Chemoprevention of cancer

Chemoprevention is a relatively new area of clinical cancer research. In this article we have presented a general overview of the concepts as well as the status of ongoing clinical trials using the most promising agents in selected populations. The reader is referred to recent excellent reviews presenting more detailed discussions of the various topics discussed, such as the selection process for new agents, in vitro and animal model screening procedures, epidemiologic studies, and other agents now being screened and tested for potential clinical study. Increased understanding of the biology of carcinogenesis will undoubtedly lead to new ideas and approaches. Pathways for conversion of proto-oncogenes to tumor-supporting oncogenes, the mechanisms of action of tumor suppressor genes, and the involvement of abnormal growth factor responses in producing "field cancerization" are some examples of future targets for chemopreventive intervention. Long-term goals of this effort will include application of the results of early promising prevention studies, such as those in oral premalignant lesions, to the design of carefully controlled trials to demonstrate actual inhibition of cancer occurrence. In the laboratory, basic studies need to be conducted to increase our understanding of the molecular events underlying carcinogenesis, in order to identify additional targets for new agents to enhance the clinical efforts. Some of the most exciting developments in the control of cancer over the next decade will very likely result from this chemopreventive approach, with application not only to prevention of the first or primary malignancy, especially in high risk populations, but also to clinical situations traditionally considered to be in the domain of chemotherapeutic strategies, such as adjuvant treatment after definitive therapy of a primary cancer.     

Chemoprevention of cancer

Cancer chemoprevention is defined as the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to invasive cancer. The success of several recent clinical trials in preventing cancer in high-risk populations suggests that chemoprevention is a rational and appealing strategy. This review will highlight current clinical research in chemoprevention, the biologic effects of chemopreventive agents on epithelial carcinogenesis, and the usefulness of intermediate biomarkers as markers of premalignancy. Selected chemoprevention trials are discussed with a focus on strategies of trial design and clinical outcome. Future directions in the field of chemoprevention will be proposed that are based on recently acquired mechanistic insight into carcinogenesis.     

Chemoprevention of cancer

This article is based on the experimental results obtained on the inhibition of tumor promotion by the application of certain compounds. Retinoids are well investigated anti-tumor promoters which inhibit the tumor promotion of 12-O-tetradecanoylphorbol-13-acetate applied to mouse skin. We screened a number of possible anti-tumor promoters by short-term tests. The compounds which gave positive results in the tests were subjected to a long-term iu vivo two-stage carcinogenesis experiment with DMBA plus teleocidin on mouse skin. We found that a calmodulin antagonist, quercetin, anti-inflammatory agents and tannic acids were able to act as new anti-tumor promoters. One of the tannic acids tested is (-)-epigallocatechin gallate, a tannic acid contained in tea. However, the short-term tests have still not been able to detect the anti-tumor promoter satisfactorily. Recently, we found that sarcophytol A inhibits tumor promotion in mouse skin with an equimolar ratio of teleocidin. A study on the action of sarcophytol A is now under investigation. In addition, the primary and the secondary chemoprevention of cancer were also briefly mentioned.     

Chemoprevention of prostate cancer

Dietary factors and other naturally occurring substances may emerge as potent therapeutic or preventative agents in the battle against prostate cancer. Much of the current support for these agents is epidemiologically based, but new prospective studies are now underway which may support their use in conventional medical practice.     

Chemoprevention of prostate cancer

Dietary factors and other naturally occurring substances may emerge as potent therapeutic or preventative agents in the battle against prostate cancer. Much of the current support for these agents is epidemiologically based, but new prospective studies are now underway which may support their use in conventional medical practice.     

Chemoprevention of breast cancer

Trials with tamoxifen have clearly shown that the risk of developing oestrogen receptor positive breast cancer can be reduced at a late stage in the natural history with prophylactic agents. About half of the oestrogen receptor positive cases were prevented, but there was no beneficial effect on ER-negative cancers. The current challenge is to find new agents which achieve this or better efficacy but with fewer side effects. Recent results indicate that the SERM raloxifene has similar efficacy to tamoxifen, but leads to fewer endometrial cancers, gynaecologic symptoms, and thromboembolic events. Results for contralateral tumours in adjuvant trials suggest that aromatase inhibitors may be able to prevent up to 70–80% of ER-positive breast cancers, and this is currently being investigated in two large prevention trials, one using anastrozole (IBIS-II) and the other exemestane (MAP.3). New agents are needed, for receptor negative breast cancer and several possibilities are currently under investigation. This article is based on an invited lecture delivered at the 15th Annual Meeting of the Japanese Breast Cancer Society, held in Yokohama 29–30 June 2007.     

Chemoprevention of lung cancer

Lung cancer is the leading cause of death worldwide. Its overall survival rate has improved only slightly, and surgery, radiotherapy, and chemotherapy remain the mainstays of current treatment. Therapies with novel targeted agents are currently under active investigation in all settings of treatment including chemoprevention, defined as the use of natural or synthetic agents to interrupt the process of carcinogenesis and to prevent or delay tumor occurrence. Thus, chemoprevention describes the collaborative efforts of researchers in basic science and clinical settings who study the biology of lung cancer with the hope of uncovering new mechanisms of treatment. Because lung cancer has become an increasingly difficult problem to treat with standard therapies, chemopreventive strategies have been developed. Small molecule compounds that target specific receptors or mutations will play an increasingly significant role in treatment of lung cancer because the side effect profiles of such agents are tolerable and they may be more effective than other treatments.     

大肠癌的化学预防

研究显示阿司匹林及环氧合酶-2抑制剂是最有效的大肠癌预防剂,但其消化道及心血管不良反应限制了临床应用.二氟甲基鸟氨酸与舒林酸联合应用能有效降低腺瘤复发、不良反应极少,是当前研究热点.5-氨基水杨酸及熊去氧胆酸是化学预防炎症性肠病癌变的主要研究方向.叶酸的双重调节作用仍值得探讨.他汀类及表皮生长因子受体抑制剂显示出一定疗...     

Chemoprevention of prostate cancer

Prostate cancer is a common malignancy with multiple potential opportunities for cancer prevention. As the genetic basis of this malignancy is further understood, prevention strategies will be developed for individual patients based on specific risk factors and pathways of carcinogenesis. The PCPT has conclusively proven that prostate cancer prevention is possible. The results of the SELECT should be available within several years. An enormous challenge for the medical community will be the development of an efficient strategy to evaluate the substantial number of dietary, behavioral, and pharmacologic prevention opportunities. Ultimately, the goal of prostate can-cer prevention is to (1) identify men who are destined to develop clinically significant prostate cancer, and (2) provide individualized agents to prevent disease development.     

Chemoprevention of prostate cancer

Over the past two decades, many more men are diagnosed with prostate cancer then die of the disease. This increase in diagnosis has led to aggressive treatment of indolent disease in many individuals and has been the impetus for finding a means of reducing the risk of prostate cancer. In the past decade, there have been eight large trials of prostate cancer risk reduction using dietary supplements, 5α-reductase inhibitors, or anti-estrogens. The only two trials which have demonstrated efficacy are those involving 5α-reductase inhibitors: the PCPT (finasteride) and REDUCE (dutasteride). This review examines prostate cancer risk reduction, with emphasis on conclusions that can be drawn from these two landmark studies.     

Chemoprevention of prostate cancer

Chemoprevention is prevention of cancer by administering natural or synthetic chemicals. Anti-androgens are among the promising chemopreventive agents for prostate cancer because prostate epithelium is androgen dependent. A National Cancer Institute supported large, randomized, clinical prostate cancer chemoprevention trial has been conducted to test the efficacy of finasteride, an inhibitor of 5--reductase, which converts testosterone to 5-hydroxy-testosterone. Now the focus is on micronutrients and phytochemicals, which have potential preventive effects against prostate cancer. Lycopene, soy isoflavones, vitamin E and selenium are among the most promising nutritional chemopreventive agents. Another NCI supported large clinical chemoprevention trial was recently started to investigate the efficacy of selenium and vitamin E, alone or in combination in the prevention of prostate cancer. Inclusion of appropriate biomarkers in clinical trials will help elucidate the mechanisms by which genetic and epigenetic pathways of carcinogenesis are modulated by nutrients and phytochemicals.     

Chemoprevention of colon cancer

Animal tumor experiments and epidemiologic studies suggest that several agents may be of potential value in blocking the development of colon adenomas and carcinoma. Recent laboratory investigations have demonstrated several intermediate markers that are altered in the colonic epithelium of high-risk individuals and that can be modulated by several possible chemopreventive agents. Calcium and ascorbic acid are two agents that have been investigated in preliminary studies. Although the results have not been striking, these studies have pointed up methodologic issues that must be addressed and will contribute greatly to the design of the next generation of trials. Given the advances in the elucidation of the carcinogenic processes in colon cancer, it is reasonable to hope that the next decade of research will discover chemoprevention strategies that will protect individuals from the development of the most common tumor in Western society.     

Chemoprevention of lung cancer

Lung cancer is a major cause of mortality and morbidity worldwide. Overall survival has only improved slightly despite advances in surgery, radiotherapy, and chemotherapy. Molecularly targeted agents are currently being studied in all treatment settings including that of chemoprevention, which is defined as the use of natural or synthetic agents to interrupt the process of carcinogenesis and to prevent or delay tumour occurrence. Lung cancer has become an increasingly difficult problem to treat with standard therapies and chemopreventive strategies have been developed. Progress in chemoprevention is reliant on the collaborative efforts of researchers in basic science and clinical settings who study the biology of lung cancer with the goal of uncovering new mechanisms of carcinogenesis. Small molecules which target specific receptors or mutations such as inhibitors of epidermal growth factor receptor or RAS will have an increasingly significant role as they are associated with more tolerable side-effects and may prove more effective. Development of a risk model with intermediate endpoints is essential for future chemoprevention studies.     

乳腺癌的药物预防

药物通过直接或间接与雌激素作用起到预防乳腺癌之作用，主要预防药物包括三苯氧胺、雷洛昔芬、芳香化酶抑制剂和环氧合酶-2抑制剂等。常用乳腺癌风险预测模型为Gail模型和Claus模型，多组大宗临床试验正在进行以寻找预防乳腺癌的新手段。     

Chemoprevention of breast cancer

Summary The hypothesis that oestrogen is an important promotor of human breast cancer raises the possibility that endrocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a doubleblind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10–15 year follow up in order to detect a 25% prevention effect.     

Chemoprevention of gastrointestinal cancer

Gastrointestinal cancer remains a significant public health threat in developed countries. Even with breath-taking gains in our understanding of the molecular underpinnings of the most common GI cancers, it is clear that the best hope in the foreseeable future lies in the chemoprevention of recurrent cancer and its associated precursors. Colon cancer is an ideal disease for the application of chemopreventive strategies. The molecular biology of colon cancer has been well studied and it is an excellent model for the development of chemopreventive interventions. This fact allows clinical investigators to utilize what is known about discrete biological phases of colon carcinogenesis to tailor clinical trial protocols that may attenuate a future risk for cancer. Among the agents currently in clinical trial testing are anti-oxidants, modulators of metabolism, and anti-proliferatives. Current clinical trials have often incorporated the use of biomarkers as intermediate endpoints to assess the efficacy of particular preventives. The current status of ongoing colon cancer prevention trials suggests that this disease, in particular, may well be suited to chemopreventive approaches.     

Chemoprevention of breast cancer

Despite a recent trend toward improvement in the U.S. breast cancer mortality rate, breast cancer incidence (182,800 new cases anticipated in 2000) and mortality figures (over 40,800 anticipated deaths) remain the highest and second highest, respectively, of all cancers in U.S. women. In 1998, the selective-estrogen-receptor-modulator (SERM) tamoxifen achieved positive results in the Breast Cancer Prevention Trial (BCPT), leading to the Food and Drug Administration (FDA) approval of tamoxifen for risk reduction in women at high risk of breast cancer (the historic first FDA approval of a cancer preventive agent). This brought about a paradigm shift in new approaches for controlling breast cancer toward pharmacologic preventive regimens, called chemoprevention. This paper presents a comprehensive clinical review of breast cancer prevention study, highlighting issues of the extensive study of tamoxifen. These issues include the record of primary tamoxifen results in several breast-cancer risk-reduction settings (primary, adjuvant, and ductal carcinoma in situ [DCIS]); critical secondary BCPT risk-benefit findings (including quality of life issues) and their effects on counseling patients on use of tamoxifen for prevention; ethic minorities; optimal tamoxifen dose/duration; and potential impact on mortality and other issues involved with potential net benefit to society. Other breast-cancer chemoprevention issues reviewed here include women at high genetic risk (especially BRCA1 mutation carriers); raloxifene in breast cancer prevention; other SERMs; SERM resistance; and new agents and combinations currently in development. Very recent developments involving PPAR- ligands, COX-2 inhibitors, and RXR-ligands are discussed in the section on new drug development.     

肺癌的化学预防

虽然近年来肺癌治疗已经取得了很大进展,但5年生存率依然不高.因此,有效的化学预防比肺癌的治疗更有意义.化学预防在肺癌以外的肿瘤中已经得到应用.在肺癌化学预防领域也对很多物质进行了研究,有些显示预防效果很好.