| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics |
Departments of Neurological Surgery [D. M. K., J. B. W.], and Internal Medicine [E. P. F.], University of Texas Southwestern Medical Center, Dallas, Texas 75390; The University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania 15213 [S. C. S.]; and Anticancer Inc., San Diego, California 92111 [ R. M. H., Q. H., M. X., Y. T.]
This study describes a novel approach to the treatment of brain tumors with the combination of recombinant L-methionine-
-deamino-
-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--deamino--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.
This article has been cited by other articles:
|
|
 |
|
  N. NAJIM, I.D. PODMORE, A. MCGOWN, and E.J. ESTLIN Biochemical Changes and Cytotoxicity Associated with Methionine Depletion in Paediatric Central Nervous System Tumour Cell Lines Anticancer Res, August 1, 2009; 29(8): 2971 - 2976. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. NAJIM, I.D. PODMORE, A. MCGOWN, and E.J. ESTLIN Methionine Restriction Reduces the Chemosensitivity of Central Nervous System Tumour Cell Lines Anticancer Res, August 1, 2009; 29(8): 3103 - 3108. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-M. Fu and G. G. Meadows Specific Amino Acid Dependency Regulates the Cellular Behavior of Melanoma J. Nutr., June 1, 2007; 137(6): 1591S - 1596S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kokkinakis, A. G. Brickner, J. M. Kirkwood, X. Liu, J. E. Goldwasser, A. Kastrama, C. Sander, D. Bocangel, and S. Chada Mitotic Arrest, Apoptosis, and Sensitization to Chemotherapy of Melanomas by Methionine Deprivation Stress Mol. Cancer Res., August 1, 2006; 4(8): 575 - 589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kokkinakis, X. Liu, and R. D. Neuner Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma Mol. Cancer Ther., September 1, 2005; 4(9): 1338 - 1348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Stankova, J. Shang, and R. Rozen Antisense Inhibition of Methylenetetrahydrofolate Reductase Reduces Cancer Cell Survival In vitro and Tumor Growth In vivo Clin. Cancer Res., March 1, 2005; 11(5): 2047 - 2052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kokkinakis, X. Liu, S. Chada, M. M. Ahmed, M. M. Shareef, U. K. Singha, S. Yang, and J. Luo Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress Cancer Res., October 15, 2004; 64(20): 7513 - 7525. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Yang, J. Wang, T. Yoshioka, B. Li, Q. Lu, S. Li, X. Sun, Y. Tan, S. Yagi, E. P. Frenkel, et al. Pharmacokinetics, Methionine Depletion, and Antigenicity of Recombinant Methioninase in Primates Clin. Cancer Res., March 15, 2004; 10(6): 2131 - 2138. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Sun, Z. Yang, S. Li, Y. Tan, N. Zhang, X. Wang, S. Yagi, T. Yoshioka, A. Takimoto, K. Mitsushima, et al. In Vivo Efficacy of Recombinant Methioninase Is Enhanced by the Combination of Polyethylene Glycol Conjugation and Pyridoxal 5'-Phosphate Supplementation Cancer Res., December 1, 2003; 63(23): 8377 - 8383. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Jaeckle, K. R. Hess, W.K. A. Yung, H. Greenberg, H. Fine, D. Schiff, I. F. Pollack, J. Kuhn, K. Fink, M. Mehta, et al. Phase II Evaluation of Temozolomide and 13-cis-Retinoic Acid for the Treatment of Recurrent and Progressive Malignant Glioma: A North American Brain Tumor Consortium Study J. Clin. Oncol., June 15, 2003; 21(12): 2305 - 2311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. B. Bocangel, S. Finkelstein, S. C. Schold, K. K. Bhakat, S. Mitra, and D. M. Kokkinakis Multifaceted Resistance of Gliomas to Temozolomide Clin. Cancer Res., August 1, 2002; 8(8): 2725 - 2734. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
