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Abstract
Methionine dependence is due to the overuse of methionine for aberrant transmethylation reactions in cancer. Methionine dependence may be the only general metabolic defect in cancer. In order to exploit methionine dependence for therapy, our laboratory previously cloned L-methionine α-deamino-γ-mercaptomethane lyase [EC 4.4.1.11]). The cloned methioninase, termed recombinant methioninase, or rMETase, has been tested in mouse models of human cancer cell lines. Ewing's sarcoma is recalcitrant disease even though development of multimodal therapy has improved patients'outcome. Here we report efficacy of rMETase against Ewing's sarcoma in a patient-derived orthotopic xenograft (PDOX) model. The Ewing's sarcoma was implanted in the right chest wall of nude mice to establish a PDOX model. Eight Ewing's sarcoma PDOX mice were randomized into untreated control group (n = 4) and rMETase treatment group (n = 4). rMETase (100 units) was injected intraperitoneally (i.p.) every 24 hours for 14 consecutive days. All mice were sacrificed on day-15, 24 hours after the last rMETase administration. rMETase effectively reduced tumor growth compared to untreated control. The methionine level both of plasma and supernatants derived from sonicated tumors was lower in the rMETase group. Body weight did not significantly differ at any time points between the 2 groups. The present study is the first demonstrating rMETase efficacy in a PDOX model, suggesting potential clinical development, especially in recalcitrant cancers such as Ewing's sarcoma.
Highlights
Methionine dependence is the enhanced requirement of methionine for cancer cells compared to normal cells
Plasma L-methionine level was effectively decreased by recombinant methioninase (rMETase) intraperitoneal injection (i.p.) in nude mice
The present study has demonstrated efficacy of rMETase on a Ewing’s sarcoma patient-derived orthotopic xenograft (PDOX) model
Summary
Methionine dependence is the enhanced requirement of methionine for cancer cells compared to normal cells. Out of 23 cell lines derived from diverse types of human tumors, 11 did not grow at all in methioninedepleted, homocysteine-containing (MET-HCY+) medium and were absolutely methionine-dependent, whereas 3 grew only slightly in this medium. The high frequency of occurrence of methionine dependence in diverse types of human cancer cells indicated that methionine dependence could be an important aspect of oncogenic transformation. Twenty-one different human tumor cell lines (4 lung, 4 colon, 4 kidney, 4 melanoma, 3 CNS, and 2 prostate) and normal cell strains were treated with recombinant methioninase (rMETase) in vitro. RMETase had a mean IC50 for the cancer cells, which was one order of magnitude lower than that for normal cell strains [4] Twenty-one different human tumor cell lines (4 lung, 4 colon, 4 kidney, 4 melanoma, 3 CNS, and 2 prostate) and normal cell strains were treated with recombinant methioninase (rMETase) in vitro. rMETase had a mean IC50 for the cancer cells, which was one order of magnitude lower than that for normal cell strains [4]
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