Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer.

Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Research Abstract Details 

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Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Abstract Text:

Junko Mitsuhashi,Satomi Tsukahara,Rieko Suzuki,Yumiko Oh-hara,Saori Nishi,Hiroyo Hosoyama,Kazuhiro Katayama,Kohji Noguchi,Sayuri Minowa,Harumi Shibata,Yoshinori Ito,Kiyohiko Hatake,Keisuke Aiba,Shunji Takahashi,Yoshikazu Sugimoto,Junko Mitsuhashi,Satomi Tsukahara,Rieko Suzuki,Yumiko Oh-hara,Saori Nishi,Hiroyo Hosoyama,Kazuhiro Katayama,Kohji Noguchi,Sayuri Minowa,Harumi Shibata,Yoshinori Ito,Kiyohiko Hatake,Keisuke Aiba,Shunji Takahashi,Yoshikazu Sugimoto,

A clinical study of an MDR1 gene therapy protocol targeting metastatic breast cancer has been conducted in which the patients received high-dose chemotherapy, a transplant of MDR1-transduced autologous CD34(+) cells, and docetaxel. We herein report the molecular results of a 6-year follow-up of an individual in this study (patient 1). HaMDR-transduced cells, which had been initially detected in the peripheral blood of this individual, were found to have gradually decreased. After 10 cycles of docetaxel (days 71-316), MDR1 transgene levels were found to have increased, and then decreased to undetectable levels by day 1461. Thirty-eight MDR1-transduced clones were identified in patient 1, of which 11 showed a retroviral integration in close proximity to genes listed in the Retrovirus Tagged Cancer Gene Database (RTCGD). Four short-life clones in this group were found to harbor retroviral integrations close to the ZFHX1B, NOTCH1, BMI1, or HHEX gene; these genes have been frequently reported in the RTCGD. In addition, a long-lived RTCGD-hit clone, L-34, had a retroviral integration at a position 179 kb upstream of the EVI1 gene. L-34 was detectable on days 327-1154, but became undetectable 3 years after the docetaxel treatments had ceased. An additional three docetaxel-induced long-life clones showed comparable polymerase chain reaction profiles, which were also similar to that of the total MDR1-transduced cells. Our results thus show that docetaxel may have been effective in promoting the expansion of several MDR1-transduced clones in patient 1, but that they persist in the peripheral blood for only a few years.

Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Publishing Authors By Initials

J Mitsuhashi,S Tsukahara,R Suzuki,Y Oh-hara,S Nishi,H Hosoyama,K Katayama,K Noguchi,S Minowa,H Shibata,Y Ito,K Hatake,K Aiba,S Takahashi,Y Sugimoto,J Mitsuhashi,S Tsukahara,R Suzuki,Y Oh-hara,S Nishi,H Hosoyama,K Katayama,K Noguchi,S Minowa,H Shibata,Y Ito,K Hatake,K Aiba,S Takahashi,Y Sugimoto,

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Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Human gene therapy

VOLUME: 18

Page Numbers: 895-906

Journal Abbreviation: Hum. Gene Ther.

ISSN: 1043-0342

DAY: 17

MONTH: Oct

YEAR: 2007

Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer. Information

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LANGUAGE: eng

NlmUniqueID: 9008950

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Grant and Affiliation Information for Retroviral integration site analysis and the fate of transduced clones in an MDR1 gene therapy protocol targeting metastatic breast cancer.

AFFILIATION: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.

Country: United States

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MEDLINETA: Hum Gene Ther

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