The goal is to develop a rationale for clinical trials in which patients whose cancer cells are methylthioadenosine (MTA) phosphorylase-deficient can be treated with a non-toxic regimen consisting of methionine deprivation and MTA supplementation.
The specific aims are 1) to screen 200-300 human cancers for MTA phosphorylase (MTAse) activity to determine the frequency of MTAase deficiency in various tumor types, 2) to determine the ability of methionine deprivation and MTA supplementation to selectively inhibit MTAase-deficient malignant cells in vivo in mice and 3) to determine the hematopoietic toxicity (if any) of this regimen in vivo. MTA is a naturally occurring nucleoside which is degraded to methylthioribose-1-phosphate (MTR-1-P) and adenine by MTA phosphorylase in all normal mammalian cells. Both of these products of MTAase action are recycled: adenine via the purine salvage pathway to the nucleotide pool and MTR-1-P via Alpha-ketomethyl-thiobutyrate to methionine. Thus, in MTAase-containing (MTAase+) but not MTAase-deficient (MTAase-) cells, supplemental MTA could theoretically be utilized as a source of methionine and adenine. In fact, in vitro work has shown that MTAase+ cells are able to proliferate normally in methionine-free medium if supplemental MTA is added to the cultures. In contrast, MTAase- cells will not proliferate in methionine-free medium when MTA is added. Moreover, in vivo studies indicate that MTA added to a methionine-free diet prevents the development of methionine deficiency in mice. In light of these observations and the recent demonstration that a proportion of human acute leukemias and solid tumors lack MTAase, it follows that some human malignancies may be treatable with a regimen of methionine starvation and MTA supplementation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA037881-01A2S1
Application #
3175795
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1986-09-30
Project End
1990-01-31
Budget Start
1987-08-01
Budget End
1988-01-31
Support Year
1
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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