Oral Recombinant Methioninase Sensitizes a Bladder Cancer Orthotopic Xenograft Mouse Model to Low-dose Cisplatinum and Prevents Metastasis

Abstract

Background/Aim: The aim of the study was to determine if oral recombinant methioninase (o-rMETase) can sensitize an orthotopic bladder tumor in nude mice to low-dose cisplatinum (CDDP). Materials and Methods: The green fluorescent protein (GFP)-expressing UM-UC-3-GFP bladder cancer was surgically orthotopically implanted (SOI) to the bladder in nude mice. The treatment was initiated when the primary tumor volume reached 100 mm 3 . Mice were assigned to 3 groups: G1: Saline vehicle (0.1 ml per mouse, oral, twice per day); G2: low-dose CDDP (0.5 mg/kg, intraperitoneal twice per week); G3: o-rMETase + low-dose CDDP (100 units per mouse, oral, twice per day + 0.5 mg/kg, intraperitoneal twice per week, respectively). Tumor volume and body weight were measured twice per week. The expression of Ki-67 was detected by immunohistochemistry to evaluate cell proliferation. Results: The combination of o-rMETase and low-dose CDDP increased inhibition efficacy compared to low-dose CDDP monotherapy, on primary-tumor growth (p=0.032) and metastasis (p=0.002). Conclusion: The combination of o-rMETase with low-dose CDDP has future clinical potential for bladder cancer.

Anticancer activity and metabolic profile alterations by ortho‐topolin riboside in in vitro and in vivo models of non‐small cell lung cancer

“…Furthermore, conventional dosing interval in anticancer activity screening studies of twice a week was selected in our study. 37,38 Interestingly, the second dose, with 50% dose increase in the first dose, did not affect the tumor growth inhibition remarkably (Figure 2B), but exerted significant changes in endogenous metabolites, as described below.…”

Oral-recombinant Methioninase Converts an Osteosarcoma from Methotrexate-resistant to -sensitive in a Patient-derived Orthotopic-xenograft (PDOX) Mouse Model

“…r-METase effectively degrades external methionine (63). The efficacy of orally-administrated r-METase (o-rMETase) was shown previously shown in many types of cancer in PDOX models (18,21,22,(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(51)(52)(53)(54)(55)(56)(57)(58). We have also reported the efficacy of rMETase on PDOX models of osteosarcoma including o-rMETase (8,10,18,21,22).…”

“…o-rMETase has also been shown to prevent obesity, diabetes and fatty liver in mouse models (47)(48)(49). o-rMETase has also shown apparent clinical efficacy in advanced prostate cancer (50), reflecting its efficacy in PDOX models of advanced cancers (51)(52)(53)(54)(55)(56)(57)(58).…”

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

“…We have previously shown in mouse models that the combination of oral rMETase (o-rMETase) and cisplatinum has a synergistic effect on colon and bladder cancer (13,14). In the present study, we investigated the efficacy of this combination in a PDOX model of primary osteosarcoma of the breast.…”