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The Effect of an Amino Acid-lowering Diet on the Rate of Melphalan Entry into Brain and Xenotransplanted Glioma¹

Department of Neurology, Northwestern University Medical School, Evanston Hospital, Evanston, Illinois 60201 [D. R. G., I. F., K. E. S., P. M.]; Department of Pathology (Neuropathology), Duke University Medical Center, Durham, North Carolina 27710 [B. E. L., D. D. B.]; The Johns Hopkins Oncology Center, Baltimore, Maryland 21287 [O. M. C.]; and Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710 [C. R. R., H. S. F.]

Melphalan (-phenylalanine mustard, L-PAM, alkeran; molecular weight, 305,000) is transported across tumor cell membranes and the blood-brain barrier by the large neutral amino acid (LNAA) transport system. Normally, plasma LNAA levels are high enough and the affinity low enough that this system does not transport much melphalan into the brain. However, plasma amino acids can be reduced by fasting and protein-free diet. We used this method to reduce competition and to increase melphalan transport into brain tumors. In nude mice fasted for 12 h and then fed a protein-free diet for 2 and 6 h, mean plasma LNAA levels were 46% and 42% of control values. Nude mice with xenotransplanted D-54MG human gliomas were used to study tissue distribution and uptake kinetics of [³H]melphalan in a control group and a diet group (after a 12-h fast and 2 h of a 0% protein diet). The K₁ (blood-to-tissue transfer constant) of melphalan, determined by graphical analysis and by nonlinear fitting to a 2-compartment model, was higher in the diet group in all tumor regions except the necrotic center of subcutaneous tumors; the increase was significant in the tumor periphery of brain and s.c. tumors. The ratio of K₁s (diet to control) varied from 1.2 to 1.3 in brain tumors, 1.9 to 2.1 in subcutaneous tumors, and 1.8 to 3.1 in tumor-free brain. The apparent [³H]melphalan distribution space was significantly higher in the tumor periphery of both brain and subcutaneous tumors of the 15- and 30-min diet group. We also measured blood-brain barrier transport of [-¹⁴C]aminoisobutyric acid and blood flow (with [¹³¹I]iodoantipyrine): the K₁ of [-¹⁴C]aminoisobutyric acid was 28.1 ± 6.6 (SE) in brain tumors and 24.3 ± 8.9 µl/g/min in subcutaneous tumors. Blood flow was 58.2 3.9 in brain tumors and 5.2 ± 0.4 ml/100 g/min in subcutaneous tumors. Fasting, when combined with a protein-free diet, reduces plasma amino acid levels and thereby reduces competition between melphalan and LNAAs. This may increase the amount of melphalan that can enter a brain tumor without increasing the administered drug dose and suggests a therapeutic manipulation that can be used to increase the delivery of melphalan.

¹ Supported by NIH Grants NS12745, RR03321, DK26912, NS20023, CA44640, CA11898, NS00958; by American Cancer Society Grant CH-403; and by the Richard M. Lilienfeld and Mark Moritz Memorial Funds. I. F. was the recipient of an Arlene and Marshall Bennett Fellowship in Neuro-oncology from the Division of Neurosurgery, Evanston Hospital.

² To whom requests for reprints should be addressed, at 2650 Ridge Avenue, Evanston, IL 60201.

³ Present address: Department of Neurosurgery, Universität des Saarlandes, Homburg/Saar, Germany.

⁴ Present address: Department of Neurology and Psychiatry, University Medical School of Debrecen, P. O. Box 31, H-4014 Debrecen, Hungary.

⁵ Present address: Department of Pathology, University Medical School of Debrecen, P. O. Box 23, H-4014 Debrecen, Hungary.

Received 3/19/91. Accepted 8/ 4/92.

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