Abstract
Methionine (MET) has been shown to be a tumor-selective therapeutic target for cancer, since cancer cells require higher amounts of MET to divide and survive than normal cells. This phenomena is known as MET dependence and is probably due to MET overuse by cancer cells. A pilot clinical trial was initially carried out with non-recombinant METase (METase) produced from Pseudomonas putida and subsequently highly purified. No acute clinical toxicity was observed for any criteria measured in the three patients. The depletion of serum MET started within 30 min of the infusion and was maintained for 4 h after the infusion was completed in patient 1 and patient 2. The lowest serum MET levels were 35% and 19% of the pretreatment level, respectively, in patient 1 and patient 2. Patient 3 received a 10 h i.v. infusion of METase without any sign of side effects. MET was depleted over 200-fold from 23.1 to 0.1 μM by the 10-h infusion of patient 3. No clinical toxicity was observed in any criteria measured in patient 3. Subsequently, another pilot Phase I clinical trial was carried out of serum MET depletion in cancer patients by recombinant METase (rMETase) cloned from Pseudomonas putida and produced in E. coli. Patients with advanced breast cancer, lung cancer, renal cancer, and lymphoma were given a single rMETase treatment at doses ranging from 5000 to 20,000 units by i.v. infusion over 6–24 h. No clinical toxicity was observed in any patient after rMETase treatment. rMETase levels were measured at 0.1 to 0.4 units per ml of serum in the patients which correspond to therapeutic levels in vitro. The lowest serum MET levels in rMETase-treated patients were 0.1% of the pretreatment levels corresponding to approximately 0.1 μM, which also correlates to therapeutic levels in vitro as well as in vivo. The results of the METase and rMETase pilot Phase I clinical trials therefore indicate that i.v. infusion of rMETase is safe and effectively depletes its biochemical target of serum MET, suggesting potential efficacy in future clinical trials.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31
Hoffman RM, Jacobsen SJ (1980) Reversible growth arrest in SV40-transformed human fibroblasts. Proc Natl Acad Sci U S A 77:7306–7310
Guo H, Lishko K, Herrera H, Groce A, Kubota T, Hoffman RM (1993) Therapeutic tumor-specific cell cycle block induced by methioninase starvation in vivo. Cancer Res 53:5676–5679
Tan Y, Zavala J Sr, Xu M, Zavala J Jr, Hoffman RM (1996) Serum MET depletion without side effects by METase in metastatic breast cancer patients. Anticancer Res 16:3937–3942
Goseki N, Yamazaki S, Shimojyu K, Kando F, Maruyama M, Endo M, Koike M, Takahashi H (1995) 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
Goseki N, Yamazaki S, Endo M (1992) Antitumor effect of methionine-depleting total parenteral nutrition with doxorubicin administration on Yoshida sarcoma-bearing rate. Cancer 69:1865–1872
Tan Y, Zavala J Sr, Han Q, Xu M, Sun X, Tan X-Z, Tan X-Y, Magana R, Geller J, Hoffman RM (1997) Recombinant METase infusion reduces the biochemical endpoint of serum MET with minimal toxicity in high-stage cancer patients. Anticancer Res 17:3857–3860
Lishko VK, Lishko OV, Hoffman RM (1993) The preparation of endotoxin-free L-methionine-α-deamino-γ-mercaptomethane-lyase (L-methioninase) from Pseudomonas putida. Protein Expr Purif 4:529–533
Tan Y, Xu M, Sun X, Kubota T, Hoffman RM (1996) Anticancer efficacy of methioninase in vivo. Anticancer Res 16:3931–3936
Tan Y, Xu M, Tan XZ, Tan X, Wang X, Saikawa S, Nagahama T, Sun X, Lenz M, Hoffman RM (1997) Overexpression and large-scale production of recombinant L-methionine-α-deamino-γ-mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif 9:233–245
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, Hoffman RM (1999) Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res 5:2157–2163
Tan Y, Xu M, Hoffman RM (2010) Broad selective efficacy of recombinant methioninase and polyethylene glycol-modified recombinant methioninase on cancer cells in vitro. Anticancer Res 30:1041–1046
Jones BN, Gilligan JP (1983) α-Phthaldialdehyde precolumn derivatization and reversed-phase high-performance liquid chromatography of polypeptide hydrolysates and physiological fluids. J Chromatogr 266:471–482
Guidelines for reporting of adverse drug reactions (1985) Division of Cancer Treatment, National Cancer Institute, Bethesda, MD
Tan Y, Han O, An Z, Wang X, Hoffman RM (1995) Methioninase (AC 9301): a selective antitumor agent with a new mechanism of action. Proc Am Soc Clin Oncol 14:493
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Hoffman, R.M., Tan, Y., Li, S., Han, Q., Zavala, J., Zavala, J. (2019). Pilot Phase I Clinical Trial of Methioninase on High-Stage Cancer Patients: Rapid Depletion of Circulating Methionine. In: Hoffman, R. (eds) Methionine Dependence of Cancer and Aging. Methods in Molecular Biology, vol 1866. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8796-2_17
Download citation
DOI: https://doi.org/10.1007/978-1-4939-8796-2_17
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4939-8795-5
Online ISBN: 978-1-4939-8796-2
eBook Packages: Springer Protocols