BIOMODULATION OF CHEMORESISTANCE IN MELANOMA

  • Braunschweiger, Paul G, (PI)

Project: Research project

Description

The focus of the program is to study the modulation of chemosensitivity
by biotherapy in human malignant melanoma. The 3 projects are focused
around a randomized clinical trial in which a promising (greater than 50%
response rate) sequential biochemotherapy regimen is being tested. The
mechanisms by which biotherapy increase drug response in melanoma are
unclear. The goal of the present project is to use experimental models
of human melanoma to better understand the time and dose response
relationships for the modulation of cellular drug resistance by IL-2 and
IFNalpha and the role of tumor macrophages in these responses. Our
working hypothesis is that macrophage derived oxidants modulate the
sensitivity of human melanoma cells to cisPlatin. Implicit in this
hypothesis is that such oxidants may either increase or decrease drug
sensitivity depending on the sequence, dose and schedule of agents. In
vivo studies with xenograft models of human melanoma to identify the
temporal aspects of cytokine biotherapy induced chemosensitization and
chemoprotection will be complemented by in vitro studies to determine the
role of resident tumor macrophage derived oxidants (H2O2, O2-,NO) in the
modulation of cisPlatin sensitivity in clonogenic melanoma cells. We
will also identify relevant cytokine and anti-oxidant pathways which may
affect cytokine mediated changes in cellular chemosensitivity. Since the
working hypothesis for our IRPG is that oxidant stress can alter the
ability of tumor cells to repair cisPlatin induce DNA injury, we will use
atomic absorption spectroscopy to determine the effect of oxidant stress
on the accumulation and retention of cisPlatin in tumor cell DNA. Our
studies will complement and interdigitate with Dr. Grimm's R0-1 project
to investigate the effects of biotherapy on macrophage functions and
plasma lipid peroxidation and with Dr. Ali-Osman's project to investigate
the effects of oxidant stress on drug sensitivity in clinical material
and the repair of cis-Platin-DNA interstrand crosslinks. Our studies
will lead to a better understanding of the interaction of biotherapy and
chemotherapy and will provide insights for the design of new more
efficacious approaches for the treatment of malignant melanoma, and other
more prevalent cancers.
StatusFinished
Effective start/end date8/12/945/31/98

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $76,249.00
  • National Institutes of Health: $73,905.00
  • National Institutes of Health: $33,658.00
  • National Institutes of Health: $76,500.00
  • National Institutes of Health

Fingerprint

Oxidants
Biological Therapy
Melanoma
Cisplatin
Macrophages
Neoplasms
Cytokines
DNA
Pharmaceutical Preparations
Drug Resistance
Heterografts
Lipid Peroxidation
DNA Damage
Interleukin-2
Spectrum Analysis
Appointments and Schedules
Randomized Controlled Trials

ASJC

  • Medicine(all)