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)

Thirty patients with Stage III non-small cell lung cancer were entered on a trial to evaluate the feasibility of combined radiation and concomitant 5-fluorouracil infusion. Patients had received prior debulking surgery (nine), induction chemotherapy (16), or no therapy (five). Radiation employed standard fractionation (180-200 rad/day) administered to a median cumulative dose of 5500 rad (range, 4500-6200 rad). 5-Fluorouracil was infused 24 hours per day throughout the period of radiation at a dose of 300 mg/m2/day for a median of 42 days (range, 28-56 days). Radiation complications included pneumonitis three of 30 (10%) and esophagitis (27%). Chemotherapy complications included stomatitis, two of 27 (7%), and hand-foot syndrome, three of 30 (10%). Treatment interruptions were necessary in six of 30 (20%) and four of 30 required parenteral nutrition. At a median follow-up of 12 months 26/30 (87%) maintained local control and eight had distant metastases (three of whom presented with Stage IV disease). 5-Fluorouracil delivered continuously throughout standard fractionation radiation to high cumulative doses is feasible and practical. Comparative clinical trials of the various combined radiation and chemotherapy schedules employed are in order. One additional clinical observation was the identification of six of 30 (20%) with brain metastases at presentation or after 12 months, all of whom had adenocarcinoma histologic subtype.
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PMID:Concomitant 5-fluorouracil infusion and high-dose radiation for stage III non-small cell lung cancer. 254 5

Thirty-seven patients with widely metastatic malignant melanoma were treated with one of three chemotherapy regimens, incorporating high-dose dacarbazine (DTIC). The chemotherapy was followed by autologous bone marrow rescue which was harvested under local anesthesia in 25 of the patients. The three regimens comprised a 24-hour infusion of DTIC (Regimen A for patients less than 45 years of age, 4.3 to 10.5 g/m2; B, if greater than 45 years of age 2.7 to 4.0 g/m2; and later C, if greater than 45 years of age 7.0 to 8.0 g/m2). The second alkylating agent was given at +8 and +16 hours from the start of DTIC. The total doses of the melphalan ranged from 60 to 130 mg/m2 for Regimen A and 30 to 40 mg/m2 for Regimen B. Ifosfamide 5.0 to 8.0 g/m2 was given instead of melphalan in Regimen C. The response rates for the regimens were 81% (25% CR) for A, 27% (11% CR) for B, and 20% (with no complete responders) for Regimen C. There was no statistically significant difference between the three regimens for survival with a median value of 6 months. One of the 16 patients treated with the very high dose Regimen A died of septicemia and three of ten patients in Regimen C died within the first 2 weeks of treatment. There was statistically significant greater myelosuppression, stomatitis, and diarrhea in the very high dosage DTIC and melphalan (Regimen A) compared with the other two regimens. No significant difference in response rate or toxicity was observed for the different dosages escalated within each of the three regimens. Although hematologic and gastrointestinal toxicity were very severe, no unusual side effects were noted except for one episode of severe acute renal failure in the high-dose DTIC and melphalan, Regimen A. Responses occurred mainly in nonvisceral, nodal, and cutaneous sites and occasionally in pulmonary metastases. The Karnofsky performance improved 4 to 6 months after treatment notably with the high-dose DTIC and melphalan therapy. No survival benefit for the combination chemotherapy despite the high dosages was detected and such an approach currently cannot be recommended.
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PMID:High-dose, double alkylating agent chemotherapy with DTIC, melphalan, or ifosfamide and marrow rescue for metastatic malignant melanoma. 264 5

A correlation between increased beta-1,6 branching of N-linked carbohydrates and the ability of a cell to metastasize or to form a tumor has been observed in several experimental models. Lec9 Chinese hamster ovary (CHO) mutants exhibit a drastic reduction in tumorigenicity in nude mice, and this phenotype directly correlates with their ability to attach an increased proportion of beta-1,6-branched carbohydrates to the G glycoprotein of vesicular stomatitis virus (J. Ripka, S. Shin, and P. Stanley, Mol. Cell. Biol. 6:1268-1275, 1986). In this paper we provide evidence that cellular carbohydrates from Lec9 cells also contain an increased proportion of beta-1,6-branched carbohydrates, although they do not possess significantly increased activity of the beta-1,6 branching enzyme (GlcNAc-transferase V). Biosynthetic labeling experiments show that a substantial degree of underglycosylation occurs in Lec9 cells and that this affects several classes of glycoproteins. Lec9 cells synthesize ca. 40-fold less Glc3Man9GlcNAc2-P-P-lipid and ca. 2-fold less Man5GlcNAc2-P-P-lipid than parental cells do. In addition, Lec9 cells possess ca. fivefold less protein-bound oligosaccharide intermediates, and one major species is resistant to release by endo-beta-N-acetylglucosaminidase H (endo H). Membranes of Lec9 cells exhibit normal mannosylphosphoryldolichol synthase, glucosylphosphoryldolichol synthase, and N-acetylglucosaminylphosphate transferase activities in the presence of exogenous dolichyl phosphate. However, in the absence of exogenous dolichyl phosphate, mannosylphosphoryldolichol synthase and glucosylphosphoryldolichol synthase activities are reduced in membranes of Lec9 cells, indicating that membranes of Lec9 cells are deficient in lipid phosphate. This was confirmed by analysis of lipids labeled by [3H]mevalonate, which showed that Lec9 cells have less lipid phosphate than parental CHO cells. Mechanisms by which a defect in the synthesis of dolichol-oligosaccharides might alter the degree of beta-1,6 branching in N-linked carbohydrates are discussed.
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PMID:Control of carbohydrate processing: increased beta-1,6 branching in N-linked carbohydrates of Lec9 CHO mutants appears to arise from a defect in oligosaccharide-dolichol biosynthesis. 272 6

Sixty women with metastatic breast cancer refractory to at least one chemotherapeutic regimen were treated with fluorouracil (FUra) and high-dose continuous infusion folinic acid (leucovorin calcium). One complete remission lasting 8.7 months and nine partial remissions ranging in duration from 1.3 to 12.8 months were observed, for an objective response rate of 17% (95% confidence interval for response, 8% to 27%). Nine of the ten responding patients had metastatic disease that had objectively progressed on previous chemotherapy with a FUra-containing regimen. This program was well tolerated, with toxicities consisting mainly of stomatitis and granulocytopenia. These results suggest that augmentation of the reduced folate levels of metastatic breast carcinomas may enhance the effectiveness of the fluoropyrimidines in this disease.
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PMID:Refractory metastatic breast cancer: salvage therapy with fluorouracil and high-dose continuous infusion leucovorin calcium. 278 92

Eighteen patients with hepatic metastases primarily from colorectal carcinoma were treated on a phase I protocol employing hepatic artery infusion (HAI) of 5-fluorouracil (FUra) and 5-iodo-2'-deoxyuridine (IdUrd) via implantable infusion pump. Patients received a 14-day continuous HAI of 300 mg/day FUra. During days 8-14 of therapy, patients received IdUrd as a separate 3-h HAI daily x 7. Treatment cycles were repeated every 28 days. IdUrd was escalated from 0.1 to 2.86 mg/kg/day x 7. Myelosuppression and stomatitis were mild and not dose limiting. Hepatotoxicity was dose limiting and similar to that reported for 5-fluoro-2'deoxyuridine alone administered as a 14-day infusion every month. One patient developed a clinical picture consistent with sclerosing cholangitis and another had biopsy-proven cholestasis and triaditis. Catheter complications occurred in 7 of 18 patients. Plasma concentrations of FUra during the 7-day continuous HAI of FUra alone were consistently either undetectable or very low (less than or equal to 0.1 microM). At level 3 (1.0 mg/kg/day IdUrd) and beyond, measurable plasma concentrations of FUra, iodouracil, and IdUrd were found at the end of the daily 3-h infusion of IdUrd. The maximum tolerated dose of IdUrd as administered in this trial is 2.2 mg/kg/day x 7 and the recommended starting dose for further clinical investigation is 1.7 mg/kg/day x 7.
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PMID:Phase I trial of hepatic artery infusion of 5-iodo-2'-deoxyuridine and 5-fluorouracil in patients with advanced hepatic malignancy: biochemically based combination chemotherapy. 280 87

Low-dose continuous infusion 5-fluorouracil (LDCI-FU) was administered to 28 women with advanced breast carcinoma. Daily doses ranged from 175 to 250 mg/m2. The LDCI-FU was delivered continuously until the appearance of toxicity and was reinstituted at a 20% dose reduction after toxicity completely resolved. Patients with a median age of 56 years and a median performance status of 60% (Karnofsky) had been previously treated with combination chemotherapy. Complete responses were observed in two patients with soft tissue metastases. Thirteen patients experienced partial responses with a median duration of response of 4+ months. Partial responses were predominantly observed in soft tissue disease; however, five patients with visceral metastases experienced partial tumor regression. Median survival for the study group was 4+ months. Hormonal receptor status did not predict response to LDCI-FU. Toxicities included stomatitis, ten patients; hand-foot syndrome, eight patients; mild leukopenia, two patients; moderate thrombocytopenia, two patients; diarrhea, three patients; ataxia, three patients. Catheter-related toxicities of sepsis and/or thrombosis occurred in six patients. Because of the demonstrated activity in previously treated patients (53% response rate), LDCI-FU should be investigated in combination chemotherapy regimens in untreated breast cancer patients.
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PMID:Low-dose continuous infusion 5-fluorouracil. Evaluation in advanced breast carcinoma. 291 20

Toxicities and complications were prospectively analyzed in patients with liver metastases receiving hepatic intra-arterial (IA) and systemic intravenous (IV) floxuridine (FUDR) with the Infusaid (Intermedics-Infusaid Corp., Norwood, MA) implantable pump. Among 55 patients treated with IA FUDR (0.3-0.1 mg/kg/day X 14, every 28 days), elevations in liver enzyme values, not attributable to disease progression, developed in 96% of patients. Serious biliary toxicity occurred in 31 patients (56%). In 16, biliary sclerosis was documented radiographically and was diagnosed clinically in 15 additional patients. Ten patients were hospitalized for biliary toxicity, including five who required cholecystectomy for acalculous cholecystitis. Because of the high reported incidence of serious gastroduodenal toxicity after IA FUDR infusion, our procedure for hepatic arterial cannulation was designed to eliminate misperfusion of the stomach and duodenum with drug; none of our patients experienced FUDR-associated gastroduodenal ulceration or bleeding. Cyclic IV FUDR (0.05-0.15 mg/kg/day X 14, every 28 days) was administered to 31 participants of the Northern California Oncology Group trial (3L-82-1) of IV versus IA FUDR. Dose-limiting toxicity was diarrhea. Serious toxicities were: protracted diarrhea (three), dermatitis (two), tear duct stenosis (two), and stomatitis (two). Three patients were hospitalized for toxicity. No hematologic or biliary toxicity occurred. The optimal route for treatment of hepatic metastases with continuous FUDR infusion has not yet been established. Systemic IV infusion has low morbidity, but preliminary response data need to be substantiated in controlled clinical trials before there can be widespread clinical application. High response rates for IA infusion have been previously documented. Morbidity due to acalculous cholecystitis and gastroduodenal ulceration can now be avoided. Despite significant progress in characterization of hepatobiliary toxicity, it remains dose-limiting. Continuous IA FUDR infusion should remain under the aegis of dedicated treatment centers until standardized protocols with diminished toxicity are established.
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PMID:Toxicities and complications of implanted pump hepatic arterial and intravenous floxuridine infusion. 293 42

Eighteen patients with advanced renal cell carcinoma were treated with recombinant interferon alpha-2a (18 million IU s.c. three times a week). 9 patients had received prior hormonal therapy (tamoxifen). On entering the therapeutic schedule with recombinant interferon alpha-2a, all patients had progressive disease with multiple metastases. Flu-like symptoms occurred in general; they were severe in 9 cases. An impairment of the liver was shown by a rise of SGOT/SGPT and alkaline phosphatase in 2 patients, the gamma-GT was raised in 7 patients. The kidney function worsened in 3 cases. A fall in blood cell counts was seen in 8 cases. Five patients developed a transient stomatitis. Five patients (5/18) showed stable disease with the longest response duration of 17 months. One patient showed a complete remission 5 months after starting therapy for a duration of 7 months until now. Both the limited benefit from this treatment as well as some severe side effects indicate the need for further special evaluation and possible improvements of this therapeutic approach.
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PMID:[Effectiveness and side effects of recombinant alpha-2a interferon in patients with metastatic hypernephroma]. 307 61

Methotrexate, Cisplatin, and Vinblastine (MCV) was followed by Cisplatin plus radiation therapy in 19 patients with muscle-invading clinical Stage T2-4NXM0 transitional cell carcinoma of the urinary bladder (including cystectomy candidates), to achieve local control and prevent distant metastases. Radical cystectomy was recommended for all patients who failed to reach a complete response (CR = biopsy negative and cytology not positive) following MCV and Cisplatin X 2 plus 4000 cGy. Completely responding patients, and those partially responding patients unsuited for cystectomy, were selected for bladder conservation treated with additional irradiation to the bladder tumor volume (total 6,480 cGy) plus one additional Cisplatin treatment. Dose reductions were required for stomatitis in 26%, mild bone marrow depression in 58%, and renal toxicity in 5% of the patients. During the Cisplatin/4000 cGy, mild dysuria occurred in 68% of patients and 36% had mild bowel hyperactivity. Serious complications have occurred in two patients to date. One patient had recurrent pulmonary emboli, marked reduction in bladder capacity, and diarrhea. A second had bladder perforation during cystoscopic evaluation after MCV and a small bowel obstruction after Cisplatin and 4000 cGy. There was no treatment-related sepsis. Three patients had initial complete transurethral resection of their tumors and therefore 16 patients are evaluable for tumor responsiveness to this protocol. Four patients (25%) were biopsy negative and cytology negative, whereas three additional patients (19%) were biopsy negative but cytology positive following initial MCV. Six patients (38%) were biopsy negative and cytology negative whereas three additional patients (19%) were biopsy negative and cytology positive following MCV and Cisplatin X 2 plus 4000 cGy pelvic radiation. Of the entire group, 9 patients were treated with full-dose radiotherapy. All of these patients are alive without evidence of tumor on rebiopsy of the original tumor site, but one has a persistent positive cytology. Seven patients had a radical cystectomy and 6 are disease free. The treatment of 3 patients deviated from the protocol. Overall, only one patient has developed distant metastases and currently 84% of the patients are disease-free, although follow-up is short. To date, this feasibility study has been clinically practical and well tolerated. The proportion of CR's suggests that this program may prove to be an organ-sparing and curative approach for a significant number of patients, but more experience and follow-up are required.
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PMID:Invasive bladder carcinoma: preliminary report of selective bladder conservation by transurethral surgery, upfront MCV (methotrexate, cisplatin, and vinblastine) chemotherapy and pelvic irradiation plus cisplatin. 318 28

The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study of the oral antiandrogen flutamide in 33 patients with metastatic breast cancer. Eight patients had received no prior systemic therapy for their metastatic disease and 13 had only one site of metastasis. Toxicity occurred in 18 of the 33 patients and was primarily gastrointestinal. It ranged in severity from mild to severe with 4 patients discontinuing treatment early because of nausea, vomiting, diarrhea or stomatitis. One response, of 8 weeks duration, was noted in 29 evaluable patients. We conclude that flutamide does not have meaningful antitumour activity in breast cancer and plan no further trials of the drug in this disease.
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PMID:Phase II study of flutamide in patients with metastatic breast cancer. A National Cancer Institute of Canada Clinical Trials Group study. 319 86


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