Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer chemotherapy celebrated its fiftieth anniversary last year. It was in 1945 that wartime research on the nitrogen mustards, which uncovered their potential use in the treatment of leukaemias and other cancers, was first made public. Fifty years later, more than sixty drugs have been registered in the USA for the treatment of cancer, but there are still lessons to be learnt. One problem, paradoxically, is that many anticancer agents produce a response in several different classes of the disease. This means that once a new agent has been shown to be effective in one cancer, much effort is devoted to further investigations of the same drug in various combinations for different disorders. While this approach has led to advances in the treatment of many childhood cancers and some rare diseases, a plethora of studies on metastatic colon cancer, for example, has yielded little benefit. 5-fluorouracil continues to be used in trials, yet there is no evidence for an increase in survival. The lesson to be learnt is that many common cancers are not adequately treated by present-day chemotherapy, and most trials of this sort are a waste of time. Significant increases in survival will only occur if the selectivity of present-day anticancer agents can be increased or new classes of more selective agents can be discovered. There are two fundamental problems in drug development: a lack of suitable laboratory tests and the difficulty of conducting early clinical trials. Firstly, no existing laboratory method can accurately predict which chemical will be effective against a particular class of human cancer. At best, tests can demonstrate a general 'anticancer' property. This is well exemplified by the discovery of cisplatin. The fact that cisplatin caused regression in a number of transplanted rodent tumours created no great excitement amongst chemotherapists. It was only later when it was tested clinically against ovarian cancer that results were sufficiently positive to encourage others to investigate. Only then was it discovered that metastatic teratoma was extraordinarily sensitive to the drug. This finding was made as a result of phase II trials and no laboratory model could have predicted it. The lesson to be learnt is that new drugs should be tested extensively in phase II trials before they are discarded. The second problem concerns early clinical trials. Because new drugs can only be tested against advanced and usually heavily pretreated disease, it is unlikely that dramatic responses will occur. The methods used to detect responses in solid tumours and metastases are crude, and it is likely that many useful drugs are missed. New techniques are needed to detect small but important responses. In addition to these technical problems, clinical trials are expensive and the time required for preclinical pharmacology and toxicology is lengthy. In the early days, drugs could enter clinical trials after fairly simple toxicological studies. The thalidomide disaster in the 1960s, however, led to the setting up of regulatory bodies to scrutinize drugs before clinical trials. This proved detrimental for cancer drug development because a series of fairly long-term tests is now required. These must be carried out in both rodents and one other species, usually the dog. This approach was probably a good thing for most medicines where a large margin of safety is required between the therapeutic dose and the dose which causes side effects, but was inappropriate for anticancer agents which are tested at the maximum possible dose which gives manageable side effects. These new regulations meant that the cost of one clinical trial after the 1970s was equivalent to the cost of ten before that time. Solutions to these problems are available, although to put them into practice would require the cooperation of government regulatory authorities, the pharmaceutical industry and other organisations such as the US National Cancer Institute (NCI), the UK Cancer Research Campaign (CRC) and the European Organisation for Research and Treatment of Cancer (EORTC). Firstly, it is important to switch from clinical trials of analogues and combinations of standard drugs to trials of new classes of anticancer agents. Further, an international effort should be launched whereby these new agents can be rapidly tested in phase II trials against common solid cancers using new techniques to detect small but significant tumour responses. Lead chemicals discovered in this way could then be taken back to the laboratory for further development. There is no shortage of new drugs which act by mechanisms quite different from present-day agents, and new approaches can greatly increase the amount of cytotoxic agents delivered to solid tumours. As long ago as 1980, the CRC introduced protocols which enabled early clinical trials to be carried out rapidly and with minimal cost. These procedures used short-term tests only in rodents to determine a safe starting dose. The test can be completed within six months and around fifty clinical trials using this protocol have been successfully carried out in collaboration with the EORTC. Despite this, the American Food and Drug Administration (FDA), regulatory authorities in many other countries and many drug companies still insist on using a second animal species before a phase I clinical trial is permitted instead of using the money spent to develop several agents with minimal toxicology testing. The EORTC and CRC also plan to introduce positron emission tomographic scanning into early clinical trials as a highly sensitive method of measuring tumour response. Cancer mortality has changed little over the past forty years, mainly because of our failure to develop curative chemotherapy for the common solid cancers. The way forward is to carry out extensive phase I and II clinical trials of the many new types of anticancer agent that have become available as a result of increased knowledge about cancer cells and how they differ from normal tissues. In order to do this, the regulatory authorities must recognize that minimal toxicology protocols are adequate, and drug companies must be persuaded to give more emphasis to the search for new chemotherapeutic agents. A coordinated effort to achieve these aims would be a wonderful way to mark the fiftieth anniversary of modern chemotherapy. Unfortunately the regulatory authorities find it less risky to stick with extensive safety testing rather than to use shortcuts, however well-validated clinically. Many but not all drug companies, mindful of profits, prefer the easy way out and concentrate on analogues, while most clinicians opt for trials of combinations of known agents, being aware that they are worth a publication or two. Reprinted with permission from Helix, Volume V, Issue 1, 1996, pp. 20-21.
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PMID:Anticancer Drug Development: The Way Forward. 1038 85

In recent years, interest in the development of immunologic approaches to malignancies has increased, and there is good evidence that the growth of renal-cell carcinoma (RCC) can be modulated by the host's immune system. Indeed, use of the immunomodulatory cytokine interleukin-2 (IL-2) has been approved for the treatment for this disease. The efficacy of this approach remains low, and there is no other reasonable conventional therapy for patients with metastatic RCC. Therefore, there is a need for the development of novel treatment strategies. The development of autologous tumor-cell vaccines that have been genetically modified to become more immunogenic is an approach that is actively being studied. One of the genetic manipulations that is being employed by several groups is the induction of overexpression of B7-1 to provide costimulation to tumor-reactive T-cells. The rationale for this strategy is that T-cells need two signals before they can mount a cytotoxic response: the binding of the T-cell receptor (TCR) to an antigenic peptide presented on major histocompatibility complex (MHC) molecules and the binding of CD28 to B7-1. Since B7-1 is not normally expressed by RCC cells, the expression forced by transfection of an exogenous B7-1 gene could make the tumor cells more immunogenic. This has been shown to be the case in mice, in which the injection of tumor cells transfected with B7-1 can result in the T-cell-mediated rejection of unmanipulated parental tumor cells. We have applied this approach to the treatment of patients with metastatic RCC. Patients enrolled on our phase I protocol are treated with autologous tumor cells modified to express B7-1, which functions as a tumor vaccine. Primary tumors or metastases are resected from the patients. The tumor cells are adapted to in vitro culture, infected with a recombinant adenoviral vector containing human B7-1 cDNA driven by the cytomegalovirus (CMV) promoter, radiated, and stored in liquid nitrogen. Aliquots of the B7-1 gene-modified tumor cells are given to the patients as a vaccine at varying intervals according to a dose-escalation scheme. The patients also receive systemic IL-2 for the dual purpose of providing accepted therapy for this disease as well as expanding the tumor-reactive T-cells activated by the vaccine. The immunogenicity and toxicity of the vaccine as well as the clinical response are being assessed in three to five patients at each of three dose levels.
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PMID:B7-1 gene-modified autologous tumor-cell vaccines for renal-cell carcinoma. 1085 53

In addition to inhibiting bone resorption, bisphosphonates also exert anti-tumor effects. The most potent compounds are the newer, nitrogen-containing bisphosphonates such as zoledronic acid. In vitro, bisphosphonates inhibit proliferation and induce apoptosis in human tumor cell lines, and interfere with cell adhesion, invasion and growth factor secretion. The combination of bisphosphonates with other anti-cancer drugs such as paclitaxel or tamoxifen markedly enhances these effects. In vivo, zoledronic acid has recently been shown to inhibit angiogenesis. Although bisphosphonates are very effective against bone metastases, their in vivo anti-tumor potential against visceral metastases remains to be explored.
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PMID:Anti-tumor potential of bisphosphonates. 1108 84

The role of reactive nitrogen species (RNS) in colon carcinogenesis is multifactorial and affects diverse processes, such as proliferation, apoptosis, differentiation, tumorigenesis, and metastases. This review describes the stages in colon carcinogenesis where nitric oxide (NO) and inducible NO synthase (NOS2) may influence the progression of a normal mucosa to overt metastatic cancer. Overexpression of NOS2 and an increase in the generation of NO and other RNS may lead to apoptosis resistance, DNA damage, mutation, up-regulation of COX-2, increased proliferation, an increase in oxidative stress and an increase in tumor vascularity and metastatic potential. Therefore, future goals are to establish mechanistically based biomarkers to assess individuals at risk for colon cancer and to implement chemopreventive and dietary strategies that reduce colon cancer risk. An understanding of NO signaling pathways in colon epithelial cells should provide the basis for novel biomarker development. Colon cancer prevention may be achieved effectively by chemically interfering with key components of the NO signaling pathways, changing dietary habits to reduce fat and increase antioxidant-containing vegetables, and dietary supplementation to increase DNA repair.
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PMID:Reactive nitrogen species in colon carcinogenesis. 1123 44

Background: Bladder cancer is a common malignancy in Egypt and other developing countries in which infection with Schistosoma haematobium is prevalent. Bladder cancer caused by bilharziasis has different clinical and biological characters than that observed in the western world. In this study, we used the TRAP technique to estimate telomerase activity in bilharzial bladder cancer specimens and we correlated the findings with other clinical and pathological findings. Patients and methods: Bladder cancer specimens were obtained from 57 patients who underwent radical cystectomy and pathological diagnosis was obtained in all patients. Tissue samples were frozen in liquid nitrogen and stored at -80 degrees C. Telomerase activity by PCR-ELISA technique was measured using TRAP technique. Results: Our patient group included 45 males and 12 females with a median age of 49 years. The majority of our patients (35/57) have squamous histology and they have proven bilharzial history shown in the pathology specimens. Stage P3b was encountered in 29/57 patients whereas thirty-five patients have grade II tumors. The majority of our patients (41/57) were negative for pelvic nodes metastases. Telomerase activity was detected in 27/57 patients (47.4%). The mean level of telomerase was 0.85+/-0.77 in positive patients and 0.029+/-0.025 in negative patients. The expression of telomerase and its mean level in patients above age of 60, in males and in those with squamous pathology, higher grade of tumors or positive node was higher than those without but the difference did not reach statistical significance (P>0.05). Alternatively, expression was significantly higher in those with stages (P1-P3a) compared with P3b-P4a disease stages (66.6% vs. 37.1, P=0.03). Conclusion: Telomerase activity is increased in bilharzial bladder cancer although to a lesser degree than that reported for TCC in the western world, which could be explained, by different biological behavior or different assay methods. Further larger studies with more number of patients are still needed to determine its potential value for early detection and possible use as a therapeutic target.
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PMID:Telomerase activity in bilharzial bladder cancer. Prognostic implications. 1141 21

Efficacy of combined treatment (203 patients) and surgical treatment (200 patients) alone was analyzed. In combined treatment either radiation therapy (RT) in the dose 20 Gy over 5 days (group 1) or hypoxyradiotherapy (HRT) in the same doses but in combination with hypoxia (10% oxygen and 90% nitrogen--hypoxic gas mixture HGM-10--group 2) were used in preoperative period. In group 3 HGM-9 (9% oxygen and 91% nitrogen) was used as radioprotector in preoperative period but in increased by 25% radiation doses: total 25 Gy, 5 Gy for 5 days. In the control group only radical surgical treatment was performed. Preoperative irradiation didn't increase the rate of postoperative complications. At the same time the 5-year survival rate was higher in all the groups of patients on combined treatment than in the group of patients on surgical radical treatment. In the group with HGM-9 and increased by 25% radiation doses postoperative complications rate was lower, recurrences and distant metastases occurred less frequently.
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PMID:[Intensive preoperative hypoxic radiotherapy in combined treatment of patients with cancer of the colon]. 1151 99

DOTA-D-Phe1-Tyr3-octreotide (DOTATOC), a newly developed somatostatin analogue which can be stably labelled with the beta-emitter yttrium-90, can be used for receptor-mediated internal radiotherapy. A 78-year-old woman suffering from a carcinoid of the small intestine with multiple metastases in the liver as well as mesenteric and supraclavicular lymph node metastases was treated with this therapy after the disease had progressed under other chemotherapy options employed years previously. The patient received four single doses of 90Y-DOTATOC at 6-week intervals, yielding a cumulative dose of 9,620 MBq (5,659 MBq/m2). Restaging revealed stable metastatic disease. Serum creatinine and urea nitrogen levels were within the normal range prior to starting and during DOTATOC therapy. However, 15 months after cessation of DOTATOC therapy, a progressive deterioration of renal function occurred, leading to end-stage renal disease. Urinalysis revealed a slight proteinuria of 700 mg/day without haematuria, leucocyturia or casts. There was no obvious risk factor for chronic renal insufficiency except DOTATOC therapy. However, it was not feasible to use kidney biopsy to prove the presence of radiation-induced nephritis. Intermittent haemodialysis was started as the creatinine clearance declined to below 10 ml/min. Diuresis was not affected. The presented case shows delayed renal insufficiency after a relatively low cumulative dose of 90Y-DOTATOC (5,659 MBq/m2). This serious adverse event indicates that further studies are needed to evaluate which dose of 90Y-DOTATOC, under which renal protection regimen, will provide optimal management, balancing risks and benefits.
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PMID:End-stage renal disease after treatment with 90Y-DOTATOC. 1200 21

Spinal cord compression (SCC) is a devastating complication of metastatic cancer. We investigated the potential beneficial effect of two palliative therapies--strontium-89 (Metastron) and the nitrogen-containing bisphosphonate olpadronate--on the incidence of SCC in hormone-refractory prostate cancer (HRPC) metastatic to the skeleton. We retrospectively studied 415 patients with histologically proven prostate cancer who underwent bone scintigraphy at the time of diagnosis and were followed up at the Leiden University Medical Center between 1990 and 1999. Medical or surgical castration was undertaken in 172 patients with evidence for skeletal metastases. Within 2 years, 147 of these patients (85%) developed HRPC associated with severe progressive bone pain. Palliative treatment was given to 131 patients in the form of local radiotherapy ( n=10), 89Sr ( n=46) or intravenous olpadronate ( n=66), with ( n=57) or without ( n=9) maintenance oral olpadronate. Nine patients received both 89Sr and olpadronate at various intervals. Sixteen patients who did not receive any of these treatments were used as historical controls. There was no significant difference in baseline characteristics between treatment modalities. The incidence of SCC was 17% in the whole group, and highest in controls receiving no palliation (50%). None of the patients treated with local radiotherapy, only 4% of patients receiving 89Sr and 21% of patients given olpadronate developed this complication. Our findings suggest a significant reduction in SCC in patients with symptomatic HRPC metastatic to the skeleton who receive palliative therapies. Local radiotherapy completely prevents the incidence of SCC, 89Sr leads to an important decrease in this complication and olpadronate induces a significant, albeit smaller decrease in the incidence of SCC. The use of these agents opens new avenues in the difficult management of patients with advanced prostate cancer who are most at risk of developing SCC.
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PMID:Strontium-89 (Metastron) and the bisphosphonate olpadronate reduce the incidence of spinal cord compression in patients with hormone-refractory prostate cancer metastatic to the skeleton. 1191 87

Breast and prostate cancer preferentially metastasize in the skeleton, inducing locally increased bone resorption by osteoclasts. Bisphosphonates (BPs), potent inhibitors of osteoclasts and bone resorption, are able to reduce metastatic bone lesions, but the metastasis-related cellular target molecules for BPs have not yet been identified. In osteoclasts, nitrogen-containing BPs inhibit the function of the mevalonate pathway, impairing the prenylation and activation of small GTPases. In addition, direct effects of BPs on cancer cells have been suggested. In the present study, the effects of two clinically used BPs, the amino-BP alendronate and clodronate, on adhesion, invasion, and migration of human PC-3 prostate cancer cells were examined in vitro. We also studied the possible role of the mevalonate pathway in invasion and migration of PC-3 cells using the beta-hydroxy-beta-methylglutaryl-CoA reductase inhibitor mevastatin and the mevalonate pathway intermediates mevalonate (mevalonic acid lactone), geranylgeraniol, and trans-trans-farnesol. The results demonstrate that alendronate pretreatment very effectively inhibited in vitro invasion of prostate cancer cells in a dose-dependent manner, with an IC50 as low as approximately 1 pM. The inhibition was similar to that of mevastatin. Clodronate also inhibited invasion, but the IC50 was 0.1 microM. Importantly, geranylgeraniol and trans-trans-farnesol reversed the inhibitory effect of alendronate and mevastatin but not the clodronate-induced inhibition of invasion. Alendronate pretreatment also inhibited migration, which was partially reversed by geranylgeraniol and trans-trans-farnesol. Adhesion of PC-3 cells to various matrices was reduced, and their F-actin organization was changed. Alendronate pretreatment also inhibited invasion of human Du-145 prostate and MDA-MB-231 breast cancer cells. As a conclusion, the results demonstrate that the mevalonate pathway leading to protein prenylation is important for cancer cell invasion and migration in vitro. They further suggest that interference with this pathway is involved in inhibition of invasion and migration of prostate cancer cells by the amino-BP alendronate but that the mechanism of clodronate inhibition is different. It is possible that BPs have therapeutic potential in preventing the spread of prostate cancer.
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PMID:Alendronate inhibits invasion of PC-3 prostate cancer cells by affecting the mevalonate pathway. 1508 15

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF-beta but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30-40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.
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PMID:Bisphosphonates in the treatment of metastatic breast cancer. 1201 36


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