Effects of Antiplatelet Drugs on Colon Cancer in the Elderly

描述(申请人提供)：恶性肿瘤是美国第二大死因，结直肠癌是第二大致命性癌症。老年人群患结直肠癌的风险尤其高，因为其发病率随着年龄的增长而增加。众所周知，循环中的血小板会随着年龄的增长而变化，这可能会影响包括癌症在内的各种退行性疾病。血小板参与促进肿瘤的发生和转移，据报道，在包括结直肠癌在内的许多实体肿瘤中，其循环数量增加。血小板与循环癌细胞的聚集似乎可以保护癌细胞并促进其转移。最近对大量接受低剂量抗血小板治疗(低剂量阿司匹林)的患者进行的心血管风险研究 据报道，阿司匹林具有显著的预防癌症形成、转移和死亡的作用。因此，阿司匹林已知的化学预防作用可能与其抗血小板作用有关。我们的假设是，调节血小板活性对于预防结直肠癌和抑制转移生长非常重要。阿司匹林广泛用于化学预防的一个局限性是它的副作用会导致急性胃肠道(GI)出血，如果不治疗可能会危及生命。这对老年人来说尤其严重，因为高龄是非甾体抗炎药引起的胃肠道溃疡/出血的危险因素。最近FDA批准的阿司匹林产品是由PI的实验室开发的GI-SAFER(阿司匹林-PC/PL2200)，它可能提供一种方法来提供显著的化学预防，同时减少GI副作用。我们建议调查：1)青年和老年受试者的血小板与癌细胞之间的体外串扰，以及它们对抗血小板药物，包括各种阿司匹林制剂，特别是阿司匹林-PC和其他药物的反应；以及2)体内结肠癌[癌症前启动模型]和年轻和老年动物的转移生长对抗血小板药物的敏感性。这些研究将有助于了解血小板在老年人结直肠癌化学预防中的作用，并可能为减少老年人癌症的转移提供一种及时和安全的方法。

DESCRIPTION (provided by applicant): Malignant cancers are the second leading cause of death in the USA with colorectal cancer being the second most fatal cancer. The elderly population is particularly at risk for colorectal cancer as its incidence increases with age. Circulating platelets are known to change with age which may affect a variety of degenerative diseases including cancers. Platelets are implicated in the promotion of carcinogenesis and its metastatic spread, and their circulating numbers are reported to be elevated in a number of solid tumors including colorectal cancer. Platelet aggregation with circulating cancer cells appears to protect the cancer cells and promote their metastasis. Recent studies of large populations of patients on low dose antiplatelet therapy (low dose aspirin) for cardiovascular risk reduction, have reported that aspirin confers significant protection against cancer formation, metastases and death. Thus, it is possible that the known chemopreventive activity of aspirin may be related to its antiplatelet action. Our hypothesis is that modulation of platelet activity i important for prevention of colorectal cancer and suppression of metastatic growth. One limitation to the widespread use of aspirin for chemoprevention is its side effect to induce acute gastrointestinal (GI) bleeding that may become life threatening if untreated. This is particularly problem for the elderly, as advanced age is a risk factor for NSAID-induced GI ulceration/bleeding. A recently FDA-approved aspirin product that is GI- safer (Aspirin-PC/PL2200) developed by the PI's laboratory may offer a means to provide significant chemoprevention with reduced GI side effects. We propose to investigate: 1) the in vitro cross-talk between platelets from young and elderly subjects and cancer cells, and their responsiveness to antiplatelet drugs, including various aspirin formulations, notably Aspirin-PC, and other agents; and 2) an in vivo colon cancer [models of both pre-cancer initiation] and metastatic growth in young and old animals for sensitivity to antiplatelet drugs. These studies will contribute to knowledge about the role of platelets in chemoprevention of colorectal cancer in the elderly, and may offer a timely and safe approach to reduce the metastatic spread of cancer in the elderly.