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Cytochrome P450 CYP3A4/5: A new prog...

Dhaini, Hassan R.

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Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma./
作者:	Dhaini, Hassan R.
面頁冊數:	107 p.
附註:	Co-Chairs: Paul F. Hollenberg; Craig Harris.
Contained By:	Dissertation Abstracts International63-07B.
標題:	Health Sciences, Toxicology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3057937
ISBN:	0493734090

Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma.
Dhaini, Hassan R.

Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma. - 107 p.

Co-Chairs: Paul F. Hollenberg; Craig Harris.

Thesis (Ph.D.)--University of Michigan, 2002.

Osteosarcoma is a primary malignancy of bone with a tendeney for early pulmonary metastasis. There is a need to identify patients who may benefit from more aggressive pre-operative therapy or perhaps require less aggressive chemotherapy. A reliable biomarker predicting clinical outcome at initiation of treatment has not yet been identified. We hypothesized that one or more drug-metabolizing enzymes, mainly cytochromes P450 are related to drug resistance and/or poor clinical outcome in osteosarcoma.

ISBN: 0493734090Subjects--Topical Terms:

1017752
Health Sciences, Toxicology.

Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma.
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035 $a (UnM)AAI3057937
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100 1 $a Dhaini, Hassan R. $3 1256329
245 1 0 $a Cytochrome P450 CYP3A4/5: A new prognostic factor for osteosarcoma.
300 $a 107 p.
500 $a Co-Chairs: Paul F. Hollenberg; Craig Harris.
500 $a Source: Dissertation Abstracts International, Volume: 63-07, Section: B, page: 3269.
502 $a Thesis (Ph.D.)--University of Michigan, 2002.
520 $a Osteosarcoma is a primary malignancy of bone with a tendeney for early pulmonary metastasis. There is a need to identify patients who may benefit from more aggressive pre-operative therapy or perhaps require less aggressive chemotherapy. A reliable biomarker predicting clinical outcome at initiation of treatment has not yet been identified. We hypothesized that one or more drug-metabolizing enzymes, mainly cytochromes P450 are related to drug resistance and/or poor clinical outcome in osteosarcoma.
520 $a To test the hypothesis, tissue microarray blocks containing 18 osteogenic and 109 soft tissue sarcoma primary tumors were used to identify the expression of P450s 1A1/2, 1B1, 2B6, 2D6, and 3A4/5 as well as metallothionein, MDR1, UGT2B7 and mdm-2 by enzyme-linked avidin-biotin-complexed immunocytochemistry. CYP1A1/2, CYP1B1, CYP3A4/5, MT, UGT2B7, MDR-1 and mdm-2 were detected in 59%, 64%, 76%, 87%, 63%, 90% and 94% of soft tissue tumors, and in 83%, 67%, 83%, 72%, 78%, 72% and 11% of osteosarcomas, respectively. CYP2B6 and CYP2D6 immunoreactivities were seen in 3% and 20% of soft tissue tumors, respectively, and were not detected in osteosarcomas. In addition, osteosarcomas were heterogenous with respect to the expression CYP3A4/5, an enzyme involved in the metabolic activation and detoxification of ifosfamide, etoposide, and doxorubicin, which are used in the treatment of osteosarcoma. This observation was extended by developing a quantitative immunofluorescence technique to assess the levels of CYP3A4/5 in 18 archival primary osteosarcoma sections. Expression of CYP3A4/5 was found to be significantly higher in primary biopsies of patients that developed distant metastatic disease compared to biopsies from metastatic disease-free patients (p ≤ 0.0004).
520 $a Results from clonogenic assays using two human osteosarcoma cell lines showed that cells expressing CYP3A4 are more resistant to etoposide compared to non-expressing cells. No difference in resistance was evident among the cell lines when exposed to ifosfamide or doxorubicin or etoposide in the presence of ketoconazole, a potent inhibitor of CYP3A4.
520 $a This thesis provides evidence that selective P450 isoenzymes are expressed in sarcomas. Moreover, increased levels of CYP3A4/5 expression appears to predict poor clinical outcome in osteosarcomas, and may confer protection through mechanisms of resistance other than regular detoxification pathways.
590 $a School code: 0127.
650 4 $a Health Sciences, Toxicology. $3 1017752
690 $a 0383
710 2 0 $a University of Michigan. $3 777416
773 0 $t Dissertation Abstracts International $g 63-07B.
790 $a 0127
790 1 0 $a Harris, Craig, $e advisor
790 1 0 $a Hollenberg, Paul F., $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3057937