Open Access
Research article | Published: 03 July 2024

The Combination of Methionine Restriction and Docetaxel Synergistically Arrests Androgen-independent Prostate Cancer But Not Normal Cells

MIZUTA KOHEI 1 2 3
, 
MORI RYOSUKE 1
, 
HAN QINGHONG 1
, 
MORINAGA SEI 1 2
, 
SATO MOTOKAZU 1 2
, 
KANG BYUNG MO 1 2
, 
BOUVET MICHAEL 2
, 
TOME YASUNORI 3
, 
NISHIDA KOTARO 3
  &  
HOFFMAN ROBERT M. 1 2

1AntiCancer Inc., San Diego, CA, U.S.A.

2Department of Surgery, University of California, San Diego, CA, U.S.A.

3Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan

Cancer Diagnosis & Prognosis Jul-Aug; 4(4): 402-407 DOI: 10.21873/cdp.10339
Received 08 March 2024 | Revised 03 December 2024 | Accepted 25 April 2024
Corresponding author
Robert M. Hoffman, Ph.D., AntiCancer, Inc., 7917 Ostrow Street, San Diego, CA 92111, U.S.A. Tel: +1 6198852284, email: all@anticancer.com and Yasunori Tome, MD, Ph.D., Department of Orthopedic Surgery, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0125, Japan. Tel.: +81 988951174, Fax: +81 988951424, email: yastome@med.u-ryukyu.ac.jp

Abstract

Background/Aim: Androgen-independent prostate cancer (AIPC) is resistant to androgen-depletion therapy and is a recalcitrant disease. Docetaxel is the first-line treatment for AIPC, but has limited efficacy and severe side-effects. All cancers are methionine-addicted, which is termed the Hoffman effect. Recombinant methioninase (rMETase) targets methionine addiction. The purpose of the present study was to determine if the combination of docetaxel and rMETase is effective for AIPC. Materials and Methods: The half-maximal inhibitory concentrations (IC50) of docetaxel and rMETase alone were determined for the human AIPC cell line PC-3 and Hs27 normal human fibroblasts in vitro. The synergistic efficacy for PC-3 and Hs27 using the combination of docetaxel and rMETase at their IC50s for PC-3 was determined. Results: The IC50 of docetaxel for PC-3 and for Hs27 was 0.72 nM and 0.94 nM, respectively. The IC50 of rMETase for PC-3 and for Hs27 was 0.67 U/ml and 0.76 U/ml, respectively. The combination of docetaxel and rMETase was synergistic for PC-3 but not Hs27 cells. Conclusion: The combination of a relatively low concentration of docetaxel and rMETase was synergistic and effective for AIPC. The present results also suggest that the effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity. The present results also suggest the future clinical potential of the combination of docetaxel and rMETase for AIPC.
Keywords: Androgen-independent prostate cancer, AIPC, PC-3, normal fibroblasts, Hs27, docetaxel, Methionine addiction, Hoffman effect, Methionine restriction, recombinant methioninase, rMETase, combination therapy, synergy

Prostate cancer is the second most common cancer in men (1). The prognosis is poor for androgen-independent prostate cancer (AIPC), which has a much higher frequency of local recurrence and distant metastasis than androgen-dependent prostate cancer (2,3). Docetaxel is first-line chemotherapy for AIPC. Docetaxel has improved clinical outcomes for AIPC (3,4). However, it has dose-limiting toxicity, and tumors treated with docetaxel can become resistant to the drug. The median overall survival of patients with metastatic AIPC with docetaxel-based chemotherapy is 18 months (5-7). Therefore, improved therapy for AIPC is urgently needed.

Methionine restriction targets the methionine addiction of cancer (8-36), which is termed the Hoffman effect (8-10,23,25,26). AntiCancer Inc. has developed recombinant methioninase (rMETase) that targets methionine addiction of cancer (11). rMETase is synergistic with chemotherapy of numerous types (12).

In the present study, we determined if the combination of docetaxel and rMETase is effective for AIPC cells and not toxic for normal cells in vitro.

Materials and Methods

Cell culture. The human AIPC cell line PC-3 and normal human Hs27 fibroblasts were obtained from the American Type Culture Collection (Manassas, VA, USA). The cells were cultured in Dulbecco’s modified Eagle’s Medium/Nutrient Mixture F-12 with GlutaMAX™ supplement (DMEM/F-12), 10% fetal bovine serum, and 100 IU/ml of penicillin/streptomycin.

Recombinant methioninase production. The methioninase gene from Pseudomonas putida was previously cloned in Escherichia coli. rMETase (Anticancer Inc., San Diego, CA, USA) was produced by fermenting recombinant E. coli. rMETase was purified with a high-yield technique that included a 60˚C thermal step, polyethylene-glycol precipitation, and diethylaminoethyl-sepharose fast-flow ion-exchange column chromatography (11).

Docetaxel and rMETase sensitivity assay. The sensitivity of PC-3 and Hs27 cells to rMETase and docetaxel was determined using the WST-8 reagent (Dojindo Laboratory, Kumamoto, Japan). The cells were cultured in 96-well plates at 1.0×103 cells/well in DMEM/F-12 overnight at 37˚C with 5% CO2. Cells were then treated with rMETase at different doses ranging from 0.125 U/ml to 16 U/ml or with docetaxel ranging from 0.5 nM to 64 nM for the 72 h at 37˚C with 5% CO2. Following rMETase or docetaxel treatment, the WST-8 (10 μl) reagent was added to each well, and the cells were incubated for 1 hour. The absorbance was then measured using a microplate reader (Sunrise; Tecan, Männedorf, Switzerland) at 450 nm. Drug sensitivity was analyzed with Microsoft Excel for Windows 2016 ver. 2309 (Microsoft, Redmond, WA, USA), ImageJ ver. 1.53t (National Institutes of Health, Bethesda, MD, USA) and GraphPad Prism 10.0.3 (GraphPad Software, Inc., San Diego, CA, USA) to create drug-sensitivity curves and calculate half-maximal inhibitory concentration (IC50) values. Experiments were repeated twice, in triplicate.

Efficacy of the combination of rMETase and docetaxel. The viability of PC-3 and Hs27 cells after treatment with the combination of docetaxel and rMETase, using the IC50 concentrations for PC-3 cells, was determined with the WST-8 reagent. Following combination treatment, the absorbances were measured, and cell viability was calculated. Experiments were repeated twice, in triplicate.

Statistical analysis. Tukey’s multiple comparison test was used to compare data between groups. Data are presented as mean±standard deviation. Statistical analyses were performed with GraphPad Prism 10.0.3. Values of p≤0.05 were considered significant.

Results

Determination of the IC50 of rMETase and docetaxel. The IC50 of docetaxel alone was 0.73 nM for PC-3 and 0.95 nM for Hs27 cells (Figure 1). The IC50 of rMETase alone was 0.67 U/ml for PC-3 and 0.76 U/ml for Hs27 cells (Figure 2).

Determination of synergy of the combination of rMETase and docetaxel. With the combination of rMETase and docetaxel, the viability of PC-3 cells was significantly reduced compared with docetaxel or rMETase alone (p=0.0081). In contrast, the viability did not differ significantly between Hs27 cells treated with docetaxel or rMETase alone and Hs27 cells treated with the combination (Figure 3).

Discussion

In the present study, we observed greater efficacy with the combination of docetaxel and rMETase than with either agent alone for PC-3 AIPC cells but not for Hs27 normal fibroblasts.

Docetaxel inhibits microtubule depolymerization and arrests cells in the G2/M phase of the cell cycle, leading to apoptosis (13). Synergy with the combination of docetaxel and rMETase may be due to cancer-cell-selective arrest in late-S/G2 phase by rMETase (14,15). The synergy of combination therapy for PC-3 cells might occur because rMETase leads to cell death in the S/G2 phase, and some cells that escape rMETase treatment are then killed by docetaxel in the G2/M phase. The combination of rMETase and docetaxel was shown to have in vivo efficacy in an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model (16). The present and previous results indicate that the cancer-specific synergy of rMETase combined with chemotherapy is a general phenomenon (12,16,30,37-45).

rMETase is effective because it targets the fundamental basis of cancer, methionine addiction (8-10,14-15,17-36), termed the Hoffman effect (8-10,23,25,26).

Conclusion

The combination of docetaxel and rMETase was synergistic and effective for PC-3 AIPC cells but not for Hs27 normal fibroblasts. The effective concentration of docetaxel can be reduced by using rMETase, which may reduce toxicity, suggesting the clinical potential of the combination of docetaxel and rMETase for AIPC, as rMETase is showing clinical promise (46-58).

Conflicts of Interest

There are no conflicts of interest, according to the Authors.

Authors’ Contributions

KM and RM performed experiments. KM, RM, and RMH wrote this article. QH provided methioninase. SM, MS, MB, YT, and KN reviewed this article.

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Professor Gordon. H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, Jack Geller, MD, Joseph R. Bertino, MD, J.A.R. Mead PhD., Eugene P. Frenkel, MD, Professor Sheldon Penman, Professor Lev Bergelson, Professor J. R. Raper and Joseph Leighton, MD. The Robert M. Hoffman Foundation for Cancer Research provided funds for this study.

References

1 Ferlay J ,  Soerjomataram I ,  Dikshit R ,  Eser S ,  Mathers C ,  Rebelo M ,  Parkin DM ,  Forman D & Bray F .  Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136(5) E359 - 86 2015. DOI: 10.1002/ijc.29210
2 Luo P ,  Jiang Q ,  Fang Q ,  Wang Y ,  Wang Z ,  Yang J ,  Tan X ,  Li W & Shi C .  The human positive cofactor 4 promotes androgen-independent prostate cancer development and progression through HIF-1α/β-catenin pathway. Am J Cancer Res. 9(4) 682 - 698 2019.
3 Lee CH & Kantoff P .  Treatment of metastatic prostate cancer in 2018. JAMA Oncol. 5(2) 263 - 264 2019. DOI: 10.1001/jamaoncol.2018.5621
4 James ND ,  Sydes MR ,  Clarke NW ,  Mason MD ,  Dearnaley DP ,  Spears MR ,  Ritchie AW ,  Parker CC ,  Russell JM ,  Attard G ,  de Bono J ,  Cross W ,  Jones RJ ,  Thalmann G ,  Amos C ,  Matheson D ,  Millman R ,  Alzouebi M ,  Beesley S ,  Birtle AJ ,  Brock S ,  Cathomas R ,  Chakraborti P ,  Chowdhury S ,  Cook A ,  Elliott T ,  Gale J ,  Gibbs S ,  Graham JD ,  Hetherington J ,  Hughes R ,  Laing R ,  McKinna F ,  McLaren DB ,  O’Sullivan JM ,  Parikh O ,  Peedell C ,  Protheroe A ,  Robinson AJ ,  Srihari N ,  Srinivasan R ,  Staffurth J ,  Sundar S ,  Tolan S ,  Tsang D ,  Wagstaff J ,  Parmar MK & STAMPEDE investigators .  Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 387(10024) 1163 - 1177 2016. DOI: 10.1016/S0140-6736(15)01037-5
5 Nozawa M ,  Mukai H ,  Takahashi S ,  Uemura H ,  Kosaka T ,  Onozawa Y ,  Miyazaki J ,  Suzuki K ,  Okihara K ,  Arai Y ,  Kamba T ,  Kato M ,  Nakai Y ,  Furuse H ,  Kume H ,  Ide H ,  Kitamura H ,  Yokomizo A ,  Kimura T ,  Tomita Y ,  Ohno K & Kakehi Y .  Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer. Int J Clin Oncol. 20(5) 1026 - 1034 2015. DOI: 10.1007/s10147-015-0820-9
6 Mukherji D ,  Omlin A ,  Pezaro C ,  Shamseddine A & de Bono J .  Metastatic castration-resistant prostate cancer (CRPC): preclinical and clinical evidence for the sequential use of novel therapeutics. Cancer Metastasis Rev. 33(2-3) 555 - 566 2014. DOI: 10.1007/s10555-013-9473-1
7 Pienta KJ .  Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol. 28(4 Suppl 15) 3 - 7 2001. DOI: 10.1016/s0093-7754(01)90148-4
8 Hoffman RM & Erbe RW .  High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci USA. 73(5) 1523 - 1527 1976. DOI: 10.1073/pnas.73.5.1523
9 Coalson DW ,  Mecham JO ,  Stern PH & Hoffman RM .  Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine-dependent cancer cells. Proc Natl Acad Sci USA. 79(14) 4248 - 4251 1982. DOI: 10.1073/pnas.79.14.4248
10 Stern PH ,  Mecham JO ,  Wallace CD & Hoffman RM .  Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine. J Cell Physiol. 117(1) 9 - 14 1983. DOI: 10.1002/jcp.1041170103
11 Tan Y ,  Xu M ,  Tan X ,  Tan X ,  Wang X ,  Saikawa Y ,  Nagahama T ,  Sun X ,  Lenz M & Hoffman RM .  Overexpression and large-scale production of recombinantl-methionine-α-deamino-γ-mercaptomethane- lyase for novel anticancer therapy. Protein Expr Purif. 9(2) 233 - 245 1997. DOI: 10.1006/prep.1996.0700
12 Kubota Y ,  Han Q ,  Aoki Y ,  Masaki N ,  Obara K ,  Hamada K ,  Hozumi C ,  Wong ACW ,  Bouvet M ,  Tsunoda T & Hoffman RM .  Synergy of combining methionine restriction and chemotherapy: the disruptive next generation of cancer treatment. Cancer Diagn Progn. 3(3) 272 - 281 2023. DOI: 10.21873/cdp.10212
13 Hoffman RM .  Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis. A review and synthesis. Biochim Biophys Acta. 738 49 - 87 1984. DOI: 10.1016/0304-419x(84)90019-2
14 Hoffman RM & Jacobsen SJ .  Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci USA. 77(12) 7306 - 7310 1980. DOI: 10.1073/pnas.77.12.7306
15 Yano S ,  Li S ,  Han Q ,  Tan Y ,  Bouvet M ,  Fujiwara T & Hoffman RM .  Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget. 5(18) 8729 - 8736 2014. DOI: 10.18632/oncotarget.2369
16 Aoki Y ,  Tome Y ,  Wu NF ,  Yamamoto J ,  Hamada K ,  Han Q ,  Bouvet M ,  Nishida K & Hoffman RM .  Oral-recombinant methioninase converts an osteosarcoma from docetaxel-resistant to -sensitive in a clinically-relevant patient-derived orthotopic-xenograft (PDOX) mouse model. Anticancer Res. 41(4) 1745 - 1751 2021. DOI: 10.21873/anticanres.14939
17 Wang Z ,  Yip LY ,  Lee JHJ ,  Wu Z ,  Chew HY ,  Chong PKW ,  Teo CC ,  Ang HY ,  Peh KLE ,  Yuan J ,  Ma S ,  Choo LSK ,  Basri N ,  Jiang X ,  Yu Q ,  Hillmer AM ,  Lim WT ,  Lim TKH ,  Takano A ,  Tan EH ,  Tan DSW ,  Ho YS ,  Lim B & Tam WL .  Methionine is a metabolic dependency of tumor-initiating cells. Nat Med. 25(5) 825 - 837 2019. DOI: 10.1038/s41591-019-0423-5
18 Stern PH & Hoffman RM .  Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro. 20(8) 663 - 670 1984. DOI: 10.1007/BF02619617
19 Yamamoto J ,  Aoki Y ,  Han Q ,  Sugisawa N ,  Sun YU ,  Hamada K ,  Nishino H ,  Inubushi S ,  Miyake K ,  Matsuyama R ,  Bouvet M ,  Endo I & Hoffman RM .  Reversion from methionine addiction to methionine independence results in loss of tumorigenic potential of highly-malignant lung-cancer cells. Anticancer Res. 41(2) 641 - 643 2021. DOI: 10.21873/anticanres.14815
20 Ghergurovich JM ,  Xu X ,  Wang JZ ,  Yang L ,  Ryseck RP ,  Wang L & Rabinowitz JD .  Methionine synthase supports tumour tetrahydrofolate pools. Nat Metab. 3(11) 1512 - 1520 2021. DOI: 10.1038/s42255-021-00465-w
21 Sullivan MR ,  Darnell AM ,  Reilly MF ,  Kunchok T ,  Joesch-Cohen L ,  Rosenberg D ,  Ali A ,  Rees MG ,  Roth JA ,  Lewis CA & Vander Heiden MG .  Methionine synthase is essential for cancer cell proliferation in physiological folate environments. Nat Metab. 3(11) 1500 - 1511 2021. DOI: 10.1038/s42255-021-00486-5
22 Yamamoto J ,  Han Q ,  Inubushi S ,  Sugisawa N ,  Hamada K ,  Nishino H ,  Miyake K ,  Kumamoto T ,  Matsuyama R ,  Bouvet M ,  Endo I & Hoffman RM .  Histone methylation status of H3K4me3 and H3K9me3 under methionine restriction is unstable in methionine-addicted cancer cells, but stable in normal cells. Biochem Biophys Res Commun. 533(4) 1034 - 1038 2020. DOI: 10.1016/j.bbrc.2020.09.108
23 Kaiser P .  Methionine dependence of cancer. Biomolecules. 10(4) 568 2020. DOI: 10.3390/biom10040568
24 Mecham JO ,  Rowitch D ,  Wallace C ,  Stern PH & Hoffman RM .  The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun. 117(2) 429 - 434 1983. DOI: 10.1016/0006-291x(83)91218-4
25 Guo R ,  Liang JH ,  Zhang Y ,  Lutchenkov M ,  Li Z ,  Wang Y ,  Trujillo-Alonso V ,  Puri R ,  Giulino-Roth L & Gewurz BE .  Methionine metabolism controls the B cell EBV epigenome and viral latency. Cell Metab. 34(9) 1280 - 1297.e9 2022. DOI: 10.1016/j.cmet.2022.08.008
26 Bin P ,  Wang C ,  Zhang H ,  Yan Y & Ren W .  Targeting methionine metabolism in cancer: opportunities and challenges. Trends Pharmacol Sci. 45(5) 395 - 405 2024. DOI: 10.1016/j.tips.2024.03.002
27 Hoffman RM ,  Jacobsen SJ & Erbe RW .  Reversion to methionine independence in simian virus 40-transformed human and malignant rat fibroblasts is associated with altered ploidy and altered properties of transformation. Proc Natl Acad Sci. 76(3) 1313 - 1317 1979. DOI: 10.1073/pnas.76.3.1313
28 Hoffman RM ,  Jacobsen SJ & Erbe RW .  Reversion to methionine independence by malignant rat and SV40-transformed human fibroblasts. Biochem Biophys Res Commun. 82(1) 228 - 234 1978. DOI: 10.1016/0006-291x(78)90600-9
29 Kubota Y ,  Sato T ,  Hozumi C ,  Han Q ,  Aoki Y ,  Masaki N ,  Obara K ,  Tsunoda T & Hoffman RM .  Superiority of [(11)C]methionine over [(18)F]deoxyglucose for PET imaging of multiple cancer types due to the methionine addiction of cancer. Int J Mol Sci. 24(3) 1935 2023. DOI: 10.3390/ijms24031935
30 Stern PH & Hoffman RM .  Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. J Natl Cancer Inst. 76(4) 629 - 639 1986. DOI: 10.1093/jnci/76.4.629
31 Hoffman RM ,  Coalson DW ,  Jacobsen SJ & Erbe RW .  Folate polyglutamate and monoglutamate accumulation in normal and SV40-transformed human fibroblasts. J Cell Physiol. 109(3) 497 - 505 1981. DOI: 10.1002/jcp.1041090316
32 Aoki Y ,  Han Q ,  Tome Y ,  Yamamoto J ,  Kubota Y ,  Masaki N ,  Obara K ,  Hamada K ,  Wang JD ,  Inubushi S ,  Bouvet M ,  Clarke SG ,  Nishida K & Hoffman RM .  Reversion of methionine addiction of osteosarcoma cells to methionine independence results in loss of malignancy, modulation of the epithelial-mesenchymal phenotype and alteration of histone-H3 lysine-methylation. Front Oncol. 12 1009548 2022. DOI: 10.3389/fonc.2022.1009548
33 Yamamoto J ,  Inubushi S ,  Han Q ,  Tashiro Y ,  Sugisawa N ,  Hamada K ,  Aoki Y ,  Miyake K ,  Matsuyama R ,  Bouvet M ,  Clarke SG ,  Endo I & Hoffman RM .  Linkage of methionine addiction, histone lysine hypermethylation, and malignancy. iScience. 25(4) 104162 2022. DOI: 10.1016/j.isci.2022.104162
34 Yamamoto J ,  Aoki Y ,  Inubushi S ,  Han Q ,  Hamada K ,  Tashiro Y ,  Miyake K ,  Matsuyama R ,  Bouvet M ,  Clarke SG ,  Endo I & Hoffman RM .  Extent and instability of trimethylation of histone H3 lysine increases with degree of malignancy and methionine addiction. Cancer Genomics Proteomics. 19(1) 12 - 18 2022. DOI: 10.21873/cgp.20299
35 Aoki Y ,  Han Q ,  Kubota Y ,  Masaki N ,  Obara K ,  Tome Y ,  Bouvet M ,  Nishida K & Hoffman RM .  Oncogenes and Methionine Addiction of Cancer: Role of c-MYC. Cancer Genomics Proteomics. 20(2) 165 - 170 2023. DOI: 10.21873/cgp.20371
36 Jacobsen SJ ,  Hoffman RM & Erbe RW .  Regulation of methionine adenosyltransferase in normal diploid and simian virus 40-transformed human fibroblasts. J Natl Cancer Inst. 65(6) 1237 - 1244 1980.
37 Sato M ,  Mizuta K ,  Han Q ,  Morinaga S ,  Kang BM ,  Kubota Y ,  Mori R ,  Baranov A ,  Kobayashi K ,  Ardjmand D ,  Kobayashi N ,  Bouvet M ,  Ichikawa Y ,  Nakajima A & Hoffman RM .  Targeting methionine addiction combined with low-dose irinotecan arrested colon cancer in contrast to high-dose irinotecan alone, which was ineffective, in a nude-mouse model. In Vivo. 38(3) 1058 - 1063 2024. DOI: 10.21873/invivo.13539
38 Morinaga S ,  Han Q ,  Kubota Y ,  Mizuta K ,  Kang BM ,  Sato M ,  Bouvet M ,  Yamamoto N ,  Hayashi K ,  Kimura H ,  Miwa S ,  Igarashi K ,  Higuchi T ,  Tsuchiya H & Hoffman RM .  Extensive synergy between recombinant methioninase and eribulin against fibrosarcoma cells but not normal fibroblasts. Anticancer Res. 44(3) 921 - 928 2024. DOI: 10.21873/anticanres.16886
39 Ardjmand D ,  Kubota Y ,  Sato M ,  Han Q ,  Mizuta K ,  Morinaga S & Hoffman RM .  Selective synergy of rapamycin combined with methioninase on cancer cells compared to normal cells. Anticancer Res. 44(3) 929 - 933 2024. DOI: 10.21873/anticanres.16887
40 Kubota Y ,  Aoki Y ,  Masaki N ,  Obara K ,  Hamada K ,  Han Q ,  Bouvet M ,  Tsunoda T & Hoffman RM .  Methionine restriction of glioma does not induce MGMT and greatly improves temozolomide efficacy in an orthotopic nude-mouse model: A potential curable approach to a clinically-incurable disease. Biochem Biophys Res Commun. 695 149418 2024. DOI: 10.1016/j.bbrc.2023.149418
41 Sato M ,  Han Q ,  Kubota Y ,  Baranov A ,  Ardjmand D ,  Mizuta K ,  Morinaga S ,  Kang BM ,  Kobayashi N ,  Bouvet M ,  Ichikawa Y ,  Nakajima A & Hoffman RM .  Recombinant methioninase decreased the effective dose of irinotecan by 15-fold against colon cancer cells: a strategy for effective low-toxicity treatment of colon cancer. Anticancer Res. 44(1) 31 - 35 2024. DOI: 10.21873/anticanres.16785
42 Aoki Y ,  Kubota Y ,  Han Q ,  Masaki N ,  Obara K ,  Bouvet M ,  Chawla SP ,  Tome Y ,  Nishida K & Hoffman RM .  The combination of methioninase and ethionine exploits methionine addiction to selectively eradicate osteosarcoma cells and not normal cells and synergistically down-regulates the expression of C-MYC. Cancer Genomics Proteomics. 20(6 suppl) 679 - 685 2023. DOI: 10.21873/cgp.20415
43 Choobin BB ,  Kubota Y ,  Han Q ,  Ardjmand D ,  Morinaga S ,  Mizuta K ,  Bouvet M ,  Tsunoda T & Hoffman RM. Recombinant methioninase lowers the effective dose of regorafenib against colon-cancer cells .  A strategy for widespread clinical use of a toxic drug. Cancer Diagn Progn. 3(6) 655 - 659 2023. DOI: 10.21873/cdp.10268
44 Miyake M ,  Miyake K ,  Han Q ,  Igarashi K ,  Kawaguchi K ,  Barangi M ,  Kiyuna T ,  Sugisawa N ,  Higuchi T ,  Oshiro H ,  Zhang Z ,  Razmjooei S ,  Bouvet M ,  Endo I & Hoffman RM .  Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer. Biochem Biophys Res Commun. 643 48 - 54 2023. DOI: 10.1016/j.bbrc.2022.12.062
45 Kim MJ ,  Han Q ,  Bouvet M ,  Hoffman RM & Park JH .  Recombinant oral methioninase (o-rMETase) combined with oxaliplatinum plus 5-fluorouracil improves survival of mice with massive colon-cancer peritoneal carcinomatosis. Anticancer Res. 43(1) 19 - 24 2023. DOI: 10.21873/anticanres.16129
46 Han Q ,  Tan Y & Hoffman RM .  Oral dosing of recombinant methioninase is associated with a 70% drop in PSA in a patient with bone-metastatic prostate cancer and 50% reduction in circulating methionine in a high-stage ovarian cancer patient. Anticancer Res. 40(5) 2813 - 2819 2020. DOI: 10.21873/anticanres.14254
47 Han Q & Hoffman RM .  Chronic treatment of an advanced prostate-cancer patient with oral methioninase resulted in long-term stabilization of rapidly rising PSA levels. In Vivo. 35(4) 2171 - 2176 2021. DOI: 10.21873/invivo.12488
48 Han Q & Hoffman RM .  Lowering and stabilizing PSA levels in advanced-prostate cancer patients with oral methioninase. Anticancer Res. 41(4) 1921 - 1926 2021. DOI: 10.21873/anticanres.14958
49 Kubota Y ,  Han Q ,  Morinaga S ,  Tsunoda T & Hoffman RM .  Rapid reduction of CEA and stable metastasis in an NRAS-mutant rectal-cancer patient treated with FOLFIRI and bevacizumab combined with oral recombinant methioninase and a low-methionine diet upon metastatic recurrence after FOLFIRI and bevacizumab treatment alone. In Vivo. 37(5) 2134 - 2138 2023. DOI: 10.21873/invivo.13310
50 Kubota Y ,  Han Q ,  Hamada K ,  Aoki Y ,  Masaki N ,  Obara K ,  Tsunoda T & Hoffman RM .  Long-term stable disease in a rectal-cancer Patient treated by methionine restriction with oral recombinant methioninase and a low-methionine diet. Anticancer Res. 42(8) 3857 - 3861 2022. DOI: 10.21873/anticanres.15877
51 Kubota Y ,  Han Q ,  Hozumi C ,  Masaki N ,  Yamamoto J ,  Aoki Y ,  Tsunoda T & Hoffman RM .  Stage IV pancreatic cancer patient treated with FOLFIRINOX combined with oral methioninase: a highly-rare case with long-term stable disease. Anticancer Res. 42(5) 2567 - 2572 2022.
52 Kubota Y ,  Han Q ,  Masaki N ,  Hozumi C ,  Hamada K ,  Aoki Y ,  Obara K ,  Tsunoda T & Hoffman RM .  Elimination of axillary-lymph-node metastases in a patient with invasive lobular breast cancer treated by first-line neo-adjuvant chemotherapy combined with methionine restriction. Anticancer Res. 42(12) 5819 - 5823 2022. DOI: 10.21873/anticanres.16089
53 Sato M ,  Han Q ,  Mizuta K ,  Mori R ,  Kang BM ,  Morinaga S ,  Kobayashi N ,  Ichikawa Y ,  Nakajima A & Hoffman RM .  Extensive shrinkage and long-term stable disease in a teenage female patient with high-grade glioma treated with temozolomide and radiation in combination with oral recombinant methioninase and a low-methionine diet. In Vivo. 38(3) 1459 - 1464 2024. DOI: 10.21873/invivo.13591
54 Sato M ,  Han Q ,  Mori R ,  Mizuta K ,  Kang BM ,  Morinaga S ,  Kobayashi N ,  Ichikawa Y ,  Nakajima A & Hoffman RM .  Reduction of tumor biomarkers from very high to normal and extensive metastatic lesions to undetectability in a patient with stage IV HER2-positive breast cancer treated with low-dose trastuzumab deruxtecan in combination with oral recombinant methioninase and a low-methionine diet. Anticancer Res. 44(4) 1499 - 1504 2024. DOI: 10.21873/anticanres.16946
55 Tan Y ,  Zavala J ,  Xu M ,  Zavala J & Hoffman RM .  Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients. Anticancer Res. 16 3937 - 3942 1996.
56 Tan Y ,  Zavala J Sr. ,  Han Q ,  Xu M ,  Sun X ,  Tan X ,  Tan X ,  Magana R ,  Geller J & Hoffman RM .  Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients. Anticancer Res. 17(5B) 3857 - 3860 1997.
57 Hoffman RM .  Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther. 15(1) 21 - 31 2015. DOI: 10.1517/14712598.2015.963050
58 Pokrovsky VS ,  Qoura LA ,  Demidova EA ,  Han Q & Hoffman RM .  Targeting methionine addiction of cancer cells with methioninase. Biochemistry (Mosc). 88(7) 944 - 952 2023. DOI: 10.1134/S0006297923070076
cdp > Vol 4 - 4 > Pages 402 - 407

Tools

Similar articles

Table of contents