Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice

D. M. Kokkinakis, R. M. Hoffman, E. P. Frenkel, J. B. Wick, Q. Han, M. Xu, Y. Tan, S. C. Schold

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Abstract

This study describes a novel approach to the treatment of brain tumors with the combination of recombinant L-methionine-α-deamino-γ-lyase and chemotherapeutic regimens that are currently used against such tumors. The growth of Daoy, SWB77, and D-54 xenografts in athymic mice was arrested after the depletion of mouse plasma methionine (MET) with a combination of a MET- and choline-free diet and recombinant L-methionine-α-deamino-γ-lyase. The treated tumor-bearing mice were rescued from the toxic effects of MET withdrawal with daily i.p. homocystine. This regimen suppressed plasma MET to levels below 5 μM for several days, with no treatment-related deaths. MET depletion for 10-12 days induced mitotic and cell cycle arrest, apoptotic death, and widespread necrosis in tumors but did not prevent tumor regrowth after cessation of the regimen. However, when a single dose of 35 mg/m2 of N,N′-bis(2-chloroethyl)-N-nitrosourea (BCNU), which was otherwise ineffective as a single therapy in any of the tumors tested, was given at the end of the MET depletion regimen, a more than 80-day growth delay was observed for Daoy and D-54, whereas the growth of SWB77 was delayed by 20 days. MET-depleting regimens also trebled the efficacy of temozolomide (TMZ) against SWB77 when TMZ was given to animals as a single dose of 180 mg/m2 at the end of a 10-day period of MET depletion. The enhanced responses of both Daoy and SWB77 to DNA alkylating agents such as BCNU and TMZ could be attributed to the down-regulation of O6-methylguanine-DNA methyltransferase activity. However, the synergy of MET depletion and BCNU observed with D-54 tumors, which do not express measurable O6-methylguanine-DNA methyltransferase protein, is probably mediated by a different mechanism. MET depletion specifically sensitizes tumors to alkylating agents and does not significantly lower the toxicity of either BCNU or TMZ for the host. In this regard, the combination approach of MET depletion and genotoxic chemotherapy demonstrates significant promise for clinical evaluation.

Original languageEnglish (US)
Pages (from-to)4017-4023
Number of pages7
JournalCancer Research
Volume61
Issue number10
StatePublished - May 15 2001

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Heterografts
Nude Mice
Brain Neoplasms
Methionine
temozolomide
Drug Therapy
Carmustine
Therapeutics
Neoplasms
Lyases
Alkylating Agents
DNA
Homocystine
Growth
Protein Methyltransferases
Poisons
Methyltransferases
Choline
Cell Cycle Checkpoints
Necrosis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kokkinakis, D. M., Hoffman, R. M., Frenkel, E. P., Wick, J. B., Han, Q., Xu, M., ... Schold, S. C. (2001). Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Research, 61(10), 4017-4023.

Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. / Kokkinakis, D. M.; Hoffman, R. M.; Frenkel, E. P.; Wick, J. B.; Han, Q.; Xu, M.; Tan, Y.; Schold, S. C.

In: Cancer Research, Vol. 61, No. 10, 15.05.2001, p. 4017-4023.

Research output: Contribution to journalArticle

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 Research, vol. 61, no. 10, pp. 4017-4023.
Kokkinakis DM, Hoffman RM, Frenkel EP, Wick JB, Han Q, Xu M et al. Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Research. 2001 May 15;61(10):4017-4023.
Kokkinakis, D. M. ; Hoffman, R. M. ; Frenkel, E. P. ; Wick, J. B. ; Han, Q. ; Xu, M. ; Tan, Y. ; Schold, S. C. / Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. In: Cancer Research. 2001 ; Vol. 61, No. 10. pp. 4017-4023.
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abstract = "This study describes a novel approach to the treatment of brain tumors with the combination of recombinant L-methionine-α-deamino-γ-lyase and chemotherapeutic regimens that are currently used against such tumors. The growth of Daoy, SWB77, and D-54 xenografts in athymic mice was arrested after the depletion of mouse plasma methionine (MET) with a combination of a MET- and choline-free diet and recombinant L-methionine-α-deamino-γ-lyase. The treated tumor-bearing mice were rescued from the toxic effects of MET withdrawal with daily i.p. homocystine. This regimen suppressed plasma MET to levels below 5 μM for several days, with no treatment-related deaths. MET depletion for 10-12 days induced mitotic and cell cycle arrest, apoptotic death, and widespread necrosis in tumors but did not prevent tumor regrowth after cessation of the regimen. However, when a single dose of 35 mg/m2 of N,N′-bis(2-chloroethyl)-N-nitrosourea (BCNU), which was otherwise ineffective as a single therapy in any of the tumors tested, was given at the end of the MET depletion regimen, a more than 80-day growth delay was observed for Daoy and D-54, whereas the growth of SWB77 was delayed by 20 days. MET-depleting regimens also trebled the efficacy of temozolomide (TMZ) against SWB77 when TMZ was given to animals as a single dose of 180 mg/m2 at the end of a 10-day period of MET depletion. The enhanced responses of both Daoy and SWB77 to DNA alkylating agents such as BCNU and TMZ could be attributed to the down-regulation of O6-methylguanine-DNA methyltransferase activity. However, the synergy of MET depletion and BCNU observed with D-54 tumors, which do not express measurable O6-methylguanine-DNA methyltransferase protein, is probably mediated by a different mechanism. MET depletion specifically sensitizes tumors to alkylating agents and does not significantly lower the toxicity of either BCNU or TMZ for the host. In this regard, the combination approach of MET depletion and genotoxic chemotherapy demonstrates significant promise for clinical evaluation.",
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