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)

The pyrimidine analog, 5-azacytidine (NSC 102816), was administered by continuous intravenous infusion in Ringer's lactate in increasing doses to sets of patients with metastatic cancer to establish a dose sufficient to produce mild toxicity. Twenty-one patients (23 trials) were treated with doses of 50-200 mg/sq/m/day for 5 days every 2-4 wk. Nausea and vomiting were moderate and easily preventable. Doses of 100-200 mg/sq/m for 5 days every 14 days produced granulocytopenia, usually after two courses. Less toxicity was observed when courses were given every 21-28 days. Forty-five patients with previously treated and refractory acute myeloblastic leukemia were treated. The majority received doses of 150 mg/sq m for 5 days every 2 wk. Eleven (24%) complete remissions and four partial remissions were observed. The number of courses to achieve remission averaged three and required an average of 59 days. Nine patients with blastic crisis of chronic myeloblastic leukemia and four with refractory acute lymphoblastic leukemia failed to respond. 5-Azacytidine administered by continuous infusion is well tolerated and is an active compound in acute myeloblastic leukemia.
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PMID:5-Azacytidine (NSC 102816): a new drug for the treatment of myeloblastic leukemia. 6 Jan 56

Drug therapy is most often used in colorectal cancer for palliation of metastatic disease. Current data also support the use of adjuvant chemotherapy following complete surgical resection in patients with locoregional lymph node metastases. The agent most widely used in the treatment of colorectal cancer is the antimetabolite fluorouracil (5-fluorouracil; 5-FU). This fluoridated pyrimidine has been available for over 30 years, yet to date no other single agent has proven to be more efficacious. Controversy exists about the most desirable schedule for administration of fluorouracil. Efforts have been made to improve upon its therapeutic index and efficacy by using the concept of biomodulation, in which chemicals which are not themselves active antineoplastic agents against colorectal cancer are administered with fluorouracil in an attempt to enhance the sensitivity of the cancer cell to fluorouracil. Biomodulation agents currently in use in clinical practice include leucovorin (calcium folinate), methotrexate, and interferon-alpha. Other biomodulation strategies are currently under investigation. Adding putatively active antineoplastic agents to fluorouracil to form combination chemotherapy regimens has not yielded convincingly superior results to treatment with fluorouracil alone, and the toxicities of many of these combination regimens have been formidable. Secondary therapies following failure of fluorouracil-based regimens have been similarly disappointing. Current areas of investigation into the chemotherapy of colorectal cancer include development of new agents, locoregional administration of chemotherapy, and manipulation of intrinsic drug resistance mechanisms of the cancer cells.
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PMID:Drug treatment of colorectal cancer. Current status. 172 64

This review delineates the subcellular distribution, biochemical characteristics, and metabolic functions of 5'-nucleotidase (5'NT), summarizes the analytical biochemistry of 5'NT, and assesses the clinical significance of 5'NT determinations in body fluids, cells, and tissues. Salient aspects of the clinical biochemistry of 5'NT, discussed herein, are as follows: (A) Serum 5'NT activity is generally elevated in hepatobiliary diseases, especially with intrahepatic obstruction, but, unlike serum alkaline phosphatase, serum 5'NT activity is not increased in infancy, childhood, pregnancy, or osteoblastic disorders. (B) In cancer patients, elevated serum 5'NT activity does not always indicate hepatobiliary involvement; in some cases, 5'NT may be released into serum from the primary tumor or local metastases. (C) Genetic deficiency of erythrocyte pyrimidine 5'NT activity is a common cause of hereditary non-spherocytic hemolytic anemia. (D) Acquired deficiency of erythrocyte pyrimidine 5'NT activity occurs in patients with beta-thalassemia and lead poisoning. (E) 5'NT activity is low in circulating monocytes, increases markedly upon their differentiation to tissue macrophages, and subsequently diminishes during macrophage activation. (F) Lymphocyte ecto-5'NT activity, a plasma membrane marker of cell maturation, is generally low in immunodeficiency states, and undergoes characteristic changes in patients with certain lymphomas and leukemias.
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PMID:The clinical biochemistry of 5'-nucleotidase. 218 4

The pyrimido-pyrimidine analogue RA 233 has pleiotropic and differential effects on cultured tumor cell clones isolated from the 13762NF rat mammary adenocarcinoma. A nonresponsive clone of low metastatic potential (MTC) was not modified in its cell fragility or invasive, adhesive or lung-colonizing properties by RA 233 treatment. In contrast, a drug-responsive clone of high metastatic potential (MTLn3) was rendered less invasive and its cell fragility was decreased with RA 233 treatment, although its adhesiveness to lung microvascular endothelial cells and subendothelial matrix was unaffected by RA 233. Lung colonization of intravenously injected MTLn3 cells in syngeneic rats was significantly increased by RA 233 treatment, whereas spontaneous metastasis from the mammary fat pad to lung sites was decreased, although this decrease was not statistically significant.
Clin Exp Metastasis
PMID:Effects of RA 233 treatment on the adhesive, invasive and metastatic properties of 13762NF rat mammary tumor cells. 292 Apr 74

RA 233, a pyrimido-pyrimidine analogue developed originally as an antiplatelet agent, has reduced the incidence of tumor metastases in clinical trials. However, in animal tumor models antimetastatic therapy using RA 233 has been inconsistent. We therefore tested RA 233 for additional effects, such as its direct action on tumor cells. Using the rat 13726NF mammary adenocarcinoma tumor system, low, nontoxic concentrations of RA 233 had pleiotropic and differential effects on two 13762NF tumor cell clones. The growth of MTC cells (low spontaneous metastatic potential) was not affected by low concentrations of RA 233 (50 microM) or epidermal growth factor (EGF) (up to 10 ng/ml) for 3 days in 0.5-10% fetal bovine serum. In contrast, MTLn3 (high spontaneous metastatic potential) cell cultures maintained for 3 days in low (0.5-1%) serum in the presence of 1.25-10 ng/ml EGF doubled in cell numbers compared with control cultures, and addition of 50 microM RA 233 abrogated the growth-stimulatory effect of EGF. The inhibitory effect of RA 233 on MTLn3 cells was dose dependent and not due to cell toxicity as determined by cell viability, cell growth, and colony formation properties after drug removal. In addition, incubation of MTLn3 cells with 50 microM RA 233 resulted in an increase of p21ras protein expression, whereas there was no effect on the level of p21ras in identically treated MTC cells or when either clone was treated with 10 ng/ml EGF. The results suggest that among the heterogeneous effects of RA 233 on tumor cells, modulation of growth factor responses and regulatory molecules may be important.
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PMID:Pyrimido-pyrimidine modulation of EGF growth-promoting activity and p21ras expression in rat mammary adenocarcinoma cells. 305 58

This article summarizes recent studies characterizing nucleoside transport in mammalian cells and discusses evidence for a role of membrane transport in the pharmacologic action of nucleoside analogues. Some of these studies have also addressed the controversy concerning the multiplicity in transport routes. It seems clear that erythrocytes and, perhaps, some other mammalian cells possess a single, broadly specific system for transporting nucleosides. However, substantial evidence from valid studies discriminating between transport and intracellular metabolism suggests that at least some mammalian cells, including some tumor cells, possess more than a single system. Evidence now exists for a determining role of membrane transport of nucleoside analogues in their cytotoxicity and, in the case of one pyrimidine nucleoside (AraC), in therapeutic responsiveness in leukemic patients. There are also numerous examples of transport-related resistance to nucleoside analogues. Included in this article are the results of studies from the authors' laboratory pertaining to the therapeutic activity of the purine nucleoside, FAraA, in murine tumor models. These studies provide evidence for a determining role of both membrane transport and intracellular phosphorylation in the selective antitumor action of this agent against murine leukemia. Substantially increased transport inward of FAraA occurs at pharmacologically achievable concentrations of this agent in tumor cells as compared to drug-limiting, normal proliferative epithelium of the small intestine. The basis for this differential appears to be the kinetic duality of FAraA and adenosine transport inward found in tumor cells, but not in proliferative intestinal epithelial cells. Tumor cells have highly saturable (low influx Km) and poorly saturable (high influx Km) systems for adenosine transport, both of which are shared by FAraA. In contrast, proliferative epithelial cells have only a poorly saturable system for these substrates. If a similar kinetic duality of nucleoside transport is found in other tumor cells certain implications arise concerning the significance of the duality to neoplastic transformation.
Cancer Metastasis Rev 1987
PMID:Membrane transport and the antineoplastic action of nucleoside analogues. 332 28

Possible prophylactic antitumor and/or antimetastatic effects of long-term oral administration of a potent inhibitor of platelet aggregation, the pyrimido-pyrimidine derivative RA233, were assessed using four phenotypically distinct clones of the mouse B16 melanoma. The clones tested included: a poorly tumorigenic, very slowly growing and poorly metastatic population (G3.15); a moderately tumorigenic and slowly growing population that frequently metastasizes to the lungs (G3.5); a highly tumorigenic, moderately growing and highly metastatic population (G3.12); and a highly tumorigenic and rapidly growing population that is generally nonmetastatic but can be slightly metastatic when tumors are initiated by very small numbers of cells (G3.26). Addition of 0.5 mg/ml RA233 to the drinking water continuously from the time of subcutaneous injection of cultured tumor cells until death from tumor growth, which resulted in a daily uptake of 80-100 mg/kg of drug per mouse, failed to significantly influence the tumorigenicities, tumor growth rates, metastatic incidences, or metastatic burdens of any of these clones. RA233 at doses equivalent to those delivered daily to experimental animals strongly inhibited ADP-induced aggregation of homologous C57BL/6 mouse platelets and exhibited selective anti-proliferative effects on cultured cells. Although RA233 prolonged bleeding times, pharmacokinetic analysis indicated that clearance of RA233 from mice was so rapid that achievement of sustained circulating levels sufficient to influence tumor cells or platelet-tumor cell interactions by oral administration was unlikely.
Clin Exp Metastasis
PMID:Failure of orally administered RA233 to influence B16 melanoma growth or metastasis. 359 74

RX-RA 69, a pyrimido-pyrimidine derivative, is a new potent PDA-inhibitor which inhibits tumor cell induced platelet aggregation in vitro. Also ex vivo an inhibition was found after pretreating mice with 1 mg/kg RX-RA 69 orally one hour before collecting the blood. The same dosage is able to prevent the drop in platelet count induced by injecting a large number of tumor cells into mice. The same dosage schedule in the amputation experiment resulted in a reduction of incidence of matastases in all treated groups; the best results, however, were obtained by starting the treatment two days after the amputation. In the spontaneous model an inhibition of metastases formation by 10-20 mg/kg RX-RA 69 starting from the fourth day after tumor cell implantation was found in four independent experiments. The mechanism of the antimetastatic action of this drug remains to be evaluated.
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PMID:Antimetastatic action of RX-RA 69, a new potent PDE-inhibitor in the Lewis lung carcinoma of the mouse. 628 86

Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole was initiated in 1972 because the pyrimido-pyrimidine derivative was shown to inhibit platelet aggregation in vivo and to increase significantly the circulation time of intravenously injected, 32P-labelled Ehrlich ascites tumour cells in mouse blood. The aggregation of platelets to circulating tumour cells and their subsequent adhesion to vascular endothelium in turn appeared to be part of the early stages of the metastatic process. It seems, however, that other related mechanisms are also involved in the clinical results obtained. Mopidamole, as other related derivatives, probably inhibits platelet aggregation by inhibition of PDE-induced decomposition of cAMP and may stimulate the synthesis and/or release of prostacyclin from the vessel wall which in turn activates adenylate cyclase involved in cAMP synthesis. The latter mechanism was definitely shown only for the related pyrimido-pyrimidine derivative dipyridamole, the methyl-xanthine derivative pentoxifylline and the methyl-pyrazoline derivative nafazatrom. The increase of cAMP levels by mopidamole results in an inhibition of 3H-thymidine incorporation into human neoplastic cells and a direct inhibition of its mitotic rate. The adding of mopidamole to a culture of a human promyelocytic leukemic cell line promotes a reverse transformation of the malignant cells to normal which appears to be a permanent phenotypic change. Furthermore, mopidamole was shown to diminish significantly spontaneous lung metastases in syngenic Wilms' tumor (nephroblastoma) of the rat, the C1300-neuroblastoma of the mouse and the HM-Kim mammary carcinoma of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Modification of metastasis formation by inhibition of platelet aggregation. Experimental and clinical results]. 636 51

Previously, we reported the effects of human lymphoblastoid interferon (HLBI), using a transplantable human renal cell carcinoma strain (AM-RC-3) in nude mice established in our laboratory. An overall anticancer effect was found from its combination with UFT (Ft-207t uracil). In the present investigation, we examined the clinical effectiveness when HLBI was administered alone or in combination with UFT to the patients. Seventy-three patients who had undergone curative surgery were divided into 3 groups, according to the type of adjuvant therapy. The HLBI group consisted of 38 patients, including those administered the agent alone over 50 times for more than six months, and or those to whom it was given in combination with UFT. The second group of 23 patients had been treated with hormones, radiotherapy, or with an anticancer drug (Fluoride pyrimidine group), while the last group of 17 patients underwent no postoperative adjuvant therapy. The survival rate calculated by the Kaplan-Meier method revealed no significant effects of HLBI on the survival period, but a significant difference (p < 0.05) was found in the HLBI group compared to the other groups in terms of much higher non-recurrence rate. When HLBI was administered alone or in combination with UFT, a definite anticancer effect was seen in 6 (complete response 3, partial response 2, minor response (MR) 1, no change 5, progression of disease 14) of the 25 treated patients. Fourteen of the 25, treated patients had postoperative recurrence, and 11 patients had distant metastases, at the time of diagnosis which were considered to be progressive and measurable lesions. In 6 patients the response was better than MR, with the effective rate being 24%. Four of the 6 patients had received HLBI in combination with UFT, which suggests a clinical effect in this combination. However, the effectiveness was limited to the lung lesions, more effective treatment of the lesions in other sites is required.
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PMID:[Clinical study of renal cell carcinoma]. 750 69


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