Meta-analyses have demonstrated that low dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the anti-platelet action of low dose aspirin likely contributes to its anti-metastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low dose aspirin also inhibits PGE2 biosynthesis. We show that low dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (p <0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells up-regulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet-tumor cell aggregates. In conclusion, low dose aspirin has a significant effect on extraplatelet cyclooxygenase, and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells.

This article is available online at http://www.jlr.org to prostaglandin H 2 (PGH 2 ). In platelets, the thromboxane synthase enzyme catalyzes conversion of PGH 2 to both thromboxane A 2 and malondialdehyde (MDA) in approximately equimolar amounts ( 1 ) (supplementary Fig. 1).MDA is an electrophile that reacts with amino groups, including the -amine of protein lysines. Reaction of MDA with lysine in vitro leads to formation of adducts with several structures ( 2, 3 ), including one that results from the reaction of this dicarbonyl with two lysines to produce intra-and intermolecular cross-links of macromolecules. Such cross-links have been demonstrated when MDA is added to purifi ed apoA-1 in vitro ( 2 ).This evidence that MDA is a major product of the thromboxane synthase and can modify protein structure in vitro suggests a hypothesis that platelet activation could lead to modifi cation of platelet proteins by MDA. However, there previously has been no evidence that this occurs.The investigations reported here demonstrate that activation of platelets ex vivo leads to thromboxane synthasedependent MDA modifi cation of platelet proteins. A stable isotope dilution method for analysis for the dilysyl-MDA cross-link utilizing LC/MS/MS has been developed, making it possible to demonstrate increased levels of MDA adducts of platelet proteins in diseases that are associated with increased platelet activation. Activation of platelets signals cytosolic phospholipase A 2 ␣ activation and an explosive release of arachidonic acid, which is metabolized by cyclooxygenase (COX

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Purpose Growth factors and antimicrobials can reduce complications of chemotherapy-induced myelosuppression. Their prophylactic use in elderly patients is important given the associated comorbidity in this age group. There is a developing trend by payers to include supportive care agents in chemotherapy care bundles, which could affect clinical practice. We examined whether the febrile neutropenia (FN) risk categories can be used to describe utilization in the Centers for Medicare & Medicaid fee-for-service system in older adults. Methods We conducted a retrospective cohort study using the Medicare 20% sample data to describe growth factor and antimicrobial use patterns in patients receiving chemotherapy for breast cancer, lung cancer, and non-Hodgkin lymphoma (NHL). Results The highest percentage of patients receiving granulocyte colony-stimulating factor (GCSF) within the first 5 days of a chemotherapy cycle were on high-FN-risk regimens, particularly for cycle 1 (73.7%, breast cancer; 61.5%, NHL) and cycle 2 (75.9%, breast cancer; 77.5%, NHL). Chemotherapy regimens for lung cancer are less myelotoxic, and growth factor use was more likely with latter cycles. Antibiotic use was lower at 15% within a cycle and appeared to be in response to complications. Conclusion Practitioners use GCSF and antibiotics for elderly patients treated with potentially toxic chemotherapy, while comorbidity burden plays a role for patients treated with less myelotoxic regimens. The complexity of these choices in clinical practice should be considered in the proposed reimbursement changes being piloted by Medicare and private insurance companies seeking treatment cost reductions, as altered use could affect safety and efficacy.