This study describes a novel approach to the treatment of
brain tumors with the combination of recombinant
L-methionine-alpha-deamino-gamma-
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-alpha-deamino-gamma-
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 microM 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/m(2) 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/m(2) 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
O(6)-methylguanine-DNA methyltransferase activity. However, the synergy of MET depletion and
BCNU observed with D-54
tumors, which do not express measurable
O(6)-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.