Abstract
An excessive requirement for methionine (MET) for growth, termed MET dependence, appears to be a general metabolic defect in cancer. We have previously shown that cancer-cell growth can be selectively arrested by MET restriction such as with recombinant methioninase (rMETase). In the present study, we utilized patient-derived orthotopic xenograft (PDOX) nude mouse models with pancreatic cancer or melanoma to determine the relationship between intra-tumor MET level and tumor size. After the tumors grew to 100 mm3, the PDOX nude mice were divided into two groups: untreated control and treated with rMETase (100 units, i.p., 14 consecutive days). On day 14 from initiation of treatment, intra-tumor MET levels were measured and found to highly correlate with tumor volume, both in the pancreatic cancer PDOX (p<0.0001, R2=0.89016) and melanoma PDOX (p<0.0001, R2=0.88114). Tumors with low concentration of MET were smaller. The present results demonstrates that patient tumors are highly dependent on MET for growth and that rMETase effectively lowers tumor MET.
Highlights
Cancer cells have an elevated requirement for methionine (MET) compared to normal cells
We previously reported on the efficacy of recombinant methioninase (rMETase) against a BRAF-V600E mutant melanoma patientderived orthotopic xenograft (PDOX) nude mouse model and that rMETase sensitized the melanoma patient-derived orthotopic xenograft (PDOX) to temozolomide (TEM) [26]
Intra-tumor MET levels highly correlated with tumor volume in both the pancreatic cancer (p
Summary
Cancer cells have an elevated requirement for methionine (MET) compared to normal cells. This phenomena is termed MET dependence [1]. MET dependence appears to be due to excess use of MET for aberrant transmethylation reactions, termed the Hoffman effect [6,7,8,9,10,11], analogous to the Warburg effect for glucose in cancer [12]. The excessive and aberrant use of MET in cancer is observed in [11C] MET PET imaging, where high uptake of [11C] MET results in a very strong and selective tumor signal compared with normal tissue background. For the large-scale production of METase, the gene from P. putida has been cloned in Escherichia coli and a purification protocol for recombinant METase (rMETase) has been established with high purity and low endotoxin [20,21,22,23,24,25]
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