Pathology of the Spread of L1210 Leukemia in the Central Nervous System of Mice and Effect of Treatment With Cytoxan

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Abstract
L1210 leukemia and the amethopterin-resistant subline, L1210 FR-9, grow diffusely in the subarachnoid space and dura after intracerebral inoculation in mice. The distribution of leukemia in the meninges in these animals is similar to leukemic-cell infiltrates in the meninges of patients with acute leukemia. Intracerebrally inoculated leukemia spreads to extracranial organs and tissues by two routes: (1) hematogenously and (2) by direct extension through tissues which surround cranial and spinal nerves and blood vessels. The median survival time of mice inoculated intracerebrally with leukemia was 8 to 9 days. Extensive deposits of leukemic cells were observed in the liver, spleen, and bone marrow at the time these animals died or were killed. Cytoxan injected subcutaneously in animals inoculated with leukemia intracerebrally prolonged the survival time of the animals and completely destroyed the leukemic cells in the liver, spleen, bone marrow, and dura, whereas the leukemic cells in the subarachnoid space continued to proliferate. Therefore, the prolonged survival in the Cytoxan-treated animals is apparently related to the effect of the drug on leukemic cells in the systemic organs and tissues and in the dura. The anatomical zone, where the antileukemic effectiveness of systemically injected Cytoxan against leukemic cells extending from the intracranial tissues stops, is illustrated and is referred to as a “therapeutic barrier.” Certain discrete areas of the brain, the area postrema, the tuber cinereum, and the walls of the supraoptic recess of the third ventricle were diffusely infiltrated by leukemic cells in the mice inoculated intracerebrally, in contrast to the brain and spinal-cord tissues generally. Some of the histologic and biochemical factors which might be related to this are mentioned. L1210 and L1210 FR-9 inoculated subcutaneously in mice reach the subarachnoid space as a result of direct spread from the dura in and through the perivascular and perineural tissues. This occurs late in the course of the disease. In other words, the tissue barriers at the capillary bed (the “blood-brain barrier”) and in the choroid plexus (the “blood-cerebrospinal fluid barrier”) prevent the passage of leukemic cells directly into the brain and into the cerebrospinal fluid.