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Article: In vitro assay-assisted treatment selection for women with breast or ovarian cancer.

Fruehauf, J P

2002 Volume 9, Issue 3, Page(s) 171–182

Abstract: The selection of chemotherapy for women with breast or ovarian carcinoma has been traditionally based on results from phase III comparative trials that define the most active drugs and drug combinations. This approach has led to a significant ... ...

Abstract	The selection of chemotherapy for women with breast or ovarian carcinoma has been traditionally based on results from phase III comparative trials that define the most active drugs and drug combinations. This approach has led to a significant prolongation of the lives of these patients. Unfortunately, few patients with advanced stage IV disease are cured using the currently available regimens. In order to improve the selection process for individual patients, various types of in vitro tests that assess the activity of standard drugs on a patient's tumor have been developed over the past five decades. As with bacterial culture and sensitivity tests, significant predictive correlations between in vitro drug-response assays and cancer patient response and survival have been demonstrated. Medicare currently covers in vitro drug-resistance assays. This review discusses the historical development of in vitro drug-response assays and the clinical validation of various technologies currently available to assist the clinician in selecting the optimal therapy for each patient.
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/mortality ; Drug Resistance, Neoplasm ; Drug Screening Assays, Antitumor/history ; Drug Screening Assays, Antitumor/methods ; Female ; History, 19th Century ; History, 20th Century ; Humans ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/mortality ; Survival Rate ; Treatment Outcome ; Tumor Cells, Cultured
Language	English
Publishing date	2002-09-17
Publishing country	England
Document type	Historical Article ; Journal Article ; Review
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1677/erc.0.0090171
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Zs.A 4192: Show issues

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Article: Redox regulation in human melanocytes and melanoma.

Meyskens, F L / Farmer, P / Fruehauf, J P

Pigment cell research

2001 Volume 14, Issue 3, Page(s) 148–154

Abstract: The human melanocyte is continuously exposed to intrinsic and extrinsic sources of reactive biochemical species, but is finely tuned via the intrinsic anti-oxidant and radical properties of melanin to suppress the build-up of an altered redox phenotype. ... ...

Abstract	The human melanocyte is continuously exposed to intrinsic and extrinsic sources of reactive biochemical species, but is finely tuned via the intrinsic anti-oxidant and radical properties of melanin to suppress the build-up of an altered redox phenotype. We propose that this control is lost during melanomagenesis and inappropriate redox-sensitive transcriptional factor activations occur which result in enhancement of an anti-apoptotic phenotype in the transformed cell. This conceptual framework offers testable steps to determine the role of redox alterations in the carcinogenic evolution, prevention and treatment of melanoma and other diseases of the melanocyte.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Free Radicals ; Humans ; Melanins/metabolism ; Melanocytes/metabolism ; Melanoma/metabolism ; Models, Biological ; Models, Chemical ; Oxidation-Reduction ; Oxidative Stress ; Phenotype ; Reactive Oxygen Species ; Transcription, Genetic
Chemical Substances	Antioxidants ; Free Radicals ; Melanins ; Reactive Oxygen Species
Language	English
Publishing date	2001-08-03
Publishing country	Denmark
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	645056-8
ISSN	1600-0749 ; 0893-5785
ISSN (online)	1600-0749
ISSN	0893-5785
DOI	10.1034/j.1600-0749.2001.140303.x
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Zs.A 2444: Show issues

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Article: Use of the extreme drug resistance assay to evaluate mechanisms of resistance in ovarian cancer: taxol resistance and MDR-1 expression.

Fruehauf, J P / Manetta, A

Contributions to gynecology and obstetrics

1994 Volume 19, Page(s) 39–52

MeSH term(s)	ATP-Binding Cassette, Sub-Family B, Member 1/drug effects ; ATP-Binding Cassette, Sub-Family B, Member 1/genetics ; Cyclosporins ; Drug Resistance ; Drug Screening Assays, Antitumor/methods ; Female ; Flow Cytometry ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Expression Regulation, Neoplastic/genetics ; Humans ; Immunohistochemistry ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Paclitaxel/therapeutic use ; Tumor Cells, Cultured
Chemical Substances	ATP-Binding Cassette, Sub-Family B, Member 1 ; Cyclosporins ; Paclitaxel (P88XT4IS4D) ; valspodar (Q7ZP55KF3X)
Language	English
Publishing date	1994
Publishing country	Switzerland
Document type	Clinical Trial ; Comparative Study ; Controlled Clinical Trial ; Journal Article
ZDB-ID	223923-1
ISSN	0304-4246
ISSN	0304-4246
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Article: Selective formation of tumor necrosis factor-alpha (TNF) degradation products contributes to TNF mediated cytotoxicity.

Fruehauf, J P / Sinha, B K

Oncology research

1992 Volume 4, Issue 3, Page(s) 91–101

Abstract: We compared tumor necrosis factor (TNF) metabolism by wild-type MCF-7 (WT) cells, by 40-fold doxorubicin resistant (40F) breast cancer cells and by PC3 and LNCaP prostate cancer cell lines. MCF-7 WT and LNCaP cell lines were sensitive to TNF cytotoxicity ...

Abstract	We compared tumor necrosis factor (TNF) metabolism by wild-type MCF-7 (WT) cells, by 40-fold doxorubicin resistant (40F) breast cancer cells and by PC3 and LNCaP prostate cancer cell lines. MCF-7 WT and LNCaP cell lines were sensitive to TNF cytotoxicity and both lines produced two major intracellular TNF degradation products of 15 kDa and 5.5 kDa. The MCF-7 40F and the PC3 cell lines were resistant to TNF and produced multiple TNF degradation products with molecular weights lower than 15 kDa. Both the breast and prostate lines showed TNF receptor crosslinking patterns consistent with a molecular weight of 55 kDa. The breast and LNCaP lines expressed TNF receptors with an apparent dissociation constant (Kd) of 0.4 to 0.6 nM, while the TNF resistant line had a Kd of 2 nM. Similar receptor numbers per cell were found for all cell types (4,000 to 8,000/cell), and comparable levels of TNF internalization were noted. TNF-conditioned medium from the TNF-sensitive cell types was cytotoxic toward both the TNF-sensitive and TNF-resistant lines, and the toxicity was significantly blocked by an anti-TNF monoclonal antibody. Hydrophobic interaction column HPLC fractionation of the TNF-degradation products produced by MCF-7 WT and LNCaP cells revealed that the trimeric, monomeric, and 5.5 kDa fractions possessed the greatest in vitro antitumor activity. These findings suggest that a TNF degradation product, produced selectively by TNF-sensitive cells, may contribute to the antitumor action of TNF.
MeSH term(s)	Antibodies, Monoclonal ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/ultrastructure ; Cell Division/drug effects ; Cytotoxicity, Immunologic/drug effects ; Doxorubicin/pharmacology ; Drug Resistance ; Electrophoresis ; Female ; Gene Expression/genetics ; Humans ; Iodine Radioisotopes ; Male ; Oncogenes/genetics ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/ultrastructure ; RNA, Messenger/analysis ; RNA, Messenger/genetics ; Receptor, Epidermal Growth Factor/genetics ; Receptor, Epidermal Growth Factor/physiology ; Receptors, Cell Surface/metabolism ; Receptors, Tumor Necrosis Factor ; Recombinant Proteins/analysis ; Recombinant Proteins/metabolism ; Recombinant Proteins/toxicity ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/metabolism ; Tumor Necrosis Factor-alpha/toxicity
Chemical Substances	Antibodies, Monoclonal ; Iodine Radioisotopes ; RNA, Messenger ; Receptors, Cell Surface ; Receptors, Tumor Necrosis Factor ; Recombinant Proteins ; Tumor Necrosis Factor-alpha ; Doxorubicin (80168379AG) ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	1992
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1114699-0
ISSN	1555-3906 ; 0965-0407
ISSN (online)	1555-3906
ISSN	0965-0407
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Zs.A 3087: Show issues

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Article: A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.

Prabhu, S / Saadat, D / Zhang, M / Halbur, L / Fruehauf, J P / Ong, S T

Oncogene

2006 Volume 26, Issue 8, Page(s) 1188–1200

Abstract: The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of ...

Abstract	The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Animals ; Antibiotics, Antineoplastic ; Benzamides ; Carrier Proteins/metabolism ; Cell Cycle Proteins ; Cyclin D3 ; Cyclins/metabolism ; Eukaryotic Initiation Factor-4F/metabolism ; Eukaryotic Initiation Factor-4G/metabolism ; Eukaryotic Initiation Factors ; Fusion Proteins, bcr-abl/antagonists & inhibitors ; Fusion Proteins, bcr-abl/physiology ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mice ; Multiprotein Complexes ; Phosphoproteins/metabolism ; Phosphorylation ; Piperazines/pharmacology ; Protein Biosynthesis/drug effects ; Proteins ; Pyrimidines/pharmacology ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases ; Transcription Factors/antagonists & inhibitors ; Transcription Factors/metabolism ; Tumor Cells, Cultured
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antibiotics, Antineoplastic ; Benzamides ; CCND3 protein, human ; Carrier Proteins ; Ccnd3 protein, mouse ; Cell Cycle Proteins ; Cyclin D3 ; Cyclins ; Eif4ebp1 protein, mouse ; Eukaryotic Initiation Factor-4F ; Eukaryotic Initiation Factor-4G ; Eukaryotic Initiation Factors ; Multiprotein Complexes ; Phosphoproteins ; Piperazines ; Proteins ; Pyrimidines ; Transcription Factors ; Imatinib Mesylate (8A1O1M485B) ; Fusion Proteins, bcr-abl (EC 2.7.10.2) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2006-08-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/sj.onc.1209901
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Zs.A 2218: Show issues

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Article: Doxorubicin-induced cross-resistance to tumor necrosis factor (TNF) related to differential TNF processing.

Fruehauf, J P / Mimnaugh, E G / Sinha, B K

Journal of immunotherapy : official journal of the Society for Biological Therapy

1991 Volume 10, Issue 3, Page(s) 165–173

Abstract: To evaluate whether cells selected for doxorubicin resistance were cross-resistant to tumor necrosis factor, the effects of doxorubicin and recombinant human tumor necrosis factor-alpha (TNF) on doxorubicin-sensitive (WT) and 40-fold doxorubicin- ... ...

Abstract	To evaluate whether cells selected for doxorubicin resistance were cross-resistant to tumor necrosis factor, the effects of doxorubicin and recombinant human tumor necrosis factor-alpha (TNF) on doxorubicin-sensitive (WT) and 40-fold doxorubicin-resistant (40F) MCF-7 cell proliferation were assessed. The median dose (MD) for doxorubicin was 14.5 nM for WT cells and 474 nM for 40F cells. The MD for TNF was 0.18 nM for WT cells, while 40F cells were highly resistant to TNF concentrations up to 60 nM. Doxorubicin and TNF in combination were synergistic against WT cells, but not 40F cells. Glutathione depletion by buthionine sulfoxamine sensitized WT cells threefold to TNF, with no change in their response to doxorubicin, while 40F cells showed a twofold increase in doxorubicin sensitivity, with no apparent change in their resistance to TNF. No significant differences in TNF receptor number, Kd, or capacity for TNF internalization were noted between the two cell types. WT cells produced a single 15 kDa TNF degradation product, while the 40F cells produced three lower molecular weight degradation products. We conclude that cross-resistance to TNF in doxorubicin-resistant MCF-7 cells may be explained in part by altered TNF degradation.
MeSH term(s)	Buthionine Sulfoximine ; Doxorubicin/pharmacology ; Drug Resistance/physiology ; Drug Screening Assays, Antitumor ; Drug Synergism ; Glutathione/metabolism ; Humans ; Methionine Sulfoximine/analogs & derivatives ; Methionine Sulfoximine/pharmacology ; Receptors, Cell Surface/metabolism ; Receptors, Tumor Necrosis Factor ; Tumor Cells, Cultured ; Tumor Necrosis Factor-alpha/pharmacology
Chemical Substances	Receptors, Cell Surface ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; Methionine Sulfoximine (1982-67-8) ; Buthionine Sulfoximine (5072-26-4) ; Doxorubicin (80168379AG) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	1991-06
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	1064067-8
ISSN	1537-4513 ; 1053-8550 ; 1524-9557
ISSN (online)	1537-4513
ISSN	1053-8550 ; 1524-9557
DOI	10.1097/00002371-199106000-00002
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Zs.A 1778: Show issues

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Article: Synergistic activity of suramin with tumor necrosis factor alpha and doxorubicin on human prostate cancer cell lines.

Fruehauf, J P / Myers, C E / Sinha, B K

Journal of the National Cancer Institute

1990 Volume 82, Issue 14, Page(s) 1206–1209

Abstract: We evaluated the action of suramin, doxorubicin, and tumor necrosis factor alpha (TNF-alpha) on the testosterone-responsive human prostate cell line LNCaP and on the testosterone-independent human prostate cell line PC-3. The synergistic action of these ... ...

Abstract	We evaluated the action of suramin, doxorubicin, and tumor necrosis factor alpha (TNF-alpha) on the testosterone-responsive human prostate cell line LNCaP and on the testosterone-independent human prostate cell line PC-3. The synergistic action of these agents in combination was tested by the Chou and Talalay method (quantitative analysis of dose-effect relationships) to determine whether in vitro doses were active at levels safely achieved in vivo. The action of suramin was potentiated threefold by doxorubicin for the PC-3 line and seven-fold by doxorubicin for the LNCaP line. Both the suramin-TNF-alpha and the doxorubicin-TNF-alpha combinations showed synergistic action against the LNCaP line. Synergistic activity was noted at drug concentrations routinely achieved clinically. This study demonstrates that suramin, doxorubicin, and TNF-alpha are active agents against prostate cancer cell lines and that their activity can be enhanced when they are used in combination.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cell Division/drug effects ; Dose-Response Relationship, Drug ; Doxorubicin/administration & dosage ; Drug Synergism ; Humans ; Male ; Prostatic Neoplasms/drug therapy ; Suramin/administration & dosage ; Tumor Cells, Cultured/drug effects ; Tumor Necrosis Factor-alpha/administration & dosage
Chemical Substances	Tumor Necrosis Factor-alpha ; Suramin (6032D45BEM) ; Doxorubicin (80168379AG)
Language	English
Publishing date	1990-07-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/82.14.1206
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Uh III Zs.131: Show issues

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Article: Long-term consequences following conservative management of epithelial ovarian cancer in an infertile patient.

Moore, M M / Tewari, K / Rose, G S / Fruehauf, J P / DiSaia, P J

Gynecologic oncology

1999 Volume 73, Issue 3, Page(s) 452–454

Abstract: A 35-year-old woman with primary infertility underwent an ovarian cystectomy for a 5 x 4 cm left adnexal mass. There was no macroscopic evidence of metastatic disease. The final pathology report revealed a poorly differentiated serous cystadenocarcinoma. ...

Abstract	A 35-year-old woman with primary infertility underwent an ovarian cystectomy for a 5 x 4 cm left adnexal mass. There was no macroscopic evidence of metastatic disease. The final pathology report revealed a poorly differentiated serous cystadenocarcinoma. Because the patient desired to retain child-bearing capacity, she refused a surgical staging of her ovarian cancer. She elected to receive combination chemotherapy. This was then followed by a negative reassessment laparotomy. The patient was diagnosed with recurrent, metastatic ovarian carcinoma 10 years later.
MeSH term(s)	Adult ; Cystadenocarcinoma, Serous/complications ; Cystadenocarcinoma, Serous/secondary ; Cystadenocarcinoma, Serous/surgery ; Female ; Humans ; Infertility, Female/etiology ; Neoplasm Recurrence, Local ; Ovarian Neoplasms/complications ; Ovarian Neoplasms/surgery ; Time Factors
Language	English
Publishing date	1999-06
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1006/gyno.1999.5357
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Zs.A 885: Show issues

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Article: Mutant p53 correlates with reduced expression of thrombospondin-1, increased angiogenesis, and metastatic progression in melanoma.

Grant, S W / Kyshtoobayeva, A S / Kurosaki, T / Jakowatz, J / Fruehauf, J P

Cancer detection and prevention

1998 Volume 22, Issue 3, Page(s) 185–194

Abstract: On the basis of reports linking mutant p53 (mp53) to decreased expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) and increased angiogenesis, we compared primary and metastatic melanoma tumor specimens to determine if these factors were ... ...

Abstract	On the basis of reports linking mutant p53 (mp53) to decreased expression of the angiogenesis inhibitor thrombospondin-1 (TSP-1) and increased angiogenesis, we compared primary and metastatic melanoma tumor specimens to determine if these factors were associated with metastatic progression. Western blotting, immunohistochemistry (IHC), and image analysis (IA) techniques were employed to evaluate the relationship between p53 status and TSP-1 expression in Zaz and M14 melanoma cell lines, and among p53, TSP-1, and angiogenesis in primary and metastatic melanomas. Zaz cells expressed wild-type p53 (WT p53) and high levels of TSP-1, while the M14 cells expressed mp53 and low TSP-1 levels. Examination of clinical melanoma specimens (N = 99) revealed an incidence of mp53 of 48%. Specimens with WT p53 (N = 46) expressed significantly higher mean levels of TSP-1 (41 +/- 27 vs. 21 +/- 24; p = 0.0004), and lower microvessel counts per 200x field (25 +/- 17 vs. 40 +/- 20; p = 0.0001) than tumors expressing mp53 (N = 42). A significantly higher incidence of mp53 expression was seen in metastatic tumors (64%, 37/58) than in primary tumors (27%, 11/41)(p < 0.0005). Primary tumors specimens had higher levels of TSP-1 (40 +/- 27 vs. 25 +/- 25; p = 0.0054) and lower microvessel counts (26 +/- 18 vs. 39 +/- 20, p = 0.0013) than metastatic tumors. These data suggest that acquisition of mp53, decreased TSP-1, and increased microvessel infiltration may be interrelated and associated with the metastatic phenotype in malignant melanoma.
MeSH term(s)	Blotting, Western ; Genes, p53/genetics ; Humans ; Immunohistochemistry ; Melanoma/blood supply ; Melanoma/genetics ; Melanoma/secondary ; Mutation/genetics ; Neovascularization, Pathologic/genetics ; Thrombospondins/antagonists & inhibitors ; Thrombospondins/biosynthesis ; Tumor Cells, Cultured
Chemical Substances	Thrombospondins
Language	English
Publishing date	1998
Publishing country	England
Document type	Journal Article
ZDB-ID	425808-3
ISSN	0361-090X
ISSN	0361-090X
DOI	10.1046/j.1525-1500.1998.0oa18.x
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Zs.A 1427: Show issues

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Article: Biochemical and pharmacological characterization of MCF-7 drug-sensitive and AdrR multidrug-resistant human breast tumor xenografts in athymic nude mice.

Mimnaugh, E G / Fairchild, C R / Fruehauf, J P / Sinha, B K

Biochemical pharmacology

1991 Volume 42, Issue 2, Page(s) 391–402

Abstract: The phenotypic expression of multidrug resistance by the doxorubicin-selected AdrR human breast tumor cell line is associated with overexpression of plasma membrane P-170 glycoprotein and increased cytosolic selenium-dependent GSH-peroxidase activity ... ...

Abstract	The phenotypic expression of multidrug resistance by the doxorubicin-selected AdrR human breast tumor cell line is associated with overexpression of plasma membrane P-170 glycoprotein and increased cytosolic selenium-dependent GSH-peroxidase activity relative to the parental MCF-7 wild-type line (WT). To determine whether doxorubicin resistance by AdrR cells persists in vivo, and to further investigate the possibility of biochemical differences between WT and AdrR solid tumors, both tumor cell lines were grown as subcutaneous xenografts in athymic nude mice. Tumorigenicity depended upon cell inoculation burden, and tumor incidence was similar for both cell lines (greater than 80% tumor takes at 10(7) cells/mouse) at 14 days, provided 17 beta-estradiol was supplied to the animals bearing the WT tumors. However, the growth rate for the AdrR xenografts was only about half that of WT xenografts. Doxorubicin (2-8 mg/kg, i.p., injected weekly) significantly diminished the growth of the WT tumors, but AdrR solid tumors failed to respond to doxorubicin. The accumulation of 14C-labeled doxorubicin was 2-fold greater in WT xenografts that in AdrR, although there were no differences in host organ drug levels in mice bearing either type of tumors. Membrane P-170 glycoprotein mRNA was detected by slot-blot analysis in the AdrR tumors, but not in WT. Electron spin resonance 5,5-dimethylpyrroline-N-oxide-spin-trapping experiments with microsomes and mitochondria from WT and AdrR xenographs demonstrated a 2-fold greater oxygen radical (superoxide and hydroxyl) formation from activated doxorubicin with WT xenographs compared to AdrR. Selenium-dependent glutathione (GSH)-peroxidase, superoxide dismutase and GSH-S-aryltransferase activities in AdrR xenografts were elevated relative to WT. Although the activities of the latter two enzymes were similar to those measured in both tumor cell lines, GSH-peroxidase activities were elevated 70-fold (WT) and 10-fold (AdrR) in xenografts compared to tumor cells. In contrast, in both WT and AdrR solid tumors in vivo, catalase, NAD(P)H-oxidoreductases, and glutathione disulfide (GSSG)-reductase activities, and GSH and GSSG levels were not markedly different, and were essentially the same as in cells in vitro. Like the MDR cells in culture, AdrR tumor xenografts were extremely resistant to doxorubicin and retained most of the characteristics of the altered phenotype. These results suggest that WT and AdrR breast tumor xenografts provide a useful model for the study of biochemical and pharmacological mechanisms of drug resistance by solid tumors in vivo.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Line/enzymology ; Cytochrome P-450 Enzyme System/metabolism ; Doxorubicin/administration & dosage ; Doxorubicin/pharmacokinetics ; Doxorubicin/pharmacology ; Drug Resistance/genetics ; Drug Tolerance/genetics ; Electron Spin Resonance Spectroscopy ; Glutathione/metabolism ; Humans ; Hydroxides/metabolism ; Hydroxyl Radical ; Membrane Glycoproteins/genetics ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Phenotype ; RNA, Messenger/analysis ; Subcellular Fractions/metabolism ; Superoxides/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Hydroxides ; Membrane Glycoproteins ; RNA, Messenger ; Superoxides (11062-77-4) ; Hydroxyl Radical (3352-57-6) ; Doxorubicin (80168379AG) ; Cytochrome P-450 Enzyme System (9035-51-2) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	1991-07-05
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/0006-2952(91)90727-m
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Zs.A 19: Show issues

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