EXPLOITING TUMOR HYPOXIA--PREDICTING AND TESTING THE OUTCOME

  • Bouley, Donna (PI)
  • Graves, Edward (PI)
  • Denko, Nicholas (PI)
  • Quynh-Thu Xuan, Le (PI)
  • Giaccia, Amato J. (PI)
  • Terris, David J (PI)
  • Brown, John Martin (PI)
  • Brown, John Martin (PI)
  • Pinto, Harlan (PI)
  • GIACCIA, AMATO (PI)
  • Sutherland, Robert (PI)

Project: Research project

Project Details

Description

The overall objectives of this project are two-fold. First, to
investigate in human tumor xenografts the cellular and tissue
characteristics that will determine the effectiveness of adding
tirapazamine to fractionated radiation. Second, to evaluate methods to
predict and to measure the extent of the potentiation of fractionated
radiation therapy by tirapazamine. This project will serve as the
laboratory underpinning of the clinical trial with tirapazamine and also
the clinical study of the different methods of measuring hypoxia in human
tumors.

The two major hypotheses to be tested are first, that the potentiation of
fractionated radiation by tirapazamine can be predicted prior to radiation
therapy, and second, that the response of the tumor to this treatment can
be measured soon after the beginning of the treatment. The prediction of
the effectiveness of tirapazamine will be determined by measuring single-
strand breaks in individual cells following a test dose of tirapazamine
using the Comet Assay. The first hypothesis is based on our previous
findings that cell killing of hypoxic cells underlies the potentiation of
fractionated radiation by tirapazamine and that it is DNA damage caused by
the metabolism of tirapazamine under hypoxic conditions that leads to cell
killing. The second hypothesis, that the potentiation of radiation can be
measured during therapy, is based on our previous work showing that stable
chromosome translocations can be measured using FISH with whole chromosome
probes and that these measurements may predict for the enhancement of
radiation-induced cell killing by the addition of tirapazamine.

An important question relevant to how tirapazamine should be given in
clinical practice is whether tumor oxygenation improves when tumors shrink
following treatment. If this is the case, it would suggest that
tirapazamine should not be given towards the end of therapy, or after
tumors have shrunk beyond a certain amount. This would allow higher and
more effective doses to be concentrated in the first part of the treatment
when the tumors were more hypoxic. We will investigate this question in
a number of transplanted mouse and human tumors using various assays of
hypoxic fraction. These measurements will allow us to directly relate
various assays for tumor hypoxia with similar measurements made with the
Eppendorf electrode and the Comet Assay in human tumors following
shrinkage of the tumors during therapy.

The tumors to be used in this investigation will be the HT29, HT1080,
A431, FaDu, SQ-20B, and A543 human tumor xenografts in scid mice. This
project will also interact in the identification of tumors with high and
low hypoxia and in preparation of the human tumor xenografts A431, FaDu
and SQ-20B, using the hypoxia marker EF-5 to label hypoxic cells in frozen
tumor sections.
StatusFinished
Effective start/end date6/15/965/31/18

ASJC

  • Medicine(all)