# PH AND IONIC EFFECTS OF HYPERTHERMIA

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 1987 · $57,729

## Abstract

When subjected to induced high fever, tumor cells undergo drastic changes,
often culminating in cell death.  Our goal has been to achieve a better
understanding of key events leading to cell death via hyperthermia, as a
correct understanding of the process may allow one to "trick" cellular
regulatory mechanisms so that it can help destroy tumor cells more
effectively with minimum harm to the surrounding normal tissues.  Success
with radiation-heat combinations has been attributed to the heat
sensitivity of hypoxic tumor cells which are otherwise radioresistant.  The
heat sensitivity of hypoxic cells in turn, has been explained in terms of
the large (two orders of magnitude) amplification of the heat effect by low
pH which hypoxia produces.  Our immediate aim is to understand the
potentiation of hyperthermia by low pH and to apply this understanding in
improving hyperthermia therapy.  Since many tumor cells maintain a normal
growth at a media pH of 6.7 and a temperature of 37 C, it is hyperthermia
that results in cells becoming sensitive to low media pH.  Evidence
suggests that the loss of K ions and the gain of H ions might be
responsible for the cellular sensitivity to low pH during hyperthermia.  In
order to reinforce this theory, it is proposed here to study the
potentiation of hyperthermia by nigericin which exchanges H for K ions.
The shift of the survival curves will be investigated as nigericin is
introduced.  The indicators of vital cellular functions will also be
monitored with the cellular content of K ions and pH.  The action of
nigericin on the mitochondria and on the plasma membrane will be separated
by employing anaerobically grown tumor cells.

When tumor cells are heated at normal pH, they also lose K and Cl ions and
gain hydrogen ions.  The driving force appears to be the accumulation of
amino acids.  The source of this excess amino acids will be found.  The
cells accumulating amino acids would be, in effect, immersed in a
hyposmolar media unless they remove their excess osmolarity instantly.  The
loss of K and chloride (Cl) ions and the gain of H ions by heated cells
are, thus, analogous to the ionic transaction known as "Volume Regulatory
Decrease" which cells placed in hyposmolar solutions undergo.  One can test
this hypothesis by the following two methods:  removing a portion or all of
amino acids in the media during hyperthermia, which should block both the
swelling and the decrease in the cell K and Cl; and secondly, demonstrating
that the KCl loss is blocked by K rich isosmolar media as the theory
predicts.

## Key facts

- **NIH application ID:** 3175442
- **Project number:** 5R01CA037660-03
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **SAM.gov UEI:** NHV3GTWSALA7
- **Principal Investigator:** PON N YI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1987
- **Award amount:** $57,729
- **Award type:** 5
- **Project period:** 1985-04-01 → 1989-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175442

## Citation

> US National Institutes of Health, RePORTER application 3175442, PH AND IONIC EFFECTS OF HYPERTHERMIA (5R01CA037660-03). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175442. Licensed CC0.

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