Methionine depletion with recombinant methioninase: In vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs Journal Article
| Authors: | Hu, J.; Cheung, N. K. V. |
| Article Title: | Methionine depletion with recombinant methioninase: In vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs |
| Abstract: | Methionine starvation can modulate gene methylation, cell cycle transition and pathways related to survival following DNA damage. Methionine depletion by recombinant methioninase (rMETase) may have in vitro and in vivo efficacy against neuroblastoma (NB), especially when combined with chemotherapeutic drugs. rMETase from Pseudomonas putida was produced in Escherichia coli and purified by ion-exchange chromatography. rMETase alone inhibited the proliferation of 15/15 NB cell lines in vitro. Among these 15 cell lines, only 66N demonstrated rMETase- induced apoptosis. rMETase alone suppressed LAN-1 and NMB-7 xenografts (p < 0.01) and no toxicities were noted other than reversible weight loss. In vitro efficacy experiments combining rME- Tase and chemotherapeutic agents were carried out using SK-NLD and SK-N-BE (1)N established at diagnosis, as well as LAN-1, SK-N-BE (2)C and NMB-7 established at relapse. Microtubule depolymerization agents including vincristine, vinorelbine, vinblatine and mebendazole showed synergism when tested in combination with rMETase in all 5 cell lines. Among DNA damaging agents, synergy with rMETase was observed only in cell lines established at diagnosis and not at relapse. Cell cycle analysis showed that rMETase arrested G2 phase and not M phase. In vivo efficacy experiments using LAN-1 and NMB-7 xenografts showed that rMETase rendered vincristine more effective than vincristine alone in tumor growth suppression (p < 0.001). In conclusion, methionine depletion inhibited NB proliferation and arrested tumor cells at G2 phase. rMETase synergized with microtubule depolymerization agents. Moreover, synergism between rMETase and DNA damaging agents was dependent on whether cell lines were established at diagnosis or at relapse. © 2008 Wiley-Liss, Inc. |
| Keywords: | controlled study; unclassified drug; human cell; cisplatin; doxorubicin; drug efficacy; drug potentiation; nonhuman; gemcitabine; paclitaxel; topotecan; antineoplastic agent; cell proliferation; mouse; animal; animals; mice; apoptosis; antimetabolites, antineoplastic; etoposide; animal experiment; animal model; 7 ethyl 10 hydroxycamptothecin; weight reduction; vincristine; in vivo study; in vitro study; drug screening; xenograft model antitumor assays; cell line, tumor; thiotepa; vinblastine; docetaxel; drug synergism; cancer inhibition; drug antagonism; xenograft; neuroblastoma; escherichia coli; recombinant proteins; recombinant protein; tumor cell line; cell cycle arrest; cancer relapse; cell cycle g2 phase; cell cycle m phase; navelbine; antineoplastic antimetabolite; microtubule; microtubule inhibitors; neuroblastoma therapy; recombinant methioninase; isofludelone; mebendazole; methionine; recombinant methionine gamma lyase; l-methionine gamma-lyase; lyase; methionine gamma lyase; depolymerization; ion exchange chromatography; pseudomonas putida; carbon-sulfur lyases |
| Journal Title: | International Journal of Cancer |
| Volume: | 124 |
| Issue: | 7 |
| ISSN: | 0020-7136 |
| Publisher: | John Wiley & Sons |
| Date Published: | 2009-04-01 |
| Start Page: | 1700 |
| End Page: | 1706 |
| Language: | English |
| DOI: | 10.1002/ijc.24104 |
| PUBMED: | 19089915 |
| PROVIDER: | scopus |
| PMCID: | PMC2700741 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: IJCNA" - "Source: Scopus" |
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