# ANTINEOPLASTIC AGENTS FROM MARINE ORGANISMS

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 1993 · $189,423

## Abstract

We have successfully identified a number of novel classes of natural
products produced by marine organisms with very potent activity against
murine and human tumors.  Specifically, in the last grant period more
than twenty papers have been published describing new biologically active
metabolites.  Major advances have also been made in the level of
sophistication and significance of the biological and the pharmacological
components of the program.  The result has been the submission of two
patents and three manuscripts describing the pharmacology of the
compounds isolated as part of this program.  Although the overall
objectives of the program remain unchanged (to characterize potential
antitumor metabolites produced by marine invertebrate animals), the
approaches to accomplishing this goal have changed greatly.  One of the
lessons that we have learned during this last grant period is that
cytotoxicity data against a single cell line is inadequate to judge the
potential utility of new classes of metabolites and to prioritize them
for further study.  Consequently, the sub-contract for L1210 screening at
Vermont was terminated and a new program was established at Utah.
Initial screening of extracts for antineoplastic activity is now
performed against a panel of human solid tumor cell lines.  This panel
includes several cell lines with specific resistance phenotypes that were
developed here at the University of Utah and a panel developed at Lederle
Laboratories.  Partially purified fractions and pure compounds are tested
in a second panel of drug sensitive Chinese Hamster Ovary (CHO) mutant
cell lines that provide information about the mechanism of action, in
vitro enzyme inhibition assays, and finally in vivo studies in athymic
mice against the specific human tumor(s) that display sensitivity in
vitro.  The mechanism of action studies and enzyme inhibition assays
focus primarily on interaction with, and inhibition of DNA function.  The
CHO mutants display specific deficiencies in DNA repair of single strand
breaks, double strand breaks, or formation of bulky adducts.  These
assays are complemented by topoisomerase (TOPO) I and II inhibition
assays, DNA strand cleavage and ethidium bromide exclusion assays.

Although there is a clear emphasis placed in the proposal on metabolites
that interact with DNA, metabolite, with promising activity but other
mechanisms of action will not be excluded or selected against by the
initial screening protocol.  Bistramide A is an excellent example. It did
not show activity in the DNA oriented mechanism screens, however it did
show a very promising profile in the cell based screen at Lederle.  Based
on these results, bistramide A was evaluated in vivo and showed
significant activity against the ovarian carcinoma Ovcar3, and in fact
was more active against the solid tumor than against P388.  In fact we
believe that our protocol is capable of selecting for compounds active
against human solid tumor diseases.

## Key facts

- **NIH application ID:** 3174221
- **Project number:** 2R01CA036622-11
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **SAM.gov UEI:** LL8GLEVH6MG3
- **Principal Investigator:** Chris M. Ireland
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $189,423
- **Award type:** 2
- **Project period:** 1983-09-01 → 1997-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3174221

## Citation

> US National Institutes of Health, RePORTER application 3174221, ANTINEOPLASTIC AGENTS FROM MARINE ORGANISMS (2R01CA036622-11). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3174221. Licensed CC0.

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