Advertisement

Afterword: Oral Methioninase—Answer to Cancer and Fountain of Youth?

  • Robert M. HoffmanEmail author
  • Qinghong Han
  • Kei Kawaguchi
  • Shukuan Li
  • Yuying Tan
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1866)

Abstract

The elevated methionine (MET) requirement of cancer cells is termed MET dependence and is possibly the only known general metabolic defect in cancer. Targeting MET by recombinant methioninase (rMETase) can arrest the growth of cancer cells in vitro and in vivo due to their elevated requirement for MET. rMETase can also potentiate chemotherapy drugs active in S phase due to the selective arrest of cancer cells in S/G2 phase during MET restriction (MR). We previously reported that rMETase, administrated by intraperitoneal injection (ip-rMETase), could inhibit tumor growth in mouse models of cancer including patient-derived orthotopic xenograft (PDOX) mouse models. We subsequently compared ip-rMETase and oral rMETase (o-rMETase) on a melanoma PDOX mouse model. o-rMETase was significantly more effective than ip-rMETase to inhibit tumor growth without overt toxicity. The combination of o-rMETase+ip-rMETase was significantly more effective than either monotherapy and completely arrested tumor growth. Thus, o-rMETase is effective as an anticancer agent with the potential of clinical development for chronic cancer therapy as well as for cancer prevention. o-rMETase may also have potential as an antiaging agent for healthy people, since MR has been shown to extend the life span of a variety of different organisms.

Key words

Recombinant methioninase Methionine dependence Oral administration Pyridoxal-l-phosphate Melanoma PDOX Nude mice Orthotopic 

References

  1. 1.
    Hoffman RM (2015) Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: a 40-year odyssey. Expert Opin Biol Ther 15:21–31CrossRefGoogle Scholar
  2. 2.
    Hoffman RM, Erbe RW (1976) High in vivo rates of methionine biosynthesis in transformed human and malignant rat cells auxotrophic for methionine. Proc Natl Acad Sci U S A 73:1523–1527CrossRefGoogle Scholar
  3. 3.
    Stern PH, Mecham JO, Wallace CD, Hoffman RM (1983) Reduced free-methionine in methionine-dependent SV40-transformed human fibroblasts synthesizing apparently normal amounts of methionine. J Cell Physiol 117:9–14CrossRefGoogle Scholar
  4. 4.
    Stern PH, Wallace CD, Hoffman RM (1984) Altered methionine metabolism occurs in all members of a set of diverse human tumor cell lines. J Cell Physiol 119:29–34CrossRefGoogle Scholar
  5. 5.
    Stern PH, Hoffman RM (1984) Elevated overall rates of transmethylation in cell lines from diverse human tumors. In Vitro 20:663–670CrossRefGoogle Scholar
  6. 6.
    Hoffman RM (1984) Altered methionine metabolism, DNA methylation and oncogene expression in carcinogenesis: a review and synthesis. Biochim Biophys Acta 738:49–87PubMedGoogle Scholar
  7. 7.
    Coalson DW, Mecham JO, Stern PH, Hoffman RM (1982) Reduced availability of endogenously synthesized methionine for S-adenosylmethionine formation in methionine dependent cancer cells. Proc Natl Acad Sci U S A 79:4248–4251CrossRefGoogle Scholar
  8. 8.
    Hoffman RM (2017) Is DNA methylation the new guardian of genome? Mol Cytogenetics 10:11CrossRefGoogle Scholar
  9. 9.
    Hoffman RM (2017) The wayward methyl group and the cascade to cancer. Cell Cycle 16:825–829CrossRefGoogle Scholar
  10. 10.
    Tan Y, Sun X, Xu M, Tan X-Z, Sasson A, Rashidi B, Han Q, Tan X-Y, Wang X, An Z, Sun F-X, Hoffman RM (1999) Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res 5:2157–2163PubMedGoogle Scholar
  11. 11.
    Kokkinakis DM, Hoffman RM, Frenkel EP, Wick JB, Han Q, Xu M, Tan Y, Schold SC (2001) Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res 61:4017–4023PubMedGoogle Scholar
  12. 12.
    Mecham JO, Rowitch D, Wallace CD, Stern PH, Hoffman RM (1983) The metabolic defect of methionine dependence occurs frequently in human tumor cell lines. Biochem Biophys Res Commun 117:429–434CrossRefGoogle Scholar
  13. 13.
    Yoshioka T, Wada T, Uchida N, Maki H, Yoshida H, Ide N, Kasai H, Hojo K, Shono K, Maekawa R, Yagi S, Hoffman RM, Sugita K (1998) Anticancer efficacy in vivo and in vitro, synergy with 5-fluorouracil, and safety of recombinant methioninase. Cancer Res 58:2583–2587Google Scholar
  14. 14.
    Murakami T, Li S, Han Q, Tan Y, Kiyuna T, Igarashi K, Kawaguchi K, Hwang HK, Miyaki K, Singh AS, Hiroshima Y, Lwin TM, DeLong JC, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2017) Recombinant methioninase effectively targets a Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:35630–35638PubMedPubMedCentralGoogle Scholar
  15. 15.
    Kawaguchi K, Igarashi K, Li S, Han Q, Tan Y, Kiyuna T, Miyake Y, Murakami T, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Eilber FC, Hoffman RM (2017) Combination treatment with recombinant methioninase enables temozolomide to arrest a BRAF V600E melanoma growth in a patient-derived orthotopic xenograft. Oncotarget 8:85516–85525PubMedPubMedCentralGoogle Scholar
  16. 16.
    Igarashi K, Kawaguchi K, Li S, Han Q, Tan Y, Murakami T, Kiyuna T, Miyake K, Miyake M, Singh AS, Eckhadt MA, Nelson SD, Russell TA, Dry SM, Li Y, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Singh RS, Eilber FC, Hoffman RM (2018) Recombinant methioninase in combination with DOX overcomes first-line DOX resistance in a patient-derived orthotopic xenograft nude-mouse model of undifferentiated spindle-cell sarcoma. Cancer Lett 417:168–173CrossRefGoogle Scholar
  17. 17.
    Kawaguchi K, Han Q, Li S, Tan Y, Igarashi K, Miyake K, Kiyuna T, Miyake M, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Singh AS, Eckardt MA, Unno M, Eilber FC, Hoffman RM (2018) Intra-tumor L-methionine level highly correlates with tumor size in both pancreatic cancer and melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse models. Oncotarget 9:11119–11125PubMedPubMedCentralGoogle Scholar
  18. 18.
    Igarashi K, Li S, Han Q, Tan Y, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Li Y, Nelson SD, Dry SM, Singh AS, Elliott I, Russell TA, Eckhadt MA, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Eilber FC, Hoffman RM (2018) Growth of a doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase. J Cell Biochem 119:3537–3544CrossRefGoogle Scholar
  19. 19.
    Kawaguchi K, Han Q, Li S, Tan Y, Igarashi K, Kiyuna T, Miyake K, Miyake M, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Eckhardt MA, Unno M, Eilber FC, Hoffman RM (2018) Targeting methionine with oral recombinant methioninase (o-rMETase) arrests a patient-derived orthotopic xenograft (PDOX) model of BRAF-V600E mutant melanoma: implications for clinical cancer therapy and prevention. Cell Cycle 17:356–361CrossRefGoogle Scholar
  20. 20.
    Igarashi K, Kawaguchi K, Kiyuna T, Miyake K, Miyake M, Li S, Han Q, Tan Y, Zhao M, Li Y, Nelson SD, Dry SM, Singh AS, Elliott I, Russell TA, Eckardt MA, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Eilber FC, Hoffman RM (2018) Tumor-targeting Salmonella typhimurium A1-R combined with recombinant methioninase and cisplatinum eradicates an osteosarcoma cisplatinum-resistant lung metastasis in a patient-derived orthotopic xenograft (PDOX) mouse model: decoy, trap and kill chemotherapy moves toward the clinic. Cell Cycle 17:801–809CrossRefGoogle Scholar
  21. 21.
    Kawaguchi K, Miyake K, Han Q, Li S, Tan Y, Igarashi K, Lwin TM, Higuchi T, Kiyuna T, Miyake M, Oshiro H, Bouvet M, Unno M, Hoffman RM (2018) Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient-derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer. Cell Cycle 21:1–6Google Scholar
  22. 22.
    Igarashi K, Kawaguchi K, Li S, Han Q, Tan Y, Gainor E, Kiyuna T, Miyake K, Miyake M, Singh AS, Eckhadt MA, Nelson SD, Russell TA, Dry SM, Li Y, Higuchi T, Oshiro H, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Eilber FC, Hoffman RM (2018) Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX-resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 9:19263–19272PubMedPubMedCentralGoogle Scholar
  23. 23.
    Hoffman RM, Jacobsen SJ (1980) Reversible growth arrest in simian virus 40-transformed human fibroblasts. Proc Natl Acad Sci U S A 77:7306–7310CrossRefGoogle Scholar
  24. 24.
    Stern PH, Hoffman RM (1986) Enhanced in vitro selective toxicity of chemotherapeutic agents for human cancer cells based on a metabolic defect. J Natl Cancer Inst 76:629–639CrossRefGoogle Scholar
  25. 25.
    Guo H, Lishko VK, Herrera H, Groce A, Kubota T, Hoffman RM (1993) Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo. Cancer Res 53:5676–5679PubMedGoogle Scholar
  26. 26.
    Yano S, Li S, Han Q, Tan Y, Bouvet M, Fujiwara T, Hoffman RM (2014) Selective methioninase-induced trap of cancer cells in S/G2 phase visualized by FUCCI imaging confers chemosensitivity. Oncotarget 5:8729–8736CrossRefGoogle Scholar
  27. 27.
    Yano S, Takehara K, Zhao M, Tan Y, Han Q, Li S, Bouvet M, Fujiwara T, Hoffman RM (2016) Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging. Cell Cycle 15:1715–1723CrossRefGoogle Scholar
  28. 28.
    Kawaguchi K, Murakami T, Chmielowski B, Igarashi K, Kiyuna T, Unno M, Nelson SD, Russell TA, Dry SM, Li Y, Eilber FC, Hoffman RM (2016) Vemurafenib-resistant BRAF-V600E mutated melanoma is regressed by MEK targeting drug trametinib, but not cobimetinib in a patient-derived orthotopic xenograft (PDOX) mouse model. Oncotarget 7:71737–71743PubMedPubMedCentralGoogle Scholar
  29. 29.
    Kawaguchi K, Igarashi K, Murakami T, Chmiewloski B, Kiyuna T, Zhao M, Zhang Y, Singh A, Unno M, Nelson SD, Russell T, Dry SM, Li Y, Eilber FC, Hoffman RM (2016) Tumor-targeting Salmonella typhimurium A1-R combined with temozolomide regresses malignant melanoma with a BRAF-V600 mutation in a patient-derived orthotopic xenograft (PDOX) model. Oncotarget 7:85929–85936PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kawaguchi K, Igarashi K, Murakami T, Zhao M, Zhang Y, Chmielowski B, Kiyuna T, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Eilber FC, Hoffman RM (2017) Tumor-targeting Salmonella typhimurium A1-R sensitizes melanoma with a BRAF-V600E mutation to vemurafenib in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Cell Biochem 118:2314–2319CrossRefGoogle Scholar
  31. 31.
    Tan Y, Xu M, Tan X, Tan X, Wang X, Saikawa Y, Nagahama T, Sun X, Lenz M, Hoffman RM (1997) Overexpression and large-scale production of recombinant L-methionine-alpha- deamino-gamma-mercaptomethane-lyase for novel anticancer therapy. Protein Expr Purif 9:233–245CrossRefGoogle Scholar
  32. 32.
    Jones BN, Gilligan JP (1983) o-Phthaldialdehyde precolumn derivatization and reversed-phase high-performance liquid chromatography of polypeptide hydrolysates and physiological fluids. J Chromatogr 266:471–482CrossRefGoogle Scholar
  33. 33.
    Kokkinakis DM, von Wronski MA, Vuong TH, Brent TP, Schold SC Jr (1997) Regulation of O6-methylguanine-DNA methyltransferase by methionine in human tumour cells. Br J Cancer 75:779–788CrossRefGoogle Scholar
  34. 34.
    Kokkinakis DM, Schold SC Jr, Hori H, Nobori T (1997) Effect of long-term depletion of plasma methionine on the growth and survival of human brain tumor xenografts in athymic mice. Nutr Cancer 29:195–204CrossRefGoogle Scholar
  35. 35.
    Lishko VK, Lishko OV, Hoffman RM (1993) The preparation of endotoxin-free L-methionine-alpha-deamino-gamma-mercaptomethane-lyase (L-methioninase) from Pseudomonas putida. Protein Expr Purif 4:529–533CrossRefGoogle Scholar
  36. 36.
    Tan Y, Zavala J Sr, Xu M, Zavala J Jr, Hoffman RM (1996) Serum methionine depletion without side effects by methioninase in metastatic breast cancer patients. Anticancer Res 16:3937–3942PubMedGoogle Scholar
  37. 37.
    Hiroshima Y, Zhang Y, Murakami T, Maawy A, Miwa S, Yamamoto M, Yano S, Sato S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, chikawa Y, Bouvet M, Endo I, Zhao M, Hoffman RM (2014) Efficacy of tumor-targeting Salmonella typhimurium A1-R in combination with anti-angiogenesis therapy on a pancreatic cancer patient-derived orthotopic xenograph (PDOX) and cell line mouse models. Oncotarget 5:12346–12357CrossRefGoogle Scholar
  38. 38.
    Fu X, Guadagni F, Hoffman RM (1992) A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci U S A 89:5645–5649CrossRefGoogle Scholar
  39. 39.
    Tan Y, Zavala J Sr, Han Q, Xu M, Sun X, Tan X, Tan X, Magana R, Geller J, Hoffman RM (1997) Recombinant methioninase infusion reduces the biochemical endpoint of serum methionine with minimal toxicity in high-stage cancer patients. Anticancer Res 17:3857–3860PubMedGoogle Scholar
  40. 40.
    Hiroshima Y, Maawy A, Zhang Y, Murakami T, Momiyama M, Mori R, Matsuyama R, Katz MH, Fleming JB, Chishima T, Tanaka K, Ichikawa Y, Endo I, Hoffman RM, Bouvet M (2014) Metastatic recurrence in a pancreatic cancer patient derived orthotopic xenograft (PDOX) nude mouse model is inhibited by neoadjuvant chemotherapy in combination with fluorescence-guided surgery with an anti-CA 19–9-conjugated fluorophore. PLoS One 9:e114310CrossRefGoogle Scholar
  41. 41.
    Hiroshima Y, Maawy AA, Katz MH, Fleming JB, Bouvet M, Endo I, Hoffman RM (2015) Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer. J Surg Oncol 111:311–315CrossRefGoogle Scholar
  42. 42.
    Fu X, Le P, Hoffman RM (1993) A metastatic-orthotopic transplant nude-mouse model of human patient breast cancer. Anticancer Res 13:901–904PubMedGoogle Scholar
  43. 43.
    Fu X, Hoffman RM (1993) Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. Anticancer Res 13:283–286PubMedGoogle Scholar
  44. 44.
    Wang X, Fu X, Hoffman RM (1992) A new patient-like metastatic model of human lung cancer constructed orthotopically with intact tissue via thoracotomy in immunodeficient mice. Int J Cancer 51:992–995CrossRefGoogle Scholar
  45. 45.
    Hiroshima Y, Zhang Y, Zhang N, Maawy A, Mii S, Yamamoto M, Uehara F, Miwa S, Yano S, Murakami T, Momiyama M, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Murata T, Endo I, Hoffman RM (2015) Establishment of a patient-derived orthotopic xenograph (PDOX) model of HER-2-positive cervical cancer expressing the clinical metastatic pattern. PLoS One 10:e0117417CrossRefGoogle Scholar
  46. 46.
    Fu X, Besterman JM, Monosov A, Hoffman RM (1991) Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci U S A 88:9345–9349CrossRefGoogle Scholar
  47. 47.
    Metildi CA, Kaushal S, Luiken GA, Talamini MA, Hoffman RM, Bouvet M (2014) Fluorescently-labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Surg Oncol 109:451–458CrossRefGoogle Scholar
  48. 48.
    Hiroshima Y, Maawy A, Metildi CA, Zhang Y, Uehara F, Miwa S, Yano S, Sato S, Murakami T, Momiyama M, Chishima T, Tanaka K, Bouvet M, Endo I, Hoffman RM (2014) Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system. J Laparoendosc Adv Surg Tech A 24:241–247CrossRefGoogle Scholar
  49. 49.
    Furukawa T, Kubota T, Watanabe M, Kitajima M, Hoffman RM (1993) Orthotopic transplantation of histologically intact clinical specimens of stomach cancer to nude mice: correlation of metastatic sites in mouse and individual patient donors. Int J Cancer 53:608–612CrossRefGoogle Scholar
  50. 50.
    Kawaguchi K, Igarashi K, Kiyuna T, Miyake K, Miyake M, Murakami T, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Singh AS, Unno M, Eilber FC, Hoffman RM (2018) Individualized doxorubicin sensitivity testing of undifferentiated soft tissue sarcoma (USTS) in a patient-derived orthotopic xenograft (PDOX) model demonstrates large differences between patients. Cell Cycle 17:627–633CrossRefGoogle Scholar
  51. 51.
    Murakami T, DeLong J, Eilber FC, Zhao M, Zhang Y, Zhang N, Singh A, Russell T, Deng S, Reynoso J, Quan C, Hiroshima Y, Matsuyama R, Chishima T, Tanaka K, Bouvet M, Chawla S, Endo I, Hoffman RM (2016) Tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin eradicate soft tissue sarcoma in a patient-derived orthotopic xenograft PDOX model. Oncotarget 7:12783–12790PubMedPubMedCentralGoogle Scholar
  52. 52.
    Hiroshima Y, Zhao M, Zhang Y, Zhang N, Maawy A, Murakami T, Mii S, Uehara F, Yamamoto M, Miwa S, Yano S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM (2015) Tumor-targeting Salmonella typhimurium A1-R arrests a chemo-resistant patient soft-tissue sarcoma in nude mice. PLoS One 10:e0134324CrossRefGoogle Scholar
  53. 53.
    Kiyuna T, Murakami T, Tome Y, Kawaguchi K, Igarashi K, Zhang Y, Zhao M, Li Y, Bouvet M, Kanaya F, Singh A, Dry S, Eilber FC, Hoffman RM (2016) High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model. Oncotarget 7:33046–33054CrossRefGoogle Scholar
  54. 54.
    Murakami T, Singh AS, Kiyuna T, Dry SM, Li Y, James AW, Igarashi K, Kawaguchi K, DeLong JC, Zhang Y, Hiroshima Y, Russell T, Eckardt MA, Yanagawa J, Federman N, Matsuyama R, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2016) Effective molecular targeting of CDK4/6 and IGF-1R in a rare FUS-ERG fusion CDKN2A-deletion doxorubicin-resistant Ewing’s sarcoma in a patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 7:47556–47564PubMedPubMedCentralGoogle Scholar
  55. 55.
    Hiroshima Y, Zhang Y, Zhang N, Uehara F, Maawy A, Murakami T, Mii S, Yamamoto M, Miwa S, Yano S, Momiyama M, Mori R, Matsuyama R, Chishima T, Tanaka K, Ichikawa Y, Bouvet M, Endo I, Hoffman RM (2015) Patient-derived orthotopic xenograft (PDOX) nude mouse model of soft-tissue sarcoma more closely mimics the patient behavior in contrast to the subcutaneous ectopic model. Anticancer Res 35:697–701PubMedGoogle Scholar
  56. 56.
    Igarashi K, Murakami T, Kawaguchi K, Kiyuna T, Miyake K, Zhang Y, Nelson SD, Dry SM, Li Y, Yanagawa J, Russell TA, Singh AS, Tsuchiya H, Elliott I, Eilber FC, Hoffman RM (2017) A patient-derived orthotopic xenograft (PDOX) mouse model of an cisplatinum-resistant osteosarcoma lung metastasis that was sensitive to temozolomide and trabectedin: implications for precision oncology. Oncotarget 8:62111–62119PubMedPubMedCentralGoogle Scholar
  57. 57.
    Igarashi K, Kawaguchi K, Kiyuna T, Murakami T, Miwa S, Nelson SD, Dry SM, Li Y, Singh A, Kimura H, Hayashi K, Yamamoto N, Tsuchiya H, Eilber FC, Hoffman RM (2017) Temozolomide combined with irinotecan caused regression in an adult pleomorphic rhabdomyosarcoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. Oncotarget 8:75874–75880PubMedPubMedCentralGoogle Scholar
  58. 58.
    Igarashi K, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Nelson SD, Dry SM, Li Y, Yanagawa J, Russell TA, Singh AS, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Eilber FC, Hoffman RM (2017) Intra-arterial administration of tumor-targeting Salmonella typhimurium A1-R regresses a cisplatin-resistant relapsed osteosarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. Cell Cycle 16:1164–1170CrossRefGoogle Scholar
  59. 59.
    Murakami T, Kiyuna T, Kawaguchi K, Igarashi K, Singh AS, Hiroshima Y, Zhang Y, Zhao M, Miyake K, Nelson SD, Dry SM, Li Y, DeLong JC, Lwin TM, Chishima T, Tanaka K, Bouvet M, Endo I, Eilber FC, Hoffman RM (2017) The irony of highly-effective bacterial therapy of a patient-derived orthotopic xenograft (PDOX) model of Ewing’s sarcoma, which was blocked by Ewing himself 80 years ago. Cell Cycle 16:1046–1052CrossRefGoogle Scholar
  60. 60.
    Igarashi K, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Singh A, Nelson SD, Dry SM, Li Y, Yamamoto N, Hayashi K, Kimura H, Miwa S, Tsuchiya H, Eilber FC, Hoffman RM (2017) High efficacy of pazopanib on an undifferentiated spindle-cell sarcoma resistant to first-line therapy is identified with a patient-derived orthotopic xenograft (PDOX) nude mouse model. J Cell Biochem 118:2739–3743CrossRefGoogle Scholar
  61. 61.
    Kiyuna T, Murakami T, Tome Y, Kawaguchi K, Igarashi K, Miyake K, Kanaya F, Singh A, Eilber FC, Hoffman RM (2017) Analysis of stroma labeling during multiple passage of a sarcoma imageable patient-derived orthotopic xenograft (iPDOX) in red fluorescent protein transgenic nude mice. J Cell Biochem 118:3367–3371CrossRefGoogle Scholar
  62. 62.
    Igarashi K, Kawaguchi K, Murakami T, Kiyuna T, Miyake K, Yamamoto N, Hayashi K, Kimura H, Nelson SD, Dry SM, Li Y, Singh AS, Miwa S, Odani A, Eilber FC, Tsuchiya H, Hoffman RM (2017) A novel anionic-phosphate-platinum complex effectively targets an undifferentiated pleomorphic sarcoma better than cisplatinum and doxorubicin in a patient-derived orthotopic xenograft (PDOX). Oncotarget 8:63353–63359PubMedPubMedCentralGoogle Scholar
  63. 63.
    Miyake K, Murakami T, Kiyuna T, Igarashi K, Kawaguchi K, Miyake M, Li Y, Nelson SD, Dry SM, Bouvet M, Elliott IA, Russell TA, Singh AS, Eckardt MA, Hiroshima Y, Momiyama M, Matsuyama R, Chishima T, Endo I, Eilber FC, Hoffman RM (2017) The combination of temozolomide-irinotecan regresses a doxorubicin-resistant patient-derived orthotopic xenograft (PDOX) nude-mouse model of recurrent Ewing’s sarcoma with a FUS-ERG fusion and CDKN2A deletion: direction for third-line patient therapy. Oncotarget 8:103129–103136PubMedPubMedCentralGoogle Scholar
  64. 64.
    Yamamoto M, Zhao M, Hiroshima Y, Zhang Y, Shurell E, Eilber FC, Bouvet M, Noda M, Hoffman RM (2016) Efficacy of tumor-targeting Salmonella typhimurium A1-R on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. PLoS One 11:e0160882CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Robert M. Hoffman
    • 1
    • 2
    Email author
  • Qinghong Han
    • 1
  • Kei Kawaguchi
    • 1
    • 2
  • Shukuan Li
    • 1
  • Yuying Tan
    • 1
  1. 1.AntiCancer, Inc.San DiegoUSA
  2. 2.Department of SurgeryUniversity of CaliforniaSan DiegoUSA

Personalised recommendations