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)

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 chloroethylating nitrosoureas (lomustine, fotemustine, cystemustine (BCNU) and methylating agents temozolomide (TMZ), dacarbazine (DTIC), procarbazine) have documented activity in metastatic malignant melanoma with single agent response rates of 15-25%. Chloroethylating agents form chloroethyl adducts at the O6 position of guanine, resulting in N1-guanine, N3-cytosine interstrand crosslinks which are cytotoxic. Methylating agents attack DNA at multiple sites, although most of their cytotoxic activity is due to the formation of methyl adducts at the O6 position of guanine. The presence of these adducts results in a futile recycling of the mismatch repair pathway resulting in DNA strand breaks and apoptotic cell death. An intact mismatch repair system is required to achieve their cytotoxic effect. Repair of adducts by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) impairs the cytotoxic action of both methylating and chloroethylating agents, and mediates a major resistance pathway to these drugs. During DNA repair, irreversible inactivation of AGT occurs. To regenerate AGT activity, synthesis of new molecules is required. Increased but variable AGT activity is found in malignant melanoma, is higher in metastatic lesions than in primary tumours, and is higher in tumours than normal skin. Expression of AGT activity, is higher in melanoma metastases after DTIC chemotherapy compared to expression prior to therapy. TMZ alone depletes human AGT in tumour tissue and peripheral blood progenitor cells. As the t1/2 of TMZ via the oral route is short (approximately 1.8 hours), and the anti-tumour activity of the drug is known to be schedule-dependent, twice daily or prolonged administration schedules of TMZ prevent regeneration of AGT, and render tumour cells more sensitive to the drug. O6-benzylguanine (BG) is a potent AGT inactivating agent. BG and its analogues reduce AGT activity, and increase the in vitro and in vivo efficacy of both methylating and chloroethylating agents. In clinical trials, non-toxic doses of BG deplete AGT to undetectable levels. AGT depleting agents in combination with methylating and chloroethylating agents are now in clinical testing, and may result in greater clinical efficacy in metastatic malignant melanoma.
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PMID:New cytotoxic agents for the treatment of metastatic malignant melanoma: temozolomide and related alkylating agents in combination with guanine analogues to abrogate drug resistance. 1100 34

The effectiveness and side-effects of various chemotherapy (CT) regimens were compared in 157 patients (74 males and 80 females, aged 23-79) with disseminated skin melanoma (DSM). Most cases had multiple metastases to the skin and subcutaneous fat tissue, regional lymph nodes (59-69%), lung (14-38%) and liver (13-36%); to other sites--82 (52%). Total response in the dacarbazine (DTIC) group was 18% (complete--5, partial--13 and stabilization--29%). DTIC was employed as first-line treatment in 71%. DBDT (cisplatin, DTIC, BCNU, tamoxifen) was used in 42 patients: as first-line--13 (31%), second-line--21 (50%) and third-line (following the first two regimens in cases refractory to treatment or those with response-based evidence of tumor progression)--8 (19%). In DBDT-treated patients, total response was 29% (complete--7, partial 22 and stabilization--38%). Similar results were recorded in the group where 69% were given CT as second- and third-line treatment. The effect of CVD (cisplatin, vinblastin, DTIC) was much the same as that of DTIC alone but was followed by a higher incidence of myelodepression and anemia. Combined treatment with prospidin+ CCNU + BCNU seems to offer more advantage.
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PMID:[Clinical evaluation of the efficacy of modern first, second, and third line regimes of chemotherapy in patients with disseminated cutaneous melanoma]. 1171 Feb 84

High dose therapy for breast cancer remains controversial. Of the 15 randomized trials of high dose therapy in breast cancer reported to date, two South African studies have been discredited leaving 13 remaining studies. Mortality was consistently low, in the 0 to 2.5% range, except for the BCNU containing American Intergroup study, which had a 7.4% toxic mortality rate. Seven of the remaining 13 studies randomized fewer than 200 patients. Three of these small studies have significant differences in disease free survival, and a fourth study has a trend in favor of high dose therapy. The other three small studies cannot exclude a survival difference of 20%. Of the 6 remaining moderately large trials of 219 to 885 randomized patients, 5 are adjuvant studies and one included patients with metastatic disease. Of the five adjuvant trials, four have significant differences in relapse rate favoring the high dose arm, and the remaining study has a trend (with a high dose sequential single agent design rather than combination therapy as in the other studies). A planned subset analysis of the first 284 patients in the largest study funded by the Dutch insurance industry showed a significant advantage for high dose therapy. Given the 2-year median time to relapse and an addition 2-year median to death after relapse, the follow up for survival of 3-5 years on these studies is still short. In the only moderately sized metastatic trial from the National Cancer Institute of Canada with a very short median follow-up of 19 months, a significant difference in disease free survival has emerged, with no difference in survival.
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PMID:Randomized trials of high-dose chemotherapy in breast cancer: fraud, the press and the data (or lessons learned in medical policy governing clinical research). 1205 18

Reduced glutathione (GSH) production by tumour cells has been proposed as a mechanism for resistance to alkylating agents. High levels of paracetamol can deplete intracellular GSH. We conducted a phase I trial of high dose paracetamol and carmustine (BCNU) in patients with advanced malignant melanoma to determine the optimal biological dose and the maximum tolerated dose (MTD) with the goal of increasing sensitivity to BCNU by GSH depletion. Groups of three to five patients received escalating doses of paracetamol (10, 15 or 20 g/m(2)) every 3 weeks. Every other cycle, BCNU (10 mg/m(2)) was given 6.5 h after administration of paracetamol and 45 min before a 20 h infusion of N-acetylcysteine. Once the MTD for paracetamol had been determined, the dose of BCNU was sequentially escalated in subsequent cohorts to 150 mg/m(2). GSH levels were measured in peripheral blood mononuclear cells (PBMCs) and, when available, in tumour biopsies. The MTD of paracetamol was 15 g/m(2). The dose of BCNU was safely escalated to 150 mg/m(2). The most common toxicity was grade II nausea/vomiting. At 15 g/m(2), peak paracetamol levels (median 253 microg/ml) were reached between 1 and 4 h. No changes in GSH levels in PBMCs were seen. There were two partial responses, including a dramatic decrease in hepatic metastases. Treatment of melanoma patients with paracetamol (15 g/m(2)) every 3 weeks and BCNU (150 mg/m(2)) every 6 weeks is safe. The observation of two partial responses has led to a phase II study to evaluate treatment with high dose paracetamol alone or in combination with BCNU.
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PMID:Phase I trial of high dose paracetamol and carmustine in patients with metastatic melanoma. 1269 Mar 4

Thirty-eight patients with disseminated skin melanoma received chemotherapy in conjunction with laser coagulation or interstitial hyperthermia of intra- or subcutaneous metastases. Use of combination therapy was followed by a rise to 37% in total response and 16%--complete regression, respectively. Most effectiveness was attained when the dacarbazine + cisplatin + BCNU + tamoxifen regime was employed. In this group of 16 patients (46%), total response was 56% and, what is most significant, 31% in complete regression. In all cases of apparent response, polychemotherapy was administered both before and after laser coagulation or interstitial hyperthermia.
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PMID:[Chemotherapy in combination with laser coagulation or interstitial hyperthermia--effective combined therapy for disseminated skin melanoma]. 1292 12

Low electric field cancer treatment-enhanced chemotherapy (LEFCT-EC) is a new treatment modality that combines chemotherapeutic agents and low electric field stimulation. LEFCT-EC was found to destroy malignant mouse tumors and cause massive death of tumor cells. This may enable the immune system cells to efficiently recognize and eliminate tumor cells at the primary tumor site and at metastatic foci. Mice with 15 mm diameter intracutaneous colon carcinomas (CT-26) were injected with BCNU (35 mg/kg), and 2 min later the tumors were exposed to low electric fields (intensity 40 V/cm, pulse duration 180 micros, frequency 500 Hz) for 12 min (LEFCT-EC). We found that treatment with LEFCT-EC achieved complete cure of 93% of the animals. In comparison, electric fields alone (13% cure), chemotherapy alone (0%), surgery (15%) or a combination of surgery and bis-chloroethyl-nitrosurea, carmustine (BCNU; 84%) treatments resulted in lower cure rates. After treatment and cure with LEFCT-EC, 50% of the cured mice developed resistance to a tumor challenge (surgery + BCNU only 15%). Furthermore, splenocytes from cured animals protected naive animals from a tumorigenic dose of tumor cells. Separation of spleen cells into lymphocyte subpopulations indicated a major role for CD4 and CD8 T cells in this protection. FACS analysis revealed restoration of normal splenocyte subpopulation proportions impaired by cytotoxic chemotherapy. Our results suggest that LEFCT-EC can directly destroy primary tumors and facilitate the destruction of metastatic disease by enforcement of antitumor immune responses.
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PMID:Involvement of the immune response in the cure of metastatic murine CT-26 colon carcinoma by low electric field-enhanced chemotherapy. 1598 Dec 17

Uveal melanoma is the most common primary intraocular malignancy in adults and the liver is the most common site for systemic metastases. We conducted a phase II clinical trial for patients with hepatic metastases from uveal melanoma using chemoembolization of the hepatic artery with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) dissolved in ethiodized oil. Gelatin sponge particles were used as a transiently occlusive agent. The responses in hepatic metastases, overall survival, time to progression and side-effects related to chemoembolization were evaluated. Thirty patients were enrolled. Twenty-four patients completed at least one treatment to all targeted liver metastases and were evaluable for hepatic response. Eighteen of these 24 patients experienced regression or stabilization of hepatic metastases for at least 6 weeks (one complete response in hepatic metastases; four partial responses; 13 stable disease). One of the 13 patients with stable disease was rendered free of disease by surgical removal of metastases after chemoembolization (surgical complete response). The overall response rates (complete and partial responses) for intention-to-treat patients and for patients who were evaluable for response were 16.7 and 20.4%, respectively. The median overall survival of the entire intention-to-treat group of patients was 5.2 months (range, 0.1-27.6 months), for patients with complete or partial response in hepatic metastases 21.9 months (range, 7.4-27.6 months), for patients with stable disease 8.7 months (range, 2.9-14.4 months) and for patients with progressive disease 3.3 months (range, 1.6-5.6 months). Importantly, 13 of the 18 patients who achieved complete response, partial response or stable disease subsequently developed progression of extrahepatic metastases with control of hepatic metastases. Chemoembolization with BCNU is a useful palliative treatment for the control of hepatic metastases in uveal melanoma patients. However, progression in extrahepatic sites after stabilization of hepatic metastases requires further improvement in the therapeutic approach to this disease.
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PMID:Chemoembolization of the hepatic artery with BCNU for metastatic uveal melanoma: results of a phase II study. 1603 9

Brain metastases continue to be a major and growing challenge in oncology, but recent advances in surgery, radiosurgery, and chemotherapy have broadened the number of treatment options. Current approaches to the management of brain metastases focus on individualizing patient care based on factors including the Karnofsky Performance Status, the tumor histology, the number of metastases, and the status of the systemic disease. A number of treatment approaches have been shown to be effective for brain metastases, including surgery; radiosurgery; whole-brain radiotherapy; and, more recently, chemotherapy. The use of adjuvant whole-brain radiotherapy with local therapies, such as surgery or radiosurgery, along with newer chemotherapy options, such as targeted biological agents, temozolomide, and implantable 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) Gliadel wafers, are at the forefront of recent advances in the treatment of patients with brain metastases that may provide longer survival and improved quality of life. Although there is no current standard treatment, some general guidelines are recommended for single metastases, oligometastases (two to three brain metastases), and multiple (four or more) brain metastases, and for new or recurrent disease. With advances in systemic therapy for cancer, the treatment of brain metastases is becoming an increasingly important determinant of the length of survival and quality of life for cancer patients.
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PMID:Current treatment paradigms for the management of patients with brain metastases. 1623 91


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