Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase

J Cell Biochem. 2018 Apr;119(4):3537-3544. doi: 10.1002/jcb.26527. Epub 2018 Jan 2.

Abstract

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

Keywords: PDOX; doxorubicin; patient-derived orthotopic xenograft; recombinant methioninase; resistant; undifferentiated spindle-cell sarcoma.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbon-Sulfur Lyases / therapeutic use*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Disease Models, Animal
  • Docetaxel
  • Doxorubicin / therapeutic use*
  • Female
  • Melanoma / drug therapy*
  • Mice
  • Mice, Nude
  • Pyrimidines / therapeutic use
  • Sarcoma, Ewing / drug therapy*
  • Sulfonamides / therapeutic use
  • Taxoids / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Pyrimidines
  • Sulfonamides
  • Taxoids
  • Deoxycytidine
  • Docetaxel
  • pazopanib
  • Doxorubicin
  • gemcitabine
  • Carbon-Sulfur Lyases
  • L-methionine gamma-lyase