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Background/Aim: Osteosarcoma is a recalcitrant neoplasm which occurs predominantly in adolescents and young adults. Recently, using a patient-derived orthotopic xenograft (PDOX) model of malignant soft-tissue sarcoma (STS), we showed that oral recombinant methioninase (o-rMETase), in combination with caffeine, was more efficacious than o-rMETase alone in inhibiting STS tumor growth. In the present report, we determined the efficacy of o-rMETase combined with oral caffeine on a cisplatinum (CDDP)resistant osteosarcoma PDOX model. Materials and Methods: Osteosarcoma PDOX models were randomly divided into seven treatment groups (6 mice in each group): untreated control; CDDP alone; o-rMETase alone; o-rMETase with caffeine; CDDP plus o-rMETase; CDDP plus caffeine; and CDDP plus o-rMETase with caffeine. Tumor size and body weight were measured throughout the treatment. Results: Tumors regressed after treatment with CDDP plus o-rMETase with caffeine. Tumors treated with CDDP plus o-rMETase with caffeine also had the most necrosis. Conclusion: The combination of o-rMETase and caffeine together with first-line chemotherapy was efficacious for drug-resistant osteosarcoma and has clinical potential in the treatment of this highly-resistant neoplasm.Osteosarcoma is the most frequent primary malignant bone tumor. Osteosarcoma is generally treated with a combination of various chemotherapy drugs and surgery (1). Cisplatinum (CDDP) has been the most effective therapeutic option for osteosarcoma, but outcome remains poor for most osteosarcoma patients when they develop chemoresistance (2).Restriction of methionine (MET) selectively arrests cancer cells in S/G 2 with subsequent apoptosis (3). Cancer cells are highly dependent addicted on MET and their need of MET is restricted by a recombinant methioninase (rMETase). We have previously demonstrated that cancer cells arrested by MET restriction orally a are highly sensitive to caffeine because it induces mitotic catastrophe (4). We recently reported that oral rMETase (o-rMETase) inhibited tumor growth in a chemoresistant malignant soft-tissue sarcoma (STS) patient derived orthotopic xenograft (PDOX) model, and that combining o-rMETase with oral caffeine increased its efficacy (4). In addition, the tumor was regressed by adding this combination to first-line drug doxorubicin (DOX) (4). Thus, we consider that the administration of o-rMETase and caffeine together with chemotherapy is a promising strategy which could overcome chemoresistance.In this study, we analysed the efficacy of combining o-4653

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Background/Aim: Liver metastasis in colorectalcancer is a recalcitrant disease. To develop precision individualized therapy of this disease, we developed a patientderived orthotopic xenograft (PDOX) model of colorectalcancer liver metastasis. In the present report, we evaluated the efficacy of oral recombinant methioninase (o-rMETase) in combination with 5-fluorouracil (5-FU) and oxaliplatinum (OXA) on the colorectal-cancer liver metastasis PDOX mouse model. Materials and Methods: Colorectal-cancer liver metastasis PDOX models were randomized into three groups of seven mice. Group 1, untreated control with phosphate buffered saline (PBS); Group 2, treated with 5-FU + OXA; and Group 3, treated with 5-FU + OXA + o-rMETase. Results: The colorectal-cancer liver metastasis PDOX model was resistant to 5-FU + OXA (p=0.83 at day 15 of treatment, Group 2). In contrast, the colorectal-cancer liver metastasis PDOX model was arrested by o-rMETase combined with 5-FU + OXA (p<0.01 at day 15, Group 3). No significant bodyweight differences were observed among the groups. Conclusion: The combination therapy of 5-FU and OXA with o-rMETase can overcome the resistance of first line drugs for colorectal-cancer liver metastasis.The liver is the most common site of metastases for colorectal cancer. The patients who have unresectable metastases are treated by chemotherapy and have a poor outcome (1-3).We developed a patient-derived orthotopic xenograft (PDOX) nude mouse model for all major cancers (4). PDOX models are especially valuable to identify effective drugs for individual patients and for identification of transformational novel agents.Cancer cells are more dependent on methionine (MET) compared to normal cells (methionine dependence/methionine addiction) (5). MET dependence may be the only known general metabolic defect in cancer (5,6). MET restriction (MR) arrests cancer cells selectively in the S/G 2 -phase of the cell cycle (7-9). MET dependence is due to excess use of MET by cancer cells for transmethylation reactions (5,10,11). The excess use of MET in cancer is observed in the very strong signal of [ 11 C] MET positron emission tomography imaging and has been termed the "Hoffman effect" analogous to the Warburg effect for glucose (12).Recombinant methioninase (rMETase), a Pseudomonas putida enzyme cloned in E. coli, has been developed to arrest MET dependent cancer cells (13,14). We have previously shown that rMETase is highly effective on melanoma, pancreatic cancer and sarcoma PDOX models (15-18). Oral 4667

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