min WANG
Author Information
- Publication Type:Journal Article
- MeSH: ATP-Binding Cassette, Sub-Family B, Member 1; analysis; Animals; Benzamides; Cell Proliferation; drug effects; Daunorubicin; pharmacokinetics; pharmacology; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; genetics; Humans; Imatinib Mesylate; K562 Cells; drug effects; Leukemia, Experimental; drug therapy; pathology; Mice; Mice, Nude; Neoplasm Transplantation; Piperazines; administration & dosage; Pyrimidines; administration & dosage; Transplantation, Heterologous; Vincristine; administration & dosage
- From: Chinese Medical Journal 2006;119(11):911-918
- CountryChina
- Language:English
-
Abstract:
BACKGROUNDThe development of the targeted signal transduction inhibitor STI571 has prompted us to treat chronic myeloid leukemia in different ways. Since STI571 may reverse multidrug-resistance of K562/MDR cells in vitro, we studied the effect of STI571 on multidrug-resistant K562 cells in vivo.
METHODSMultidrug-resistant human leukemia cell line K562-n/VCR expresses both bcr/abl fusion gene and multi-drug resistance (mdr1) gene. It is a vincristine resistant cell line subcloned from the vincristine (VCR) sensitive cell line K562-n induced by vincristine in vitro. K562-n and K562-n/VCR cells were inoculated subcutaneously into both sides of nude mice breast (5 x 106 cells/each) to establish a human leukemia xenograft model. The incidence and volume of tumor were observed. In the tumor-bearing nude mice, anti-tumor drugs vincristine, daunorubicin (DNR), STI571, and STI571 plus VCR for the treatment of mdr1 and bcr/abl double positive leukemia were studied respectively.
RESULTSThe tumor incidence was 100% in the nude mice inoculated with either K562-n or K562-n/VCR. The transcription of the mdr1 gene and expression of P-gp were negative in K562-n cells but positive in K562-n/VCR cells. The intracellular accumulation of DNR in K562-n cells was higher than that in K562-n/VCR cells (P < 0.05). The tumor incidence of K562-n/VCR cells in nude mice was much higher than that of K562-n cells in chemotherapy groups, and the mean volume of the tumors was also larger (P < 0.05). STI571 combined with VCR significantly suppressed the proliferation of K562-n/VCR cells.
CONCLUSIONSThe MDR characteristics of K562-n/VCR in vivo were the same as in vitro. STI571 had a significant tumor-suppressing effect on VCR-sensitive leukemia cells and a moderate effect on MDR leukemia cells. VCR combined with STI571 had an excellent tumor-suppressing effect on both K562-n/VCR and K562-n in the human-nude mice xenograft model.