1AntiCancer Inc., San Diego, CA, U.S.A.
2Department of Surgery, University of California, San Diego, CA, U.S.A.
3Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
Cancer Diagnosis & Prognosis
Jan-Feb;
5(1):
27-31
DOI: 10.21873/cdp.10408
Received 26 August 2024 |
Revised 19 February 2025 |
Accepted 14 October 2024
Corresponding author
Robert M. Hoffman, Ph.D., AntiCancer Inc, 7917 Ostrow St, Suite B, San Diego, CA, 92111, U.S.A. Tel: +1 6198852284
all@anticancer.com
Abstract
Background/Aim: Metastatic prostate cancer is a recalcitrant disease. Our laboratory has previously treated prostate-cancer patients with methionine restriction effected by a low methionine diet and oral recombinant methioninase (o-rMETase), both alone and in combination with other agents. The present case is a 66-year-old patient who had a radical prostatectomy in 2019 with a Gleason score 3+3 and 3+4. The patient subsequently was treated with immunotherapy in 2021 and salvage proton-beam therapy in 2022, and subsequently treated only with o-rMETase and a low-methionine diet. The aim of the present study was to determine the long-term efficacy of methionine restriction on the patient's prostate cancer. Case Report: Starting in September 2022, the patient started methionine restriction with a low methionine-diet and o-rMETase, twice a day, after meals, at 250 units/dose. Since the start of methionine restriction, the patients’ prostate-specific antigen (PSA) has remained stable, under 2 ng/ml. Positron emission tomography/computed tomography (PET/CT) and prostate specific membrane antigen (PSMA)-PET imaging indicated in September 2023 a right pelvic-side-wall metastatic lymph node that was stable when the PSMA-PET scan was repeated in March 2024, with the standardized uptake value (SUV) decreasing from 19.39 to 14.98. A very small possible metastatic external-iliac lymph node was detected in March 2024. Thus, the lymph-node metastases were stable and did not increase. Conclusion: During the time the patient was on methionine restriction alone, effected by a low-methionine diet and o-rMETase, the metastatic prostate cancer did not progress. Further clinical studies of methionine restriction and metastatic prostate cancer are needed, including randomized clinical trials.
Keywords: prostate cancer, lymph-node metastasis, methioninase, methionine-restricted diet, PSA, PET scan, PSMA scan, stable disease
Metastatic prostate cancer is a recalcitrant disease treated by androgen-deprivation therapy (ADT) (1) and chemotherapy if the patient becomes resistant to ADT (2).
Our laboratory has discovered that methionine addiction, termed the Hoffman effect, is a fundamental and general hall-mark of cancer (3,4). We have shown that methionine addiction of cancer is effectively treated by methionine restriction with oral recombinant methioninase (o-rMETase) in mouse models of all major tumor types, including patient-derived orthotopic xenograft (PDOX) models (5-23).
Patients with metastatic cancer of major types have been treated with methionine restriction comprising o-rMETase, a low-methionine diet alone or in combination with chemotherapy, with promising results.
We have treated prostate-cancer patients similarly and have found the following: Previously a 76-year-old male with bone-metastatic prostate cancer, took o-rMETase twice a day at 250 units per dose for three months, during which the patient's prostate-specific antigen (PSA) dropped approximately 70%. During this time the patient's hemoglobin increased (24). In another previous case, a patient had a rapid rise in PSA levels, from 39 to 56 ng/ml, within 6 weeks. At the 15th week of o-rMETase administration, the PSA levels stabilized at 62 ng/ml. No overt side effects were observed (25). In another previous study, two advanced prostate-cancer patients took o-rMETase for approximately one month. One of the patients taking o-rMETase showed a 38% reduction of PSA levels and the second patient showed a 20% PSA reduction (26).
The present study is on a metastatic prostate-cancer patient who for the last two years was only treated with methionine restriction including o-rMETase and a low-methionine diet and has had a stable PSA and no further growth of a lymph node metastasis.
Case Report
The present case is a 66-year-old male who had a radical prostatectomy in 2019 with Gleason score 3+3 and 3+4. The patient subsequently was treated with immunotherapy in 2021 and salvage proton-beam therapy in 2022. Starting in September 2022, the patient started methionine restriction with a low-methionine diet and o-rMETase, twice a day after meals at 250 units/dose. Since the start of methionine restriction, the patients’ PSA has remained stable under 2 ng/ml (Figure 1). Positron emission tomography/computed tomography (PET/CT) and prostate specific membrane antigen (PSMA)-PET imaging indicated in September 2023 a right pelvic side wall metastatic lymph node that was stable when the PSMA-PET scan was repeated in March 2024, with the standardized uptake value (SUV) decreasing from 19.39 to 14.98. A very small possible metastatic external-iliac lymph node was detected in March 2024. Thus, the lymph-node metastases were stable and did not increase during methionine restriction.
Discussion
The present patient had been previously treated with a radical prostatectomy, immunotherapy and with proton beam radiation therapy. Since September 2022, the patient has only been on methionine restriction effected by a low-methionine diet and o-rMETase. The patient’s PSA has remained under 2 ng/ml for this time period (Figure 1) and a metastatic lymph node has not grown, as detected with PSMA scans, which are very sensitive. Previously we have treated prostate-cancer patients with o-rMETase and one case observed a 70% reduction in PSA over 3 months (24) and in other cases decreasing PSA, as well as stable disease (25,26).
The present case shows promise for prostate cancer patients to be treated with methionine restriction. Additional studies are needed, including randomized clinical trials, to demonstrate the efficacy of rMETase on prostate cancer.
Methionine restriction is effective because it targets the fundamental hallmark of cancer (3,4,27-50).
o-rMETase is showing clinical promise in other cancer types in addition to prostate cancer (28,51-57).
Conflicts of Interest
The Authors declare no competing interests.
Authors’ Contributions
SM was a major contributor to writing the manuscript and RMH revised the paper. QH produced o-rMETase and critically read the manuscript. KM, BMK, MS, MB, NY, KH, HK, SM, KI, TH, HT and SD critically read and approved the final manuscript.
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, John Medelsohn, MD, Professor Lev Bergelson, Professor Sheldon Penman, Professor John R. Raper and Joseph Leighton, MD.
References
1
Narayan V
,
Ross AE
,
Parikh RB
,
Nohria A
&
Morgans AK
. How to treat prostate cancer with androgen deprivation and minimize cardiovascular risk: a therapeutic tightrope. JACC CardioOncol.
3(5)
737
- 741
2021.
DOI:
10.1016/j.jaccao.2021.09.014
2
Posdzich P
,
Darr C
,
Hilser T
,
Wahl M
,
Herrmann K
,
Hadaschik B
&
Grünwald V
. Metastatic prostate cancer-a review of current treatment options and promising new approaches. Cancers (Basel).
15(2)
461
2023.
DOI:
10.3390/cancers15020461
3
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
4
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
5
Kawaguchi K
,
Igarashi K
,
Li S
,
Han Q
,
Tan Y
,
Kiyuna T
,
Miyake K
,
Murakami T
,
Chmielowski B
,
Nelson SD
,
Russell TA
,
Dry SM
,
Li Y
,
Unno M
,
Eilber FC
&
Hoffman RM
. Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget.
8(49)
85516
- 85525
2017.
DOI:
10.18632/oncotarget.20231
6
Lim HI
,
Sun YU
,
Han Q
,
Yamamoto J
&
Hoffman RM
. Efficacy of oral recombinant methioninase and eribulin on a PDOX model of triple-negative breast cancer (TNBC) liver metastasis. In Vivo.
35(5)
2531
- 2534
2021.
DOI:
10.21873/invivo.12534
7
Igarashi K
,
Li S
,
Han Q
,
Tan Y
,
Kawaguchi K
,
Murakami T
,
Kiyuna T
,
Miyake K
,
Li Y
,
Nelson SD
,
Dry SM
,
Singh AS
,
Elliott IA
,
Russell TA
,
Eckardt MA
,
Yamamoto N
,
Hayashi K
,
Kimura H
,
Miwa S
,
Tsuchiya H
,
Eilber FC
&
Hoffman RM
. Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase. J Cell Biochem.
119(4)
3537
- 3544
2018.
DOI:
10.1002/jcb.26527
8
Sugisawa N
,
Higuchi T
,
Han Q
,
Hozumi C
,
Yamamoto J
,
Tashiro Y
,
Nishino H
,
Kawaguchi K
,
Bouvet M
,
Murata T
,
Unno M
&
Hoffman RM
. Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Cancer Chemother Pharmacol.
88(1)
61
- 67
2021.
DOI:
10.1007/s00280-021-04261-x
9
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
10
Aoki Y
,
Tome Y
,
Han Q
,
Yamamoto J
,
Hamada K
,
Masaki N
,
Kubota Y
,
Bouvet M
,
Nishida K
&
Hoffman RM
. Oral-recombinant methioninase converts an osteosarcoma from methotrexate-resistant to -sensitive in a patient-derived orthotopic-xenograft (PDOX) mouse model. Anticancer Res.
42(2)
731
- 737
2022.
DOI:
10.21873/anticanres.15531
11
Murakami T
,
Li S
,
Han Q
,
Tan Y
,
Kiyuna T
,
Igarashi K
,
Kawaguchi K
,
Hwang HK
,
Miyake K
,
Singh AS
,
Nelson SD
,
Dry SM
,
Li Y
,
Hiroshima Y
,
Lwin TM
,
DeLong JC
,
Chishima T
,
Tanaka K
,
Bouvet M
,
Endo I
,
Eilber FC
&
Hoffman RM
. Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget.
8(22)
35630
- 35638
2017.
DOI:
10.18632/oncotarget.15823
12
Lim HI
,
Yamamoto J
,
Han Q
,
Sun YU
,
Nishino H
,
Tashiro Y
,
Sugisawa N
,
Tan Y
,
Choi HJ
,
Nam SJ
,
Bouvet M
&
Hoffman RM
. Response of triple-negative breast cancer liver metastasis to oral recombinant methioninase in a patient-derived orthotopic xenograft (PDOX) model. In Vivo.
34(6)
3163
- 3169
2020.
DOI:
10.21873/invivo.12151
13
Kawaguchi K
,
Han Q
,
Li S
,
Tan Y
,
Igarashi K
,
Kiyuna T
,
Miyake K
,
Miyake M
,
Chmielowski B
,
Nelson SD
,
Russell TA
,
Dry SM
,
Li Y
,
Singh AS
,
Eckardt MA
,
Unno M
,
Eilber FC
&
Hoffman RM
. Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for chronic clinical cancer therapy and prevention. Cell Cycle.
17(3)
356
- 361
2018.
DOI:
10.1080/15384101.2017.1405195
14
Masaki N
,
Han Q
,
Samonte C
,
Wu NF
,
Hozumi C
,
Wu J
,
Obara K
,
Kubota Y
,
Aoki Y
,
Bouvet M
&
Hoffman RM
. Oral-recombinant methioninase in combination with rapamycin eradicates osteosarcoma of the breast in a patient-derived orthotopic xenograft mouse model. Anticancer Res.
42(11)
5217
- 5222
2022.
DOI:
10.21873/anticanres.16028
15
Igarashi K
,
Kawaguchi K
,
Li S
,
Han Q
,
Tan Y
,
Murakami T
,
Kiyuna T
,
Miyake K
,
Miyake M
,
Singh AS
,
Eckardt MA
,
Nelson SD
,
Russell TA
,
Dry SM
,
Li Y
,
Yamamoto N
,
Hayashi K
,
Kimura H
,
Miwa S
,
Tsuchiya H
,
Singh SR
,
Eilber FC
&
Hoffman RM
. Recombinant methioninase in combination with doxorubicin (DOX) overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma. Cancer Lett.
417
168
- 173
2018.
DOI:
10.1016/j.canlet.2017.12.028
16
Kawaguchi K
,
Miyake K
,
Han Q
,
Li S
,
Tan Y
,
Igarashi K
,
Lwin TM
,
Higuchi T
,
Kiyuna T
,
Miyake M
,
Oshiro H
,
Bouvet M
,
Unno M
&
Hoffman RM
. Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer. Cell Cycle.
17(7)
868
- 873
2018.
DOI:
10.1080/15384101.2018.1445907
17
Masaki N
,
Han Q
,
Wu NF
,
Samonte C
,
Wu J
,
Hozumi C
,
Obara K
,
Kubota Y
,
Aoki Y
,
Miyazaki J
&
Hoffman RM
. Oral-recombinant methioninase lowers the effective dose and eliminates toxicity of cisplatinum for primary osteosarcoma of the mammary gland in a patient-derived orthotopic xenograft mouse model. In Vivo.
36(6)
2598
- 2603
2022.
DOI:
10.21873/invivo.12994
18
Park JH
,
Han Q
,
Zhao M
,
Tan Y
,
Higuchi T
,
Yoon SN
,
Sugisawa N
,
Yamamoto J
,
Bouvet M
,
Clary B
,
Singh SR
&
Hoffman RM
. Oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil regressed a colon cancer growing on the peritoneal surface in a patient-derived orthotopic xenograft mouse model. Tissue Cell.
61
109
- 114
2019.
DOI:
10.1016/j.tice.2019.09.006
19
Park JH
,
Zhao M
,
Han Q
,
Sun Y
,
Higuchi T
,
Sugisawa N
,
Yamamoto J
,
Singh SR
,
Clary B
,
Bouvet M
&
Hoffman RM
. Efficacy of oral recombinant methioninase combined with oxaliplatinum and 5-fluorouracil on primary colon cancer in a patient-derived orthotopic xenograft mouse model. Biochem Biophys Res Commun.
518(2)
306
- 310
2019.
DOI:
10.1016/j.bbrc.2019.08.051
20
Igarashi K
,
Kawaguchi K
,
Kiyuna T
,
Miyake K
,
Miyaki M
,
Yamamoto N
,
Hayashi K
,
Kimura H
,
Miwa S
,
Higuchi T
,
Singh AS
,
Chmielowski B
,
Nelson SD
,
Russell TA
,
Eckardt MA
,
Dry SM
,
Li Y
,
Singh SR
,
Chawla SP
,
Eilber FC
,
Tsuchiya H
&
Hoffman RM
. Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma. Biochem Biophys Res Commun.
506(4)
912
- 917
2018.
DOI:
10.1016/j.bbrc.2018.10.119
21
Higuchi T
,
Sugisawa N
,
Yamamoto J
,
Oshiro H
,
Han Q
,
Yamamoto N
,
Hayashi K
,
Kimura H
,
Miwa S
,
Igarashi K
,
Tan Y
,
Kuchipudi S
,
Bouvet M
,
Singh SR
,
Tsuchiya H
&
Hoffman RM
. The combination of oral-recombinant methioninase and azacitidine arrests a chemotherapy-resistant osteosarcoma patient-derived orthotopic xenograft mouse model. Cancer Chemother Pharmacol.
85(2)
285
- 291
2020.
DOI:
10.1007/s00280-019-03986-0
22
Higuchi T
,
Han Q
,
Miyake K
,
Oshiro H
,
Sugisawa N
,
Tan Y
,
Yamamoto N
,
Hayashi K
,
Kimura H
,
Miwa S
,
Igarashi K
,
Bouvet M
,
Singh SR
,
Tsuchiya H
&
Hoffman RM
. Combination of oral recombinant methioninase and decitabine arrests a chemotherapy-resistant undifferentiated soft-tissue sarcoma patient-derived orthotopic xenograft mouse model. Biochem Biophys Res Commun.
523(1)
135
- 139
2020.
DOI:
10.1016/j.bbrc.2019.12.024
23
Oshiro H
,
Tome Y
,
Kiyuna T
,
Yoon SN
,
Lwin TM
,
Han Q
,
Tan Y
,
Miyake K
,
Higuchi T
,
Sugisawa N
,
Katsuya Y
,
Park JH
,
Zang Z
,
Razmjooei S
,
Bouvet M
,
Clary B
,
Singh SR
,
Kanaya F
,
Nishida K
&
Hoffman RM
. Oral recombinant methioninase overcomes colorectal-cancer liver metastasis resistance to the combination of 5-fluorouracil and oxaliplatinum in a patient-derived orthotopic xenograft mouse model. Anticancer Res.
39(9)
4667
- 4671
2019.
DOI:
10.21873/anticanres.13648
24
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
25
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
26
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
27
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
28
Yamamoto J
,
Han Q
,
Simon M
,
Thomas D
&
Hoffman RM
. Methionine restriction: ready for prime time in the cancer clinic. Anticancer Res.
42(2)
641
- 644
2022.
DOI:
10.21873/anticanres.15521
29
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
30
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
31
Stern PH
,
Wallace CD
&
Hoffman RM
. Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol.
119(1)
29
- 34
1984.
DOI:
10.1002/jcp.1041190106
32
Stern PH
&
Hoffman RM
. Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. JNCI J Natl Cancer Inst.
76(4)
629
- 639
1986.
DOI:
10.1093/jnci/76.4.629
33
Stern PH
&
Hoffman RM
. The chemical synthesis of high specific-activity [35S]adenosylhomocysteine. Anal Biochem.
158(2)
408
- 412
1986.
DOI:
10.1016/0003-2697(86)90568-3
34
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
35
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
36
Kaiser P
. Methionine dependence of cancer. Biomolecules.
10(4)
568
2020.
DOI:
10.3390/biom10040568
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
Abo Qoura L
,
Balakin KV
,
Hoffman RM
&
Pokrovsky VS
. The potential of methioninase for cancer treatment. Biochim Biophys Acta Rev Cancer.
1879(4)
189122
2024.
DOI:
10.1016/j.bbcan.2024.189122
45
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
46
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
47
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
48
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
49
Tan Y
,
Xu M
&
Hoffman RM
. Broad selective efficacy of recombinant methioninase and polyethylene glycol-modified recombinant methioninase on cancer cells In Vitro.. Anticancer Res.
30(4)
1041
- 1046
2010.
50
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
1034
- 1038
2020.
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.
DOI:
10.21873/anticanres.15734
52
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
53
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
54
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
55
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
56
Sato M
,
Han Q
,
Hozumi C
,
Kujiraoka H
,
Mizuta K
,
Morinaga S
,
Kang BM
,
Kobayashi N
,
Ichikawa Y
,
Nakajima A
&
Hoffman RM
. First-line Chemotherapy in combination with oral recombinant methioninase and a low-methionine diet for a stage IV inoperable pancreatic-cancer patient resulted in 40% tumor reduction and an 86% CA19-9 biomarker decrease. Anticancer Res.
44(9)
3885
- 3889
2024.
DOI:
10.21873/anticanres.17215
57
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