Recombinant methionine a, g-lyase (rMETase)
° Active on all major tumor types in vivo
° Synergistic with many chemotherapy drugs
° Induces tumor apoptosis
° Induces DNA hypomethylation
° Tumor selective
Synergistic effect of Methioninase (rMETase) and BCNU on human brain tumor in nude mice
D. M. Kokkinakis et al. Synergy between Methionine Stress and Chemotherapy in the Treatment of Brain Tumor Xenografts in Athmic Mice. Cancer Research 61, 4017-4023, 2001
BCNU - 35 mg/m2, rMETase - 1500 units/kg
Methioninase (rMETase) induces DNA hypomethylation in cancer cells
D. Machover et. al. Treatment of Cancer Cells with Methioninase Produces DNA Hypomethylation and Increases DNA Synthesis. Cancer Research 62, 4685-4689, 2002
Effect of rMETase on DNA methylation of CCRF-CEM cells. DNA methylation was measured by incorporationof the methyl radical from L-[methyl3-H]SAM in genomic DNA. Histogram represents DNA methylation by SssI CpG methylase in untreated control cells, in cells exposed to 0.3mm 5-AzaCr for 48h, and in cells exposed to rMETase at 0.2 unit/ml for 6h [rMETase(A)] and 0.02 unit ml for 72 h [rMETase(B)].
Methioninase (rMETase) PATENTS
US 5,690,929 US 5,715,835 US 5,861,154 US 5,863,788 US 5,888.506 US 5,891,704 US 6,231,854 US 6,461,851
Australia 687,768 Australia 708,361 Japan 2,930,723
1.
Hoffman, R.M. and Erbe, R.W. High
in vivo rates of methionine
biosynthesis in transformed human and malignant rat cells auxotrophic for
methionine. Proc. Natl. Acad. Sci.
USA 73, 1523-1527, 1976.
2.
Hoffman, R.M., Jacobsen, S.J., and Erbe, R.W.
Reversion to methionine independence by malignant rat and
SV40-transformed human fibroblasts. Biochem.
Biophys. Res. Commun. 82, 228-234,
1978.
3.
Hoffman, R.M., Jacobsen, S.J., and Erbe, R.W.
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. USA 76, 1313-1317,
1979.
4.
Jacobsen, S.J., Hoffman, R.M., and Erbe, R.W.
Regulation of methionine adenosyltransferase in normal diploid and
SV40-transformed human fibroblasts. J.
Natl. Cancer Inst. 65, 1237-1244,
1980.
5.
Hoffman, R.M., and Jacobsen, S.J. Reversible
growth arrest in simian virus 40-transformed human fibroblasts. Proc. Natl.
Acad. Sci. USA 77, 7306-7310, 1980.
6.
Diala, E.S., Plent, M.M., Coalson, D.W. and Hoffman, R.M.
DNA methylation in normal and SV40-transformed human fibroblasts.
Biochem. Biophys. Res. Commun. 102,
1379-1384, 1981.
7.
Coalson, D.W., Mecham, J.O., Stern, P.H. and Hoffman, R.M.
Reduced availability of endogenously synthesized methionine for S-adenosylmethionine
formation in methionine dependent cancer cells.
Proc. Natl. Acad. Sci. USA 79,
4248-4251, 1982.
8.
Diala, E.S. and Hoffman, R.M. Hypomethylation
of HeLa cell DNA and the absence of 5-methylcytosine in SV40 and adenovirus
(type 2) DNA: analysis by HPLC. Biochem.
Biophys. Res. Commun. 107, 19-26,
1982.
9.
Hoffman, R.M. Methionine
dependence in cancer cells – A review. In
Vitro 18, 421-428, 1982.
10.
Diala, E.S. and Hoffman, R.M. DNA
methylation levels in normal and chemically transformed mouse 3T3 cells. Biochem.
Biophys. Res. Commun. 104,
1489-1494, 1982.
11.
Diala, E.S., Cheah, M.S.C., Rowitch, D., and Hoffman, R.M.
Extent of DNA methylation in human tumor cells. J. Natl. Cancer Inst. 71,
755-764, 1983.[PDF]
12.
Mecham, J.O., Rowitch, D., Wallace, C.D., Stern, P.H. and Hoffman, R.M.
The metabolic defect of methionine dependence occurs frequently in human
tumor cell lines. Biochem. Biophys.
Res. Commun. 117, 429-434, 1983.
13.
Oden, K.L., Carson, K., Mecham, J.O., Hoffman, R.M. and Clarke, S.
S-adenosylmethionine synthetase in cultured normal and oncogenically-transformed
human and rat cells. Biochem.
Biophys. Acta 870,
270-277, 1983.[PDF]
14.
Stern, P.H., Mecham, J.O., Wallace, C.D. and Hoffman, R.M.
Reduced free-methionine in methionine-dependent SV40-transformed human
fibroblasts synthesizing apparently normal amounts of methionine.
J. Cell Physiol. 117, 9-14,
1983.[PDF]
15.
Cheah, M.S.C., Wallace, C.D., and Hoffman, R.M.
Hypomethylation of DNA in human cancer cells: a site-specific change in
the c-myc oncogene.
J. Natl. Cancer Inst. 73,
1057-1065, 1984.
16.
Hoffman, R.M. Altered
methionine metabolism, DNA methylation and oncogene expression in carcinogenesis:
a review and synthesis. Biochem.
Biophys. Acta, Reviews on Cancer 738,
49-87, 1984.
17.
Stern, P.H. and Hoffman, R.M. Elevated
overall rates of transmethylation in cell lines from diverse human tumors. In
Vitro – Rapid Commun. in Cell
Biology 20, 663-670, 1984.
18.
Stern, P.H., Wallace, C.D., and Hoffman, R.M.
Altered methionine metabolism occurs in all members of a set of diverse
human tumor cell lines. J. Cell
Physiol. 119, 29-34, 1984.
19. Hoffman, R.M. Altered methionine metabolism and transmethylation in cancer. Anticancer Research 5, 1-30, 1985.[PDF]
20.
Hoffman, R.M. and Stern, P.H. Cancer,
methionine and transmethylation. In
Biological Methylation and Drug Design,
Borchardt, R.T., Creveling, C.R., and Ueland, P.M., eds., Clifton, New Jersey,
The Human Press Inc., 215-225, 1986.
21.
Stern, P.H. and Hoffman, R.M. Enhanced
in vitro selective toxicity of
chemotherapeutic agents for human cancer cells based on a metabolic defect.
J. Natl. Cancer Inst. 76,
629-639, 1986.
22.
Hoffman, R.M. Altered
methionine metabolism and unbalanced methylation: a possible basis for the
dynamic phenotype of cancer. Absorption
and Utilization of Amino Acids, M. Friedman, ed., CRC Press, Boca Raton,
Florida, 1-7, 1989.
23.
Hoffman, R.M. Unbalanced
transmethylation and the perturbation of the differentiated state leading to
cancer. BioEssays 12, 163-166, 1990.
24.
Guo, H.Y., Herrera, H., Groce, A., and Hoffman, R.M.
Expression of the biochemical defect of methionine dependence in fresh
patient tumors in primary histoculture. Cancer
Res. 53, 2479-2483, 1993.
25.
Guo, H.Y., Herrera, H., and Hoffman, R.M.
Unchecked DNA synthesis and blocked cell division induced by methionine
deprivation in a human prostate cancer cell line.
In Vitro Cell. Dev. Biol. 29A,
359-361, 1993.
26.
Lishko, V.K., Lishko, O.V., and Hoffman, R.M.
The preparation of endotoxin-free l-methionine-a-deamino-g-mercaptomethane-lyase
(l-methioninase) from Pseudomonas
putida. Protein Expression and
Purification 4, 529-533, 1993.
27.
Lishko, V.K., Lishko, O.V., and Hoffman, R.M.
Depletion of serum methionine by methioninase in mice. Anticancer
Research 13, 1465-1468, 1993.
28.
Guo, H., Lishko, V., Herrera, H., Groce, A., Kubota, T., and Hoffman, R.M.
Therapeutic tumor-specific cell-cycle block induced by methionine
starvation in vivo.
Cancer Res. 53, 5676-5679,
1993.
29.
Hoshiya, Y., Guo, H., Kubota, T., Inada, T., Asenuma, F., Yamada, Y., Koh,
J., Kitajima, M., and Hoffman, R.M. Human tumors are methionine dependent in
vivo. Anticancer Research
15, 717-718, 1995.
30.
Goseki, N., Yamazaki, S., Shimojyu, K., Kando, F., Maruyama, M., Endo,
M., Koike, M., and Takahashi, H. Synergistic effect of methionine-depleting
total parenteral nutrition with 5-fluorouracil on human gastric cancer: A
randomized, prospective clinical trial. Jpn.
J. Cancer Res. 86, 484-489, 1995.
31.
Tan, Y., Xu, M., Guo, H., Sun, X., Kubota, T., and Hoffman, R.M.
Anticancer efficacy of methioninase in
vivo. Anticancer Research 16,
3931-3936, 1996.
32.
Tan, Y., Zavala Sr., J., Xu, M., Zavala Jr., J., and Hoffman, R.M.
Serum methionine depletion without side effects by methioninase in
metastatic breast cancer patients. Anticancer
Research 16, 3937-3942, 1996.
33.
Guo, H., Tan, Y., Kubota, T., Moossa, A.R., and Hoffman, R.M.
Methionine depletion modulates the antitumor and antimetastatic efficacy
of ethionine. Anticancer Research 16,
2719-2724, 1996.
34.
Hoshiya, Y., Kubota, T., Matsuzaki, S., Kitajima, M., and Hoffman, R.M.
Methionine starvation modulates the efficacy of cisplatin on human breast
cancer in nude mice. Anticancer
Research 16, 3515-3518, 1996.[PDF]
35.
Goseki, N., et al. Evaluation
of the survival time of A0-90 clinical trial for progressive or recurrent
gastric cancer. J. Jpn. Soc. for
Cancer Ther., Vol. XXXI, No. 8, p. 610 (172), 20 September 1996.
36.
Tan, Y., Xu, M., Tan, X-Z., Tan, X-Y., Wang., X., Saikawa, S., Nagahama,
T., Sun, X., Lenz, M., and Hoffman, R.M. Overexpression
and large-scale production of recombinant l-methionine-a-deamino-g-
mercaptomethane-lyase for novel anticancer therapy.
Protein Expression and Purification 9,
233-245, 1997. [PDF]
37.
Hoffman, R.M. Recombinant
Methioninase. Drugs of the Future 22,
130-134, 1997.
38.
Hoffman, R.M. Methioninase:
A therapeutic for diseases related to altered methionine metabolism and
transmethylation: cancer, heart disease, obesity, aging, and Parkinson’s
disease. Human Cell 10,
69-80, 1997.
39.
Tan, Y., Zavala, J. Sr., Han, Q., Xu, M., Sun, X., Tan, X-H., Tan, X.,
Magana, R., Geller, J., and Hoffman, R.M. Recombinant methioninase infusion
reduces the biochemical endpoint of serum methionine with minimal toxicity in
high-stage cancer patients. Anticancer
Research 17, 3857-3860, 1997.
40.
Hoffman, R.M. Is methioninase useful for the prevention of
hyperhomocysteinemia-associated cardiovascular disease? Homocysteine Metabolism:
From Basic Science to Clinical Medicine. Ed: I. Graham, H. Refsum, I.H.
Rosenberg, P.M. Ueland, Kluwer Academic Publishers, Massachusetts, pp. 155-156,
1997.
41.
Kokkinakis, D.M., Schold, S.C. Jr., Hori, H., and Nobori, T.
Effect of long-term depletion of plasma methionine on the growth and
survival of human brain tumor xenografts in athymic mice.
Nutrition and Cancer 29,
195-204, 1997.
42.
Kokkinakis, D.M., von Wronski, M.A., Vuong, T.H., Brent, T.P., and Schold,
S.C. Jr. Regulation of
O6-methylguanine-DNA methyltransferase by methionine in human tumour cells.
British Journal of Cancer 75,
779-788, 1997.
43.
Hoshiya, T., Kubota, T., Inada, T., Kitajima, M., and Hoffman, R.M.
Methionine-depletion modulates the efficacy of 5-fluorouracil on human
gastic cancer in nude mice. Anticancer
Research 17, 4371-4376, 1997.
44.
Tan, Y., Sun, X., Xu, M., An, Z., Tan, X-Z., Tan, X-Y., Han, Q.,
Miljkovic, D.A., Yang, M., and Hoffman, R.M. Polyethylene glycol conjugation of
recombinant methioninase for cancer therapy.
Protein Expression and Purification 12,
45-52, 1998.
45.
Nagahama, T., Goseki, N., and Endo, M.
Doxorubicin and vincristine with methionine depletion contributed to
survival in the Yoshida sarcoma bearing rats.
Anticancer Research 18,
25-32, 1998.
46.
Yoshioka, T., Wada, T., Uchida, N., Maki, H., Yoshida, H., Ide, N.,
Kasai, H., Hojo, K., Shono, K., Maekawa, R., Yagi, S., Hoffman, R.M., and
Sugita, K. Anticancer efficacy in
vivo and in vitro, synergy with
5-fluorouracil, and safety of recombinant methioninase.
Cancer Research 58,
2583-2587, 1998.
47.
Tan, Y., Sun, X., Xu, M., Tan, X-Z., Sasson, A., Rashidi,
B., Han,
Q., Tan,
X-Y., Wang, X., An, Z., Sun, F-X.,
and Hoffman, R.M. Efficacy of
recombinant methioninase in combination with cisplatin on human colon tumors in
nude mice. Clinical Cancer Research
5, 2157-2163, 1999.
48.
Miki, K., Xu, M., An, Z., Wang, X., Yang, M., Al-Refaie, W., Sun, X.,
Baranov, E., Tan, Y., Chishima, T., Shimada, H., Moossa, A.R., Hoffman, R.M.
Survival efficacy of the combination of the methioninase gene and
methioninase in a lung cancer orthotopic model.
Cancer Gene Therapy 7,
332-338, 2000.
49.
Miki, K., Al-Refaie, W., Xu, M., Jiang, P., Tan, Y., Bouvet, M., Zhao,
M., Gupta, A., Chishima, T., Shimada, H., Makuuchi, M., Moossa, A.R., and
Hoffman, R.M. Methioninase gene
therapy of human cancer cells is synergistic with recombinant methioninase
treatment. Cancer Research 60,
2696-2702, 2000.
50.
Sridhar, V., Xu, M., Han, Q., Sun, X., Tan, Y., Hoffman, R.M., and Prasad,
G.S. Crystallization and
preliminary crystallographic characterization of recombinant L-methionine-a-deamino-g-mrcaptomethane
lyase (Methioninase). Acta Cryst., D56,
1665-1667, 2000.[PDF]
51.
Machover, D., Zittoun, J., Broet, P., Metzger, G., Orrico, M.,
Goldschmidt, E., Schilf, A., Tonetti, C., Tan, Y., Delmas-Marsalet, B., Luccioni,
C., Falissard, B., and Hoffman, R.M. Cytotoxic synergism of methioninase in
combination with 5-fluorouracil and folinic acid. Biochem. Pharmacology 61,
867-876, 2001.
52.
Kokkinakis, D.M., Hoffman, R.M., Frenkel, E.P., Wick, J.B., Han, Q., Xu,
M., Tan, Y., Schold, S.C. Synergy
between methionine stress and chemotherapy in the treatment of brain tumor
xenografts in athymic mice. Cancer
Research 61, 4017-4023, 2001.
53.
Miki, K, Xu, M., Gupta, A., Ba, Y., Tan, Y., Al-Refaie, W., Bouvet, M.,
Makuuchi, M., Moossa, A.R., and Hoffman, R.M.
Methioninase cancer gene therapy with selenomethionine as suicide prodrug
substrate. Cancer Research 61,
6805-6810, 2001. [PDF]
54. Machover D., Zittoun J., Saffroy R., Broet P., Giraudier S., Magnaldo T., Goldschmidt E., Debuire B., Orrico M., Tan Y., Mishal Z., Chevallier O., Tonetti C., Jouault H., Ulusakaraya A., Tanguy M.-L., Metzger G., Hoffman R.M. Treatment of Cancer Cells with Methioninase Produces DNA Hypomethylation and Increases DNA Synthesis. Cancer Research, 62, 4685-4689, 2002. [PDF]
55. Li, S., Yang, Z., Sun, X., Tan, Y., Yagi, S., and Hoffman, R.M. A simultaneous colorimetric assay of free and protein-coupled polyethylene glycol. Anal. Biochem. 313, 335-337, 2003.[PDF]
56. Yamamoto, N., Gupta, A., Xu, M., Miki, K. Tsujimoto, Y., Tsuchiya, H., Tomita, K., Moossa, A.R., Hoffman, R.M. Methioninase gene therapy with selenomethionine induces apoptosis in bcl-2-overproducing lung cancer cells. Cancer Gene Therapy 10, 445-450. 2003 [PDF]
57. Gupta, A., Miki, K., Xu, M., Yamamoto, N., Moosa, A.R., and Hoffman, R.M. Combination efficacy of doxorubicin and adenoviral methioninase gene therapy with prodrug selenomethionine. Anticancer Research 23, 1181-1188, 2003.[PDF]
58. Hoffman, R.M. PEG-methioninase. In: Advances in Experimental Medicine and Biology: Polymer Drugs in the Clinical Stage, vol. 519, 69-79. Maeda, H., Kabanov, A., Kataoka, K., Okano, T., eds. Dordecht, The Netherlands: Kluwer Academic/Plenum Publishers, 2003.
59. Sun, X., Yang, Z., Li,S., Tan, Y., Zhang, N., Wang, X., Yagi, S., Yoshioka, T., Takimoto, A., Mitsushima, K., Suginaka, A., Frenkel, E.P., and Hoffman, R.M. In vivo efficacy of recombinant methioninase is enchanced by the combination of polyethylene glycol conjugation and pyridoxal 5' phosphate supplementation. Cancer Research, 63, 8377-8383, 2003. [PDF]
60. Takakura, T., Mitsushima, K., Yagi, S., Inagaki, K., Tanaka, H., Esaki, N., Soda, K., Takimoto, A. Assay method for antitumor L-methionine g-lyase: comprehensive kinetic analysis of the complex reaction with L-methionine. Analytical Biochemistry 327, 233-240.2004. [PDF]
61. Yang, Z., Wang, J., Yoshioka, T., Li, B., Lu, Q., Li, S., Sun, X., Tan, Y., Yagi, S., Frenkel, E.P., Hoffman, R.M. A. Pharmacokinetics, Methionine Depletion, and Antigenecity of Recombinant Methioninase in Primates. Clinical Cancer Research 10, 2131-2138, 2004. [PDF]
62. Li, S-K., Yang, Z., Sun, X., Tan, Y., Yagi, S., and Hoffman, R.M. A. Protein carboxyl amidation increases the potential extent of protein polyethylene glycol conjugation. Analytical Biochemistry, 330, 264-271, 2004.[PDF]
63. Yang, Z., Sun, X., Li, S., Tan, Y., Wang, X., Zhang, N., Yagi, S., Takakaura, T., Kobayashi, Y., Takimoto, A., Yoshioka, T., Suginaka, A., Frenkel, E.P., and Hoffman, R.M. Circulating half-life of PEGylated recombinant methioninase holoenzyme is highly dose dependent on cofactor pyridoxal-5'-phosphate. Cancer Research 64, 5775-5778, 2004. [PDF]
64. Yang, Z., Wang, J., Lu, Q., Xu, j., Kobayashi, Y., Takakura, T., Takimoto, A., Yoshioka, T., Lian, C., Chen, C., Zhang, D., Zhang, Y., Li, S., Sun, X., Tan, Y., Yagi, S., Frenkel, E.P., and Hoffman, R.M. PEGylation confers greatly extended half-life and attenuated immunogenecity to recombinant methioninase in primates. Cancer Research 64, 6673-6678, 2004.[PDF]
65. Sun, X., Tan, Y., Yang, Z., Li, S., and Hoffman, R.M. A rapid HPLC method for the measurement of ultra-low plasma methionine concentrations applicable to methionine depletion therapy. AntCancer Research 24, 59-62, 2005.[PDF]
66. Takakura, T., Ito, T., Yagi, S., Notsu, Y., Itakura, T., Nakamura, T., Inagaki, K., Esaki, N., Hoffman, R.M., Takimoto, A. High-level expression and bulk crystallisation of recombinant L-methionine-g-lyase, an anticancer agent. Appl. Microbiol. Biotechnol. 70, 183-192, 2006. DOI: 10.1007/s00253-005-0038-2.[PDF]
67. Takakura, T., Takimoto, A., Notsu, Yoshida, H., Ito, T., Nagatome, H., Ohno, M., Kobayashi, Y., Yoshika, T., Inagaki, K., Yagi, S., Hoffman, R.M., and Esaki, N. Physicochemical and pharmacocinetic characterization og highly potent recombinant L-methionine-g-lyase conjugated with polyethylene glycol as an antitumor agent. Cancer Res. 66, 2807-2814, 2006. [PDF]