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)

While carcinomas of the stomach is decreasing in incidence in the Dnited States, it is still a major cause of cancer death. But gastric neoplasms are not decreasing in some other geographic areas. According to some studies, 30% of all cancer in the U.S.S.R. originates in the stomach. The rate of gastric neoplasms is greatest in Japan, and over 54% of all cancer in the male population arises in the stomach. The peak age for development of stomach cancer is between 70 and 80 years; over 60% of all stomach cancer is diagnosed in patients between the ages of 60 and 70, while more than 10% is found in those over 80. The main hope for cure at this time rests with surgical treatment. However, despite increased use of surgery, the 5-year survival rate of approximately 13% for patients diagnosed during 1955-59 has not improved to any degree since that time. The major drugs commonly used to treat gastric cancer are 5-fluorouracil (5-FU) and mitomycin C. Controversy still exists concerning the optimum method for administering 5-FU, the most frequently used drug in the United States. The standard loading-course method was attended by a high risk of severe toxicity and drug-related deaths. Several variations of the loading course have evolved. Currently, the Mayo Clinic group uses a 5-day course of 13.5 mg 5-FU/kg repeated every 5 weeks, with therapy interrupted if stomatitis or diarrhea develops; with this regimen the drug-related mortality rate was reported to be less than 1%. Studies have shown that 5-FU plus radiotherapy can enhance survival in patients with locally unresectable diseases. The overall objective with 5-FU is 20-25% with an average of 4-5 months' duration of response. Despite the many patients treated with 5-FU, rarely has a systematic analysis been done of factors such as age, sex, disease-free interval, histologic grade of the tumor, or sites or metastases, which might predispose to a favourable or unfavorable response. In Japan the most commonly used drug for treatment of gastric cancer is mitomycin C, the second most frequently used drug in the United States. The overall objective response rate with mitomycin C is between 20 and 30%, with the higher response rates being reported in the Japanese data. The average duration of response ranges from 1 to 3 months. The nitrosoureas [1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), 1,3-cis(2-chloroethyl)-1-nitrosourea (CCNU), and methyl CCNU (MeCCNU)] have shown some evidence of activity against gastric cancer. BCNU has yielded an objective response rate of 18% (6/33) and an average duration of response of 4.5 months in gastric cancer patients, most of whom had no prior therapy. Adriamycin recently has been shown to have some antitumor activity, with an approximate response rate of 25%. Combination approaches have been more successful in stomach cancer than in any other gastrointestinal neoplasm. The Japanese have reported higher response rates with a combination of 5-FU, mitomycin C, and cytosine arabinoside...
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PMID:Gastric cancer: current status of treatment. 40 78

Pyrazine diazohydroxide (sodium salt, NSC 361456; PZDH) is a new antitumor drug with relatively broad activity in initial evaluations against murine leukemias, solid tumors, and two human tumor xenografts in vivo. The present studies were designed to address questions about PZDH activity on different treatment schedules, its activity against metastases, and the extent of its cross-resistance with established drugs. Human LOX amelanotic melanoma xenografts in athymic mice were used to explore schedule dependence and activity against natural metastases, and a series of drug-resistant murine leukemias provided an in vivo cross-resistance profile. Single-dose treatment and prolonged treatment provided equivalent therapeutic responses to PZDH by both the i.p. and i.v. routes in the i.p. LOX model. A s.c. LOX model resulting in spontaneous pulmonary metastases was adapted for bioassay and quantitation of the numbers of LOX cells killed by PZDH among both primary and metastatic cell populations. It was demonstrated that PZDH afforded about 2-log10 orders of magnitude greater cell kill among pulmonary metastases than against primary s.c. LOX tumors in the same mouse. Murine leukemias resistant to doxorubicin (ADR), vincristine (VCR), cisplatin (DDPt), methotrexate (MTX), N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), and cyclophosphamide (CPA) were not cross-resistant to PZDH. However, both P388 and L1210 leukemia sublines resistant to melphalan (L-PAM) were cross-resistant to PZDH, suggesting that patients previously treated with L-PAM might have less likelihood of response to PZDH than those who had had no opportunity to develop L-PAM resistance. Although these observations should not be applied to clinical studies without due caution, they support clinical evaluation of PZDH as well as continued investigation of its molecular pharmacology.
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PMID:Schedule dependence, activity against natural metastases, and cross-resistance of pyrazine diazohydroxide (sodium salt, NSC 361456) in preclinical models in vivo. 231 Nov 70

The effect of treatment with the hypoxic cell radiosensitizer misonidazole (MISO) and the radioprotector diethyldithiocarbamate (DDC) on the formation of spontaneous lung metastases of four different spontaneously metastasizing murine tumors was investigated. The tumors were mammary carcinoma MCA-K, hepatocarcinoma HCA-1, and sarcomas SA-4020 and SA-NH. Multiple daily treatments with MISO significantly enhanced the incidence of metastases only in MCA-K. Because only MCA-K, but not the three remaining tumors, is immunogenic, the treatment with MISO may be associated with the promotion of metastasis primarily in the immunogenic tumors. Treatment of mice with DDC had no influence on metastatic spread. However, when given prior to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), DDC reduced BCNU-induced enhancement of HCA-1 metastases.
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PMID:Effect of the radiosensitizer misonidazole and the radioprotector diethyldithiocarbamate on spontaneous metastasis formation of murine tumors. 301 3

The ability of the in vitro sister chromatid exchange (SCE) assay to predict in vivo tumor drug sensitivity was investigated using a spontaneous hepatocarcinoma in C3Hf/Kam mice and 3 chemotherapeutic agents: melphalan; cis-platinum; and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). For hepatocarcinoma cells grown in monolayer culture, melphalan was the most efficient at inducing SCEs, and BCNU, the least. cis-Platinum induced a range in SCEs that overlapped those of BCNU and melphalan, suggesting that hepatocarcinoma is not a homogeneous population with intermediate sensitivity, but is a mixture of cis-platinum-sensitive and -resistant cells. According to in vitro cell survival curves, hepatocarcinoma was most sensitive to melphalan, less sensitive to cis-platinum, and essentially resistant to BCNU. The relative antineoplastic effects of melphalan, cis-platinum, and BCNU in vivo were compared by the response of artificial and spontaneous pulmonary metastases and solid tumors to these agents. For artificial metastases, there was a dose-dependent decrease in the number of lung nodules in mice treated with melphalan or cis-platinum, with melphalan being the more effective. BCNU had no effect. Spontaneous pulmonary metastases generated from hepatocarcinoma leg tumors were reduced in those mice treated with melphalan, unaffected by cis-platinum, and increased by BCNU. In hepatocarcinoma leg tumors (5 to 6 mm in diameter), melphalan induced the longest growth delay, and BCNU the least. Therefore, the relative effects produced by these three drugs in vivo were the same as predicted by SCE induction in vitro. The SCE assay may thus have potential clinical application.
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PMID:Prediction of in vivo tumor response to chemotherapeutic agents by the in vitro sister chromatid exchange assay. 403 20

Resistance of mouse M5076 (M5) ovarian reticular cell sarcoma to cyclophosphamide (CTX) was obtained in vivo by repeated drug treatment followed by transplantation of the regrowing tumor. After 16 passages, we obtained an M5 subline resistant to CTX (M5-CTX-16R). Median survival times were approximately 29 and 39 days for M5 and M5-CTX-16R, respectively. Survival of M5-bearing mice given a single i.p. dose of 200 or 300 mg/kg was 160 and 168% of controls, respectively, whereas in M5-CTX-16R it ws 103 and 123%, respectively. The resistance was not reversible after 14 additional passages with no further CTX treatment. M5 and M5-CTX-16R appear similar in histological features, pattern of metastasis formation, and DNA content, as assessed by flow cytometry (hypotetraploid). Metastases of M5-CTX-16R were also resistant to CTX. Flow cytometry studies 12 and 24 hr after CTX treatment revealed a block in S and G2-M phases in both tumors. After 48 hr and at subsequent times, no cytokinetic pertubation was evident in M5-CTX-16R, whereas in M5 marked accumulation of cells in G2-M was observed at 48, 72, 96, and 120 hr. Cross-resistance was found between CTX, L-phenylalanine mustard, chlorambucil, and hexamethylmelamine. M5-CTX-16R was sensitive, but less so than M5, to cis-platinum, 1,3-bis(2-chloroethyl)-1-nitrosourea, and imidazole-4-carboxamide,5-(3,3-dimethyl-1-triazene). Adriamycin was equally active on M5 and M5-CTX-16R, while 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidine-beta-D-glucopyranoside) was inactive. This model appears to be suitable for studies on the mechanism of resistance to CTX and alkylating agents and for screening new, non-cross-resistant drugs.
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PMID:Ovarian reticular cell sarcoma of the mouse (M5076) made resistant to cyclophosphamide. 635 29

173 patients with regional lymphatic metastases (n = 139) or distant disease (n = 34) were prospectively randomised, following resection of all clinically detectable tumour, to observation (n = 88) or adjuvant chemotherapy (n = 85). The treatment group received 1, 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) 80 mg/m2 intravenously (i.v.) every 4 weeks, and actinomycin-D 10 micrograms/kg, vincristine 1.0 mg/m2 i.v. every 2 weeks for 6 months. The disease-free survival curves between the two groups were significantly different (P = 0.03). The estimated 5-year disease-free survival rate for the observation group was 9% and for the treatment group 29%. However, the overall survival curves were not significantly different for the two groups. Nitrosoureas may have a weak effect as adjuvant treatment in malignant melanoma.
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PMID:Adjuvant chemotherapy with a nitrosourea-based protocol in advanced malignant melanoma. 826 Feb 35

Local chemotherapy with biodegradable polymers prolongs survival with minimal morbidity in patients with intracranial high-grade gliomas. However, use of local chemotherapy for metastatic brain tumors has not been defined. We studied the safety and the efficacy of locally delivered chemotherapy with and without concurrent radiation therapy in treating tumors that frequently metastasize to the brain. The chemotherapeutic agents 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), carboplatin, and camptothecin were incorporated into controlled-release polymers and tested individually against intracranial challenges with one of four tumors (lung carcinoma, renal cell carcinoma, colon carcinoma, and melanoma). For each combination of drug and tumor type, four groups were tested: (a) empty polymer (no drug); (b) external beam radiotherapy (XRT) alone; (c) local chemotherapy from biodegradable polymer alone; and (d) local chemotherapy and XRT together. Polymers were implanted 5 days after tumor inoculation; XRT was given on days 7-9 (300 cGy/day). BCNU and XRT together were effective against all four tumors. BCNU polymer alone significantly prolonged survival in mice with intracranial melanoma or renal cell carcinoma. Carboplatin alone was effective against both melanoma and colon carcinoma and in combination with XRT against colon and renal cell carcinomas. Camptothecin was effective only with XRT against melanoma. These studies demonstrate that local delivery of chemotherapy with concurrent radiation therapy is safe and can significantly prolong survival in models of common intracranial metastatic tumors. Concurrent use of local chemotherapy with standard XRT appears to be more effective than either treatment alone. Local chemotherapy may also be of benefit to patients who have previously received maximal cranial irradiation but suffer an intracranial recurrence.
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PMID:Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. 891 60

Glioblastomas extensively invade the surrounding normal brain tissue, with a concomitant expression of various proteolytic enzymes, in particular urokinase-type plasminogen activator (uPA). In this study we used cis-diamminedichloroplatinum (cisplatin) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), commonly used anti-cancer drugs for the treatment of glioblastomas, to study the expression of uPA in three human glioblastoma cell lines in vitro. Cells were treated with 25 microM cisplatin and 50 microM BCNU, and uPA levels were estimated by fibrin zymography during a 72-h time course. Treatment of glioblastoma cells with cisplatin resulted in significantly decreased levels of uPA in serum-free conditioned medium and cell extracts, compared to BCNU-treated and untreated cell lines. Quantitative levels of uPA enzyme activity assessed by scanning laser densitometry and uPA protein by ELISA using antibody against uPA showed decreased levels of uPA in cisplatin-treated glioma cell lines relative to BCNU and untreated cell lines. Our results suggest that anti-tumor compound, cisplatin, may exert its anti-neoplastic effects by inhibiting uPA in malignant glioblastomas.
Clin Exp Metastasis 1997 Jul
PMID:Cisplatin but not BCNU inhibits urokinase-type plasminogen activator levels in human glioblastoma cell lines in vitro. 921 34

Immunotherapy with the immunomodulating thymic humoral factor-gamma 2 (THF-gamma 2) octapeptide, combined with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) chemotherapy, will be used for enhancing host immune response to arrest pulmonary metastases of a B16-F10.9 melanoma tumor. In this experimental model of pulmonary metastasis, the highly metastatic B16-F10.9 melanoma tumor cells (2 x 10(5)) were inoculated into the footpad of mice to form a primary tumor. The tumor-bearing leg was surgically removed on reaching the size of 5.5 mm, which resulted in the appearance of metastases in the lungs of the animals. After tumor excision, mice were treated intraperitoneally with a single dose of BCNU (20 or 35 mg/kg) followed by a series of intraperitoneal THF-gamma 2 injections (1 microgram/0.5 ml/injection). Relative to untreated mice and those receiving chemotherapy alone, the antitumor action of the combined THF-gamma 2 chemoimmunotherapy protocol was significantly augmented according to the following in vivo parameters: (a) decreased postsurgical spontaneous metastatic burden; (b) prolonged survival time; (c) increased resistance to tumor cell challenge; and (d) massive infiltration of lymphocytes, polymorphonuclear cells, and macrophages in the lung tissue. The THF-gamma 2 immunotherapy also prevented a decrease in lymphocyte reactivity, otherwise induced by the tumor/BCNU chemotherapy. THF-gamma 2 immunotherapy resulted in restoration of the response to Lipopolysaccharide mitogenic stimulation and the allogeneic response. Our data suggest that postoperative THF-gamma 2 immunotherapy could be a valuable adjunct to anticancer chemotherapy as a treatment for metastatic arrest of melanoma tumor.
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PMID:THF-gamma 2-mediated reduction of pulmonary metastases and augmentation of immunocompetence in C57BL/6 mice bearing B16-melanoma. 1009 35

The purpose of this study was to assess the efficacy of high-dose chemotherapy (HDC) with autologous stem cell transplant in stage IV breast cancer patients with minimal metastases. Eligible patients had (a) disease that could be resected en bloc and/or irradiated with curative intent using a single field and could, thus, be rendered as having no evidence of disease (NED); and/or (b) <5% bone marrow involvement. From September 1991 to August 1997, 40 consecutive patients were prospectively entered on the study. Pre-HDC local treatment consisted of surgery (n = 31) and radiotherapy (XRT; n = 3). All patients received HDC with cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea and autologous stem cell transplant, with or without CD34 selection. Following HDC, 22 patients received XRT. Four patients died of treatment-related complications. Eighteen patients developed grade 3 nonhematological toxicities (15 lung, 2 cardiomyopathy, and 1 optic neuritis), which resolved with therapy. Within a median follow-up of 49 (15-91) months, 14 patients had relapsed. Twenty-five patients (62.5%) were alive, and 22 patients (55%) were alive and free of disease. Median event-free and overall survivals were 43 and 77 months, respectively. In the subset of patients with one metastatic site, 17 of 24 (68%) remained relapse free. Grade 2 tumors, a single metastatic site, and delivery of XRT were favorable predictors of relapse-free survival in univariate but not multivariate analyses. Inclusion of HDC, as described, in the multimodal treatment of stage IV breast cancer patients with minimal metastases is promising. These results warrant prospective randomized trials with a HDC-containing arm in this patient population.
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PMID:Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease. 1043 76


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