Identification and Characterization of Cysteinyl‐Leukotriene Formation in Tissue Slices from Human Intracranial Tumors: Evidence for Their Biosynthesis Under In Vivo Conditions

Abstract

In previous studies, it had been shown that human gray and white matter tissue slices have the capacity to synthesize large amounts of cysteinyl-leukotrienes (cysteinyl-LT) in vitro. This study was initiated to investigate cysteinyl-LT formation by tissue slices from intracranial tumors in comparison with cyclooxygenase products such as prostaglandin (PG) F2 alpha and thromboxane (TX) B2. Tissue slices from meningiomas and astrocytomas were found to release large amounts of cysteinyl-LT spontaneously and even higher amounts after ionophore A 23187 stimulation, which could not be accounted for by blood possibly remaining in the tissue slices. Cysteinyl-LT were identified by their immunoreactive characteristics, their biological activity in the guinea pig ileum bioassay, and their retention time on reversed-phase HPLC. With increasing malignancy, astrocytomas were shown to have an increasing biosynthetic capacity for cysteinyl-LT and TXB2 in vitro. In comparison with meningioma patients, malignant astrocytoma patients had an enhanced urinary excretion of LTE4, the major urinary metabolite of cysteinyl-LT in humans, which dropped in level within 7 days after operation by 79%. A correlation exists between the in vivo cysteinyl-LT production in patients with malignant astrocytomas and that observed under basal conditions in the tissue slices in vitro. The results provide evidence that in malignant astrocytoma patients, the tumor tissue produces large amounts of cysteinyl-LT, which may be detected in the patients' urine.

P2X7Receptor Activation in Rat Brain Cultured Astrocytes Increases the Biosynthetic Release of Cysteinyl Leukotrienes

“…They have been extensively studied as mediators in the pathobiologic processes of allergic asthma and other respiratory disorders, but little is known on their role and cellular source in the CNS. However, CysLTs levels have been reported to increase in brain injuries, including cerebral ischemia, hemorrhage and epileptic seizures (14,50). Recently we reported that astrocytes and microglia release CysLTs both under resting conditions and following stimulation with the calcium ionophore A23187 or with ATP through P2Y 1 metabotropic receptor subtypes (12,3).…”

“…Another group of pro-inflammatory agents, the cysteinyl leukotrienes, (CysLTs), namely LTC4' LTD4 and LTE4' playa role in diverse pathological processes in brain, including seizures, hemorrhage, ischemia and tumors (50,14,51,49). CysLTs are members of a large family of molecules known as eicosanoids whose biosynthesis is triggered by the action of cytosolic phospholipase A2 followed by the action of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP) on arachidonic acid (9).…”

P2Y1and Cysteinyl Leukotriene Receptors Mediate Purine and Cysteinyl Leukotriene Co-Release in Primary Cultures of Rat Microglia

“…Cysteinyl leukotrienes (CysLTs) production was consistently increased in cerebrospinal fluid in patients with multiple sclerosis (51) or intracerebral hemorrhage (60) as well as in brain tumors (54).…”

Differential expression of arachidonate 5-lipoxygenase transcripts in human brain tumors: evidence for the expression of a multitranscript family.

“…In the first experiment (Fig. 1 Right), the most abundant 5-LO transcripts (2.7, 3.1, and 4.8 kb) were detected in two meningiomas (lanes 1 and 2) 16 hr at 22°C, and 3 days at -70°C. The size of the hybridization bands is indicated in kb.…”

“…Moreover, administration of leukotriene C4 selectively increases the permeability of the blood-brain barrier in brain tumors (15), suggesting that these molecules may mediate the vasogenic edema associated with brain tumors. Cerebral meningiomas and astrocytomas are hypothesized to release cysteinylleukotrienes to blood at rates that correlate with the grade of malignancy (16). If this were the case, then the level of the 5-LO mRNA in brain tumors may also correlate with malignancy.…”