# STEP-DOWN HEATING & X-IRRADIATION OF RIF TUMORS IN VIVO

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 1989 · $93,709

## Abstract

We propose to evaluate the feasibility of tumor-targeted therapy
based on enzymes that are associated with invasiveness of tumors.
The concept relies on elevated levels of hydrolytic enzymes in
many tumors, including the RIF mouse tumor.  Normally
hydrolytic enzymes are contained in lysosomes; in tumors,
however, hydrolytic enzymes are often released in the
extracellular space.  We plan to use water-soluble conjugates of
drugs that become hydrophobic after deconjugation by tumor
enzymes (limited washout) and that sensitizer tumor cells to
hyperthermia at low concentrations.  Regional heating should then
increase differential tumor cell killing.  Deconjugated drug that
becomes trapped in normal tissue should have limited toxicity
since these tissues are not heated.

Specifically, we are evaluating differential deposition of 8-
hydroxyquinoline (8-OHQ) in RIF tumors based on the
deconjugation of 8-OHQ-glucuronide by tumor beta-glucuronidase.
We found significantly higher glucuronidase activity in RIF tumors
than in liver, kidney, duodenum, muscle or skin, both in tissue
homogenates and in minced tissue fragments.  8-OHQ-glucuronide
is nontoxic even at high concentrations and water soluble up to 10
mg/m1.  However, the aglycone 8-OHQ is insoluble in water and is
both a cytotoxin and a heat sensitizer in micromolar
concentrations.  Our preliminary data demonstrate free 8-OHQ in
RIF tumors after acidifying tumors with glucose inary data
demonstrate free 8-OHQ in RIF tumors acidifying tumors with
glucose and injecting 8-OHQ-glucuronide i.p.  Tumor
acidification, using glucose loading, may enhance tumor
glucuronidase activity (pH optimum=5), but should not affect
normal tissues.

Our principal objectives are the study of 1) cytotoxicity and heat
sensitization by 8-OHQ and selected analogs, 2) measurement of
8-OHQ accumulation and localization in vivo (tumors and normal
tissues), 3) methods for maximizing 8-OHQ trapping in tumors,
and 4) evaluation of long-term tumor control by combinations of
8-OHQ and hyperthermia with and without X-irradiation.
Methods include in vitro colony-forming ability, HPLC techniques
for 8-OHQ quantitation in tissues, fluorescent microscopy for 8-
OHQ localization, and TCD50/120 (or tumor volume)
measurements for assessing tumor control.

## Key facts

- **NIH application ID:** 3173292
- **Project number:** 5R01CA035689-06
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **SAM.gov UEI:** VDFYLZPJEAV6
- **Principal Investigator:** KURT J HENLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $93,709
- **Award type:** 5
- **Project period:** 1983-07-01 → 1990-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3173292

## Citation

> US National Institutes of Health, RePORTER application 3173292, STEP-DOWN HEATING & X-IRRADIATION OF RIF TUMORS IN VIVO (5R01CA035689-06). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3173292. Licensed CC0.

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