# CELLULAR MECHANISMS OF HYPERTHERMIA DAMAGE

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 1987 · $135,708

## Abstract

The long-term objective of the proposed research is to gain an
understanding of the cellular lesions resulting by hyperthermia that kill
mammalian cells.  Knowledge of the cellular/molecular mechanisms by which
heat kills cells is important in developing clinical protocols utilizing
hyperthermia alone and in combination with other therapeutic modalities in
the treatment of cancer.

This proposal focuses on one potential target for critical damage, the
subplasmalemmal cytoskeleton.  The major aim will be to test the hypothesis
that damage to the microfilamentous cytoskeleton represents one of several
of the critical lesions induced by heat in mammalian cells, and that this
cytoskeletal damage is toxic if not repaired.  The role of increased levels
of cellular Ca++ on the induction and repair of cytoskeletal damage,
induced by drug manipulation and/or heat, will also be assessed.  A
comprehensive quantitative morphological study of the effects of heat on
the cytoskeletal/plasma membrane complex using synchronous CHO cells is
proposed.  Cells will be examined at varying times beginning immediately
after treatment to determine repairable and irrepairable lesions.  The
subcellular morphological endpoints and Ca++ influx will be compared to
cell survival.  Local anesthetics, cytochalasin B and D, the calcium
ionophore A23187, and the calmodulin antagonist trifluoperazine will be
used to reversibly disrupt the cytoskeleton.  Two modifiers that protect
cells against heat damage--thermotolerance and glycerol--will also be
used.  The morphological and functional integrity of the microfilamentous
cytoskeleton will be studied using light microscopy, timelapse
cinematography, fluorescence microscopy, and transmission electron
microscopy.  Emphasis will be placed on the use of critical point dried
cell fragments for quantifying ultrastructural damage to the cortical
cytoskeleton.  A bioassay for a functional cytoskeleton (the ability of
cells to respread following heat) will be used to quantify attachment with
cell survival.  Ca++ influx will be monitored using 45Ca++.  Changes in
free Ca++ levels within treated cells will be quantified using the
fluorescent quinoline Ca++-indicator "Quin 2".  Results from this project
should demonstrate whether or not damage to the microfilamentous
cytoskeleton associated with the plasma membrane represents a critical
lesion of heat (possibly modulated by increased Ca++ levels), with repair
of the damage being a prerequisite for reproductive intregrity.

## Key facts

- **NIH application ID:** 3176817
- **Project number:** 5R01CA038656-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **SAM.gov UEI:** R8JEVL4ULGB7
- **Principal Investigator:** RONALD Allen COSS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $135,708
- **Award type:** 5
- **Project period:** 1985-07-01 → 1988-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3176817

## Citation

> US National Institutes of Health, RePORTER application 3176817, CELLULAR MECHANISMS OF HYPERTHERMIA DAMAGE (5R01CA038656-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3176817. Licensed CC0.

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