Identification of gene expression profiles predicting tumor cell response to L-alanosine
Abstract
The methylthioadenosine phosphorylase (MTAP) gene gained considerable interest as therapeutic target for tumors with the 9p21 deletion. This gene maps to 9p21 and loss of this chromosomal region in tumors offers an unique opportunity for chemoselective treatment, since MTAP is an important salvage enzyme for the formation of adenine that is needed for DNA synthesis. L-Alanosine, an antibiotic from Streptomyces alanosinicus, blocks the common de novo purine biosynthesis pathway and, thereby, inhibits tumor cells with MTAP deficiency. Normal cells escape the detrimental effects of L-alanosine due to their proficiency in the MTAP salvage pathway. The present analysis was undertaken to gain insights into the molecular architecture of tumor cells that determines the response to L-alanosine apart from the MTAP gene. Analysis of cell doubling times and IC(50) values for L-alanosine showed that slowly growing cell lines were more resistant to L-alanosine than rapidly growing ones. Mining the database of the National Cancer Institute (N.C.I.), for the mRNA expression of 9706 genes in 60 cell lines by means of Kendall's tau-test, false discovery rate calculation, and hierarchical cluster analysis pointed to 11 genes or expressed sequence tags whose mRNA expression correlated with the IC(50) values for L-alanosine. Furthermore, we tested L-alanosine for cross-resistance in multidrug-resistant cell lines which overexpress selectively either the P-glycoprotein/MDR1 (CEM/ADR5000), MRP1 (HL-60/AR), or BCRP (MDA-MB-231-BCRP) genes. None of the multidrug-resistant cell lines was cross-resistant to L-alanosine indicating that L-alanosine may be suitable to treat multidrug-resistant, refractory tumors in the clinic. Finally, the IC(50) values for L-alanosine of the 60 cell lines were correlated to the p53 mutational status and expression of p53 downstream genes. We found that p53 mutated cell lines were more resistant to L-alanosine than p53 wild type cell lines.
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L-alanosine inhibits conversion of inosine monophosphate to AMP and shows selective toxicity towards MTAP-null cancer cells.
“L-alanosine inhibits conversion of inosine monophosphate (IMP) to AMP, and shows selective toxicity towards MTAP-null cancer cells (Batova et al., 1999; Efferth et al., 2003; Harasawa et al., 2002), but was found to be clinically ineffective in patients with advanced MTAP-deficient tumors in a Phase II trial (Kindler et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Efferth et al., 2003
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- Authors
- Efferth, T., Gebhart, E., Ross, D. D., & Sauerbrey, A.
- Affiliations
- Heidelberg University (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- University of Maryland, Baltimore (US)
- Friedrich Schiller University Jena (DE)
- Corresponding author
- Efferth, Thomas
- ORCID
- Efferth, Thomas
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 66
- Issue
- 4
- Pages
- 613-621
- ISSN
- 0006-2952 (ISSN-L)
- OpenAlex
- W2019591001
- Cited by
- 29
- References
- 53
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 2 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2015: 1 · 2014: 4 · 2013: 1 · 2012: 3
- FWCI
- 0.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- MTAP, 9p21 deletion, purine biosynthesis inhibition, chemosensitization, gene expression profiling, multidrug resistance, cross-resistance, TP53 mutation, cell line sensitivity, IC50
- MeSH terms
- Alanine, Antibiotics, Antineoplastic, Cell Division, Humans, Cluster Analysis, Tumor Suppressor Protein p53, Drug Resistance, Multiple, HL-60 Cells, Gene Expression Profiling
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