Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.
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PMID:A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors. 1077 49

In spite of extensive research in molecular carcinogenesis, genes that can be considered primary targets in human carcinogenesis remain to be identified. Mutated oncogenes or cellular growth regulatory genes, when incorporated into normal human epithelial cells, failed to immortalize or transform these cells. Therefore, they may be secondary events in human carcinogenesis. Based on some experimental studies we have proposed that downregulation of a differentiation gene may be the primary event in human carcinogenesis. Such a gene could be referred to as a tumor-initiating gene. Downregulation of a differentiation gene can be accomplished by a mutation in the differentiation gene, by activation of differentiation suppressor genes, and by inactivation of tumor suppressor genes. Downregulation of a differentiation gene can lead to immortalization of normal cells. Mutations in cellular proto-oncogenes, growth regulatory genes, and tumor suppressor genes in immortalized cells can lead to transformation. Such genes could be called tumor-promoting genes. This hypothesis can be documented by experiments published on differentiation of neuroblastoma (NB) cells in culture. The fact that terminal differentiation can be induced in NB cells by adenosine 3',5'-cyclic monophosphate (cAMP) suggests that the differentiation gene in these cells is not mutated, and thus can be activated by an appropriate agent. The fact that cAMP-resistant cells exist in NB cell populations suggests that a differentiation gene is mutated in these cancer cells, or that differentiation regulatory genes have become unresponsive to cAMP. In addition to cAMP, several other differentiating agents have been identified. Our proposed hypothesis of carcinogenesis can also be applied to other human tumors such as melanoma, pheochromocytoma, medulloblastoma, glioma, sarcoma, and colon cancer.
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PMID:Differentiation genes: are they primary targets for human carcinogenesis? 1156 2

Neoangiogenesis and enhanced glucose metabolism in neoplasms are likely to be activated by the same biochemical stimulus; hypoxia. A correlation between these two parameters has been postulated. The objective of this study was to evaluate the relationship between Fluoro-desoxi-glucose uptake at positron emission tomography scan and angiogenesis in lung metastasis. Fluoro-desoxi-glucose activity, expressed as a standard uptake value, and microvessel intratumoural density, were retrospectively calculated in a series of 43 lung metastasis resected in 19 patients. Primary sites were colorectal cancer in 16 metastases, sarcoma in eight, gynaecological in four and other sites in 15. The correlation between the two parameters was tested by logistic regression and multivariate analysis. Positron emission tomography scan was positive in 17 patients (sensitivity 89%). No correlation was observed between standard uptake value and microvessel intratumoural density in this series of lung metastasis. Positron emission tomography negative and positive nodules presented comparable value of microvessel intratumoural density (12.9 vs 11.3). Standard uptake value was significantly correlated with nodules size and was higher in colon cancer metastasis than in sarcoma ones. Microvessel intratumoural density was independent from nodule size but significantly higher in sarcoma than in colon cancer metastasis. The lack of correlation was confirmed by multivariate analysis after adjustment for tumour type and nodules size. The present study demonstrated that positron emission tomography scan is positive in a high proportion of patients regardless of microvessel density. Glucose uptake and angiogenesis appear to be independent biological features in lung metastasis. This observation may have implications for future antiangiogenic therapies.
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PMID:Fluoro-deoxi-glucose uptake and angiogenesis are independent biological features in lung metastases. 1198 69

Salvianolic acid A (1) is one of the active components from Salvia miltiorrhiza, which was found to suppress the growth of mouse tumors. S-3-1 (a 2-allyl-3,4-dihydroxybenzaldehyde, 2) is a synthetic intermediate of a salvianolic acid A derivative with strong inhibitory effects on the growth of cancer cells in vitro. The inhibitory effects of 2 on tumor growth and its molecular targets were studied. 2 significantly suppressed the growth of mouse Lewis lung carcinoma, S180 sarcoma and H22 hepatic carcinoma in a dose-dependent manner. With a simple scrape-loading dye transfer method, 20 microg/ml of 2 was found to significantly enhance gap junction intercellular communication (GJIC) in human pancreatic adenocarcinoma PaCa Cells, human lung epithelial carcinoma W1-38 cells and human lung adenocarcinoma A549 cells, but 2 had no marked effect on GJIC in human colon cancer CACO2 cells. With Northern blot analysis, 2 was found to inhibit the expression of c-myc gene in A549 cells and have no marked effect on H-ras oncogene expression, and increase the cellular P53 mRNA contents, though it did not affect the expression of RB tumor suppressor gene. 2 also suppressed the P46 (JNK/SAPK) expression in A549 cells. Western blot analysis was applied to visualize the P21ras protein. Results shows that 2 at concentrations ranging from 10 to 20 microg/ml decreases the contents of the membranous P21ras and total P21ras and increases the contents of cytosolic P21ras protein in a time-dependent manner. However, 2 had no significant effects on farnesyl protein transferase activities at the concentrations that could efficiently decrease the membranous P21ras content. This suggested that 2 might suppress tumor growth partly through enhancement of GJIC and reversion of the transformed phenotypes. The other mechanisms may be that 2 can suppress the overexpression of c-myc oncogene, inhibit the function of Ras oncoprotein, increase the expression of P53 tumor suppressor gene and interrupt P46-associated mitogen-activated pathway other than farnesylation of Ras protein.
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PMID:Inhibition of tumor growth by S-3-1, a synthetic intermediate of salvianolic acid A. 1245 Feb 55

Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease with multiple extrarenal manifestations. It accounts for 7% to 11% of patients receiving dialysis or renal transplantation (RT) for end-stage renal disease (ESRD) in Europe. We analyzed retrospectively the causes of death, the prevalence of cardiovascular risk factors (CVRF) and the patient and graft survivals in 62 consecutive ADPKD patients who received 63 cadaveric grafts (29 men and 34 women), of the 600 RTs performed between 1980-2001. The diagnosis of ADPKD was established by family history and ultrasound techniques. At present, 50 patients (79.4%) have functioning grafts, with a mean follow-up of 84.7 months (range, 12-255), and 13 patients have lost their grafts. The main cause of failure was patient death with a functioning graft (9 cases). Malignancies occurred in 5 patients, including 2 lymphomas, 1 renal carcinoma, 1 pancreas sarcoma, and 1 lung cancer associated with infection. Three patients died of cardiocerebrovascular events, and 1 patient of pneumonia. One patient lost the graft after decreasing the immunosuppression for an obstructing colon cancer. Three additional patients now on dialysis lost their grafts due to chronic rejection in 2 cases and primary nonfunction in 1 case. The prevalence of cardiovascular risk factors among the 50 patients with functional grafts were: hypertension, 70%; hypercholesterolemia, 62%; hyperhomocysteinemia, 30%; hyperfibrinogenemia, 68%; increased lipoprotein (a), 18%; microalbuminuria, 22%; hyperuricemia, 48%; hyperparathyroidism, 24%; overweight status, 24%; and nonlethal myocardial infarction, 10%. We conclude that ADPKD patients have good graft and patient survivals, and that the presence of malignancy is the main cause of death and graft failure at our center.
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PMID:Autosomal-dominant polycystic kidney disease: high prevalence of graft loss for death-related malignancies and cardiovascular risk factors. 1296 69

We prepared a colon cancer-bearing Yoshida sarcoma rat model to examine the dose-response relationship of antitumor activity of intracolonically or orally administered 5-fluorouracil (5-FU; 45, 30, 20, 13, and 8 mg/kg). At doses of > or =20 mg/kg and > or =30 mg/kg, the 5-FU intracolonic and oral administration groups each showed a statistically significant difference in antitumor activity against the control group (P<0.05, Williams' test). A statistically significant dose-response relationship was noted in the two routes of administration, with an ED(50) value of 29 mg/kg. White blood cell count tended to decrease at high doses when 5-FU was administered intracolonically and showed a statistically significant decrease at doses of > or =30 mg/kg when 5-FU was administered orally. Regarding the time-course of body weight, even the 5-FU highest dose (45 mg/kg) intracolonic administration group showed no inhibited body weight increase compared to the control group. However, the 5-FU (> or =20 mg/kg) oral administration groups showed a statistically significant difference in body weight increase against the control group. These facts suggested that the intracolonic administration of 5-FU, while exhibiting more potent antitumor activity than that observed in oral administration, allows an extensive reduction in its toxicities compared to oral administration.
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PMID:A comparative pharmacology study between the intracolonic and oral routes of 5-FU administration in a colon cancer-bearing Yoshida sarcoma rat model. 1521 40

We investigated how agonists at purinoceptors may affect tumour cell metabolism. This was investigated in vitro in tumour cell lines by microphysiometry, which method monitors extracellular acidification rate (ECAR), on-line. The cell lines investigated were the murine sarcoma, MCG 101, and the human colon cancer, HT-29. In MCG 101, adenosine-5'-triphosphate (ATP) or uridine-5'-triphosphate (UTP) caused a concentration-dependent increase in ECAR, most likely due to the ligation of P2Y(2) receptors, which response was blocked by suramin. In HT-29, ATP or UTP elicited a concentration-dependent, biphasic change in ECAR (increase/decrease). The pharmacological analysis suggests the involvement of P2Y(2) receptors, although other P2 receptor subtypes cannot be entirely excluded. This biphasic response to UTP or ATP was resistant to suramin. The expression of P2Y(2) receptors was demonstrated in both cell lines by immunocytochemistry and Western blot. The current study, thus, shows the functional and morphological expression of a purinoceptor subtype with partly different effects on metabolism in two different tumour cell lines.
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PMID:Expression of P2Y2 purinoceptors in MCG 101 murine sarcoma cells, and HT-29 human colon carcinoma cells. 1523 32

We investigated the association between occupational factors and risk of bone sarcoma, a rare tumor with a largely unknown aetiology. A multicentric case-control study was conducted in 7 European countries in 1995-97. Ninety-six cases aged 35-69 years with a centrally reviewed diagnosis of bone sarcoma (68 chondrosarcomas and 28 osteosarcomas) were compared to 2,632 population (68%) or colon cancer (32%) controls. Subjects were interviewed to obtain information on occupational, medical and reproductive history, smoking and alcohol consumption and selected exposures including use of pesticides. Response proportions were 90% among cases and 66% among controls. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for selected categories of job titles and branches of industry and for use of pesticides. We found an increased OR for bone sarcoma among blacksmiths, toolmakers, machine-tool operators (OR = 2.14, 95% CI 1.08-4.26), woodworkers (OR = 2.68, 95% CI 1.36-5.29) and construction workers (OR = 1.62, 95% CI 0.92-2.87). Ever users of pesticide had an OR of 2.33 (95% CI 1.31-4.13), with similar risks for exposure to insecticides and exposure to herbicides. Neither duration of employment in any of the analyzed occupational categories nor duration of use of pesticides showed an increasing trend in the risk of bone sarcoma. ORs of bone sarcoma were 1.03 (95% CI 0.23-4.57), 3.13 (95% CI 1.26-7.76) and 1.44 (95% CI 0.43-4.85) for the first, second and third tertile of days of use of pesticides. Our study suggests that novel and previously reported (woodworking) occupational factors play a role in the aetiology of bone sarcomas.
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PMID:Occupational factors and risk of adult bone sarcomas: a multicentric case-control study in Europe. 1610 52

The concept of postradiation sarcoma is widely appreciated, however carcinomas arising in previously irradiated fields, the putative "postradiation carcinoma," are less well understood. Fifteen patients who developed gynecological malignancies after pelvic radiation therapy were studied. Five of these patients had HPV-related tumors both pre- and post- irradiation. Ten were irradiated for cervical cancer, one for endometrial carcinoma, one for vulvar carcinoma, one for colon cancer and 2 for benign conditions. The mean and median latent periods from the initiation of radiation therapy to the development of the second malignancy were 22.8 and 19 years, respectively (22.4 and 19.5 years, respectively, for non-HPV-related cancers; 24 and 18 years for HPV-related cancers). The "postradiation" malignancies included 2 ovarian carcinomas, 5 vaginal carcinomas (3 invasive, 2 in situ), 4 endometrial carcinomas, one cervical carcinoma, one vulvar carcinoma, one distal urethral carcinoma, and one pelvic carcinoma of unclear primary site. Gynecological carcinomas may occur many years after pelvic irradiation. Although the evidence for a causative role is circumstantial, these tumors appear to have a similar latent period as postradiation sarcomas.
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PMID:Carcinomas of the female genital tract occurring after pelvic irradiation: a report of 15 cases. 1681 69

IPdR (5-iodo-2-pyrimidinone-2'-deoxyribose) is a novel orally available, halogenated thymidine (TdR) analog and is a potential radiosensitizer for use in human tumors, such as rectal, pancreas, sarcoma and glioma tumors. IPdR is a prodrug that is efficiently converted to IUdR (5-iodo-2'-deoxyuridine), an intravenous radiosensitizer by a hepatic aldehyde oxidase, resulting in high IPdR and IUdR plasma levels in mice for > or = 1 h after oral IPdR. Athymic mice tolerated oral IPdR to doses up to 1500 mg/kg/day t.i.d. for 6 - 14 days without significant systemic toxicities. A number of in vivo preclinical studies have demonstrated that IPdR is a superior radiosensitizer compared with IUdR given as a continuous infusion in terms of safety and efficacy with a significantly lower toxicity profile, including gastrointestinal and hematologic side effects. A preclinical study has shown that IPdR is effective in inducing human colon cancer xenograft radiosensitization in drug-resistant DNA mismatch repair-proficient and -deficient tumor models, as well as in human globlastoma xenograft. In anticipation of performing a clinical Phase I trial in humans, investigators also studied the drug pharmacokinetics and host toxicities in two non-rodent, animal species during a 14-day treatment course. Dose-limiting systemic toxicities (diarrhea, emesis, weight loss and decreased motor activity) were observed in ferrets receiving IPdR at 1500 mg/kg/day on a 14-day schedule that were not found previously in athymic mice. Recently, a once-daily IPdR dosing up to 2000/mg/kg for 28 days in Fischer-344 rats showed reversible mild-to-moderate systemic toxicities without any severe or life-threatening toxicities. However, in all preclinical toxicity studies so far, no significant hematologic, biochemical or histopathologic changes have been found. Hepatic aldehyde oxidase activity was reduced in a dose-dependent fashion in the ferret liver, suggesting partial enzyme inactivation by this IPdwR schedule, but that is not found in Fischer-344 rats. The plasma pharmacokinetic profile in Rhesus monkeys showing biexponential clearance are similar to previously published data in athymic mice. In this paper, the authors review the development, mechanism of action, preclinical data and rationale for clinical studies.
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PMID:IPdR: a novel oral radiosensitizer. 1771 27


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