Selective transgene expression for detection and elimination of contaminating carcinoma cells in hematopoietic stem cell sources

被引:57
作者
Chen, L
Pulsipher, M
Chen, DS
Sieff, C
Elias, A
Fine, HA
Kufe, DW
机构
[1] HARVARD UNIV,SCH MED,DANA FARBER CANC INST,DIV CANC PHARMACOL,BOSTON,MA 02115
[2] HARVARD UNIV,SCH MED,DANA FARBER CANC INST,DIV PEDIAT HEMATOL & ONCOL,BOSTON,MA 02115
关键词
adenovirus; bone marrow; breast cancer; thymidine kinase; gene therapy;
D O I
10.1172/JCI119072
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Tumor contamination of bone marrow (BM) and peripheral blood (PB) may affect the outcome of patients receiving high dose chemotherapy with autologous transplantation of hematopoietic stem cell products. In this report, we demonstrate that replication defective adenoviral vectors containing the cytomegalovirus (CMV) or DF3/MUC1 carcinoma-selective promoter can be used to selectively transduce contaminating carcinoma cells, Adenoviral-mediated reporter gene expression in breast cancer cells was five orders of magnitude higher than that found in BM, PB, and CD34(+) cells. Our results demonstrate that CD34(+) cells have low to undetectable levels of integrins responsible for adenoviral internalization. We show that adenoviral-mediated transduction of a reporter gene can detect one breast cancer cell in 5 x 10(5) BM or PB cells with a vector containing the DF3/MUC1 promoter. We also show that transduction of the HSV-tk gene for selective killing by ganciclovir can be exploited for purging cancer cells from hematopoietic stem cell populations. The selective expression of TK followed by ganciclovir treatment resulted in the elimination of 6-logs of contaminating cancer cells. By contrast, there was little effect on CFU-GM and BFU-E formulation or on long term culture initiating cells. These results indicate that adenoviral vectors with a tumor-selective promoter provide a highly efficient and effective approach for the detection and purging of carcinoma cells in hematopoietic stem cell preparations.
引用
收藏
页码:2539 / 2548
页数:10
相关论文
共 47 条
[1]   CHARACTERIZATION OF CIS-ACTING ELEMENTS REGULATING TRANSCRIPTION OF THE HUMAN DF3 BREAST CARCINOMA-ASSOCIATED ANTIGEN (MUC1) GENE [J].
ABE, M ;
KUFE, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (01) :282-286
[2]  
ANDERSON IC, 1989, CANCER RES, V49, P4659
[3]   A PHASE-II STUDY OF HIGH-DOSE CYCLOPHOSPHAMIDE, THIOTEPA, AND CARBOPLATIN WITH AUTOLOGOUS MARROW SUPPORT IN WOMEN WITH MEASURABLE ADVANCED BREAST-CANCER RESPONDING TO STANDARD-DOSE THERAPY [J].
ANTMAN, K ;
AYASH, L ;
ELIAS, A ;
WHEELER, C ;
HUNT, M ;
EDER, JP ;
TEICHER, BA ;
CRITCHLOW, J ;
BIBBO, J ;
SCHNIPPER, LE ;
FREI, E .
JOURNAL OF CLINICAL ONCOLOGY, 1992, 10 (01) :102-110
[4]   Breast cancer selective gene expression and therapy mediated by recombinant adenoviruses containing the DF3/MUC1 promoter [J].
Chen, L ;
Chen, DS ;
Manome, Y ;
Dong, YH ;
Fine, HA ;
Kufe, DW .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 96 (06) :2775-2782
[5]   A RECOMBINANT BCL-X(S) ADENOVIRUS SELECTIVELY INDUCES APOPTOSIS IN CANCER-CELLS BUT NOT IN NORMAL BONE-MARROW CELLS [J].
CLARKE, MF ;
APEL, IJ ;
BENEDICT, MA ;
EIPERS, PG ;
SUMANTRAN, V ;
GONZALEZGARCIA, M ;
DOEDENS, M ;
FUKUNAGA, N ;
DAVIDSON, B ;
DICK, JE ;
MINN, AJ ;
BOISE, LH ;
THOMPSON, CB ;
WICHA, M ;
NUNEZ, G .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (24) :11024-11028
[6]   PREDICTION OF EARLY RELAPSE IN PATIENTS WITH OPERABLE BREAST-CANCER BY DETECTION OF OCCULT BONE-MARROW MICROMETASTASES [J].
COTE, RJ ;
ROSEN, PP ;
LESSER, ML ;
OLD, LJ ;
OSBORNE, MP .
JOURNAL OF CLINICAL ONCOLOGY, 1991, 9 (10) :1749-1756
[7]   SENSITIVE DETECTION OF OCCULT BREAST-CANCER BY THE REVERSE-TRANSCRIPTASE POLYMERASE CHAIN-REACTION [J].
DATTA, YH ;
ADAMS, PT ;
DROBYSKI, WR ;
ETHIER, SP ;
TERRY, VH ;
ROTH, MS .
JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (03) :475-482
[8]  
DIEL IJ, 1992, J CLIN ONCOL, V10, P1234
[9]  
FRIEDMAN EL, 1986, CANCER RES, V46, P5189
[10]   SPECIFIC DETECTION OF CARCINOEMBRYONIC ANTIGEN-EXPRESSING TUMOR-CELLS IN BONE-MARROW ASPIRATES BY POLYMERASE CHAIN-REACTION [J].
GERHARD, M ;
JUHL, H ;
KALTHOFF, H ;
SCHREIBER, HW ;
WAGENER, C ;
NEUMAIER, M .
JOURNAL OF CLINICAL ONCOLOGY, 1994, 12 (04) :725-729