MODULATION OF MULTIDRUG RESISTANCE BY CYCLOSPORIN A

  • Erlichman, Charles, (PI)

Project: Research project

Project Details

Description

Resistance to antineoplastic drugs is a major obstacle to the effectiveness
of systemic therapy for cancer. Whereas the mechanisms of drug resistance
are multiple and multifactorial, recent information suggests that the
multidrug resistance (MDR) phenotype may be an important determinant of
both experimental and clinical resistance to doxorubicin and other
anthracyclines, to vinca alkaloids, and to etoposide. Studies in tissue
culture and experimental animals have suggested the potential for reversal
of MDR by a variety of drugs. We propose to relate the clinical outcome of
anthracycline therapy to the presence of P-glycoprotein in cells of human
tumors, and to investigate the possible reversal of the MDR phenotype using
cyclosporin A. The specific aims of this proposal are: 1) to relate response to
anthracycline therapy, to initial tumor levels of P-glycoprotein in
patients with metastatic breast cancer; 2) to compare P-glycoprotein levels
in tumor and normal tissue before and after anthracycline treatment; 3) to
determine the maximally tolerated doses of cyclosporin A and doxorubicin
used in combination, and to study their pharmacokinetics; and 4) to
determine whether cyclosporin A can reverse doxorubin resistance in
patients with metastatic colorectal or ovarian cancer. A phase II trial of anthracycline therapy in patients with metastatic
carcinoma of the breast who have failed CMF and other non-anthracyclines
containing first line treatment will be performed to assess aims 1 and 2.
Patients with a measurable lesion amenable to biopsy scheduled to receive
anthracyclines, will receive treatment after tissue biopsies have been
taken for P-glycoprotein (as determined by immunoperoxidase staining) from
tumor, white blood cells and buccal mucosa. Tumor response will be assessed
and P-glycoprotein will be re-evaluated on cessation of treatment. A phase
I trial to define the MTD and drug disposition of cyclosporin A and
doxorubicin will be performed to address aim 3. Dose escalation of
cyclosporin A given by infusion will be undertaken to reach the MTD
followed by dose escalation of doxorubicin. On completion of the phase I trial, two phase II trials of doxorubicin and
cyclosporin A will be performed in colorectal and ovarian cancer. Tumor
response will be correlated with P-glycoprotein levels before and after
treatment and with pharmacokinetic parameters. The proposed studies will
evaluate the importance of P-glycoprotein in clinical resistance to MDR and
determine whether cyclosporin A can reverse the MDR phenotype in patients.
StatusFinished
Effective start/end date6/1/905/31/93

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $130,714.00

ASJC

  • Medicine(all)

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