Abstract

The objective of this application is to investigate what roles mutations resulting in multidrug resistance play in human cancer. Such mutations are thought to limit successful chemotherapeutic treatment of advanced disease. The immediate aim is to develop sensitive and specific probes for detecting multidrug resistance cells in patient biopsies. This will be accomplished by generating monoclonal antibodies against the 170,000 dalton cell surface P-glucoprotein shown to be expressed in multidrug resistance cells. Heteroantisera against this protein already developed will be used to screen biopsy samples from cancer patients using the highly sensitive immunoblot (Western blot) procedure. DNA sequence specific for human P-glycoprotein will be cloned and used as probes for multidrug resistance mutations. Multidrug-resistant cell will be isolated in vitro from cell lines established from patient tumors. These will be studied and compared with resistant cells found in patients. This program should provide significant information concerning how drug-resistance limits chemotherapeutic treatment of malignancies. It may in addition, provide new vistas for improving therapeutic management.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037130-05
Application #
3174832
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-04-01
Project End
1990-04-30
Budget Start
1988-05-01
Budget End
1989-04-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Ontario Cancer Institute
Department
Type
DUNS #
City
Toronto
State
Country
Canada
Zip Code

  Publications

Chan, H S; Grogan, T M; Haddad, G et al. (1997) P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer Inst 89:1706-15
Chan, H S; Gallie, B L; DeBoer, G et al. (1997) MYCN protein expression as a predictor of neuroblastoma prognosis. Clin Cancer Res 3:1699-706
Shapiro, A B; Ling, V (1997) Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem Pharmacol 53:587-96
Chan, H S; Haddad, G; Zheng, L et al. (1997) Sensitive immunofluorescence detection of the expression of P-glycoprotein in malignant cells. Cytometry 29:65-75
Chan, H S; Lu, Y; Grogan, T M et al. (1997) Multidrug resistance protein (MRP) expression in retinoblastoma correlates with the rare failure of chemotherapy despite cyclosporine for reversal of P-glycoprotein. Cancer Res 57:2325-30
Chan, H S; Grogan, T M; DeBoer, G et al. (1996) Diagnosis and reversal of multidrug resistance in paediatric cancers. Eur J Cancer 32A:1051-61
Gallie, B L; Budning, A; DeBoer, G et al. (1996) Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114:1321-8
Chan, H S; DeBoer, G; Thiessen, J J et al. (1996) Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res 2:1499-508
Chan, H S; DeBoer, G; Haddad, G et al. (1995) Multidrug drug resistance in pediatric sarcomas. Hematol Oncol Clin North Am 9:889-908
Muller, C; Laurent, G; Ling, V (1995) P-glycoprotein stability is affected by serum deprivation and high cell density in multidrug-resistant cells. J Cell Physiol 163:538-44

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