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Updated: Nov 24, 2025
Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
Published on: June 20, 2015
Triple-Methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer
Norihiko Sugisawa, Jun Yamamoto, Qinghong Han1
1From the AntiCancer, Inc, San Diego.
Objectives:
Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer.
Methods:
The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control).
Results:
Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%).
Conclusions:
This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.
Insights
Triple-methyl blockade therapy effectively arrested pancreatic cancer growth in a preclinical model. This novel approach significantly reduced tumor volume and DNA methylation, offering new hope for this challenging disease.
Area of Science:
- Oncology
- Cancer Metabolism
Background:
- Methionine addiction, driven by enhanced methyl flux, is a key characteristic of cancer.
- Targeting methionine metabolism offers a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To investigate the efficacy of a novel methionine-methylation blockade strategy.
- To evaluate this strategy in a patient-derived orthotopic xenograft model of pancreatic cancer.
Main Methods:
- Pancreatic cancer xenograft mouse models were treated with various agents, including azacitidine, oral recombinant methioninase (o-rMETase), cycloleucine, and gemcitabine.
- A triple-methyl blockade therapy combining o-rMETase, cycloleucine, and azacitidine was tested.
- Tumor growth and DNA methylation levels (5-methylcytosine staining) were assessed.
Main Results:
- Triple-methyl blockade therapy significantly arrested tumor growth, outperforming individual agents and gemcitabine.
- This therapy led to a substantial increase in cancer cells negative for 5-methylcytosine, indicating reduced DNA methylation.
- Gemcitabine inhibited tumor growth but did not achieve arrest.
Conclusions:
- Triple-methyl blockade therapy demonstrates significant potential for treating pancreatic cancer.
- This novel therapeutic concept warrants further clinical investigation for this recalcitrant disease.
