Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Advances in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas continue in the Intergroup Rhabdomyosarcoma Study Group (IRSG) and European cooperative groups. The use of molecular biology techniques in soft tissue sarcomas are redefining the classic pathology of these small blue cell tumors. Improvements in imaging, radiotherapy, and surgery, in part, deserve credit for the better survival seen in all cooperative trials. These advances confound the interpretation of consecutively run chemotherapy trials using historical comparisons. The IRSG has reported improvement in the prognosis of both nonmetastatic and metastatic embryonal rhabdomyosarcoma as attributable to three, three-drug regimens that use cyclophosphamide at 2.2 g/m2 in either maintenance or induction and maintenance therapy. Patients of any age with metastatic, nonembryonal, and those over 10 years of age with metastatic embryonal rhabdomyosarcoma continue to have a poor prognosis, which even megatherapy has failed to change. The doublet of ifosfamide and etoposide in combination with vincristine, actinomycin D, and cyclophosphamide at 2.2 g/m2 achieved a remarkable 3-year survival of 58% in patients with metastatic rhabdomyosarcoma and undifferentiated soft tissue sarcoma. The topoisomerase I inhibitor, topotecan, has recently been found by the IRSG to have a 57% overall response rate in patients with metastatic alveolar rhabdomyosarcoma. Topotecan has completed testing with cyclophosphamide in a phase II window study in newly diagnosed patients with metastatic disease and has been incorporated into a randomized trial in intermediate risk patients in IRSG-V. Molecular studies in IRSG-V will be applied in the detection of occult bone marrow metastases and the evaluation of resection margins at initial and second-look surgery. Long-term follow-up will be required in patients with gross residual sarcoma randomized to conventional and hyperfractionated radiotherapy in IRSG-IV to assess late effects. Although older patients with unfavorable histology and metastatic disease continue to have a poor prognosis, the overall 5-year survival of children and adolescents with nonmetastatic and metastatic rhabdomyosarcoma is approaching 80%. As molecular discoveries advance the diagnosis and detection of rhabdomyosarcoma, it is hoped that the futuristic molecular based treatment strategies in development and early testing will further improve survival in high-risk patients with metastatic soft tissue sarcoma.
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PMID:Progress in the diagnosis and treatment of rhabdomyosarcoma and related soft tissue sarcomas. 1075 91

We recently reported that forced overexpression of the transcription factor E2F-1 in human HT-1080 fibrosarcoma cells resulted in corresponding high levels of thymidylate synthase (TS) and resistance to 5-fluoropyrimidines (D. Banerjee et al., Cancer Res., 58: 4292-4296, 1998). Because colorectal metastasis to the lung has higher TS levels than liver metastasis and is less responsive to treatment with 5-fluorouracil (R. Gorlick et al., J. Clin. Oncol., 16: 1465-1469, 1998), it was, therefore, of interest to measure E2F-1 expression in these tumors. In contrast to marginally increased levels of dihydrofolate reductase and topoisomerase I in lung metastasis as compared with liver metastasis, lung tumors had a 5-fold increase in E2F-1 expression as compared with liver tumors, corresponding to the relative levels of TS in these metastases. These data indicate that there exists a close correlation between E2F-1 and TS levels and provide a rationale for targeting this transcription factor, ie., E2F-1, for the treatment of certain cancers.
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PMID:Levels of E2F-1 expression are higher in lung metastasis of colon cancer as compared with hepatic metastasis and correlate with levels of thymidylate synthase. 1081 Nov 10

We conducted a phase II randomized trial of recombinant granculocyte-macrophage colony-stimulating factor (GM-CSF) administered before topotecan chemotherapy to determine whether it could prevent myelosuppression and to determine the antitumor activity of this topoisomerase I inhibitor in 53 patients with metastatic malignant melanoma and renal cell cancer. All patients received GM-CSF after topotecan at a dose of 250 microg/m(2) daily for at least 8 days. Patients randomly assigned to receive GM-CSF priming were treated with GM-CSF at 250 microg/m(2) twice daily for 5 days before treatment. Twenty-five patients were randomly assigned to receive GM-CSF priming and 28 to receive topotecan without priming. The primary analysis was restricted to the protective effects seen during the first cycle of therapy. Grade 4 neutropenia occurred in 8 of 23 patients (35%) and grade 3 neutropenia in 5 of 23 patients (22%) randomized to GM-CSF priming, whereas 18 of 26 (69%) and 5 of 26 (19%) patients experienced grade 4 or 3 neutropenia, respectively, without GM-CSF priming (P =.0074). The mean duration of neutropenia was reduced by GM-CSF priming: grade 3 neutropenia from 5.2 +/- 0.7 to 2.8 +/- 0.7 days (P =.0232) and grade 4 neutropenia from 2.7 +/- 0.6 to 1.1 +/- 0.4 days (P = 0.0332). The protective effects of GM-CSF extended to the second cycle of treatment. The incidence of febrile neutropenia was also reduced. Chemotherapy-induced anemia and thrombocytopenia were similar in both groups. One partial response was seen in a patient with melanoma, and one patient with renal cell cancer had complete regression of pulmonary metastases and was rendered disease-free by nephrectomy. (Blood. 2001;97:1942-1946)
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PMID:A prospective randomized phase II trial of GM-CSF priming to prevent topotecan-induced neutropenia in chemotherapy-naive patients with malignant melanoma or renal cell carcinoma. 1126 56

Colorectal carcinoma is one of the most common malignancies in the western world, and although fluorouracil (5-FU) has been used in its treatment for almost 40 years, new agents with significant activity have been introduced recently. Irinotecan (CPT-11, Camptosar), a topoisomerase I inhibitor, administered at 300 to 350 mg/m2 every 3 weeks is significantly more active than continuous-infusion 5-FU in patients who have experienced disease progression after conventional therapy with 5-FU. In comparison to best supportive care, irinotecan improves survival and preserves quality of life despite treatment-related toxicity. Moreover, the combination of irinotecan and 5-FU has been explored in a number of different schedules. In previously untreated patients, overall response rates are high. Irinotecan can also be combined with mitomycin (mitomycin-C [Mutamycin]), oxaliplatin, or raltitrexed (Tomudex). Oxaliplatin is a new-generation platinum compound that has demonstrated activity against colorectal carcinoma in preclinical trials. It has been evaluated as a single agent against advanced colorectal carcinoma in the salvage setting and also in combination with 5-FU as initial therapy for metastatic disease (where it shows significant activity). The toxicity profile of oxaliplatin (chiefly characterized by neurotoxicity) differs from that of irinotecan (primarily producing diarrhea) and the potential, therefore, exists for combining these agents or for exploiting their possible synergy with 5-FU. The introduction of these two new active agents of different pharmacologic classes promises to enable significant improvements in the treatment of patients with colorectal carcinoma.
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PMID:The role of irinotecan and oxaliplatin in the treatment of advanced colorectal cancer. 1134 31

Traditionally, the role of chemotherapy in the treatment of squamous carcinoma of the head and neck has been confined to patients with recurrent or metastatic disease who are deemed incurable with surgery or radiation therapy. Over the past decade, however, the role of chemotherapy has changed dramatically. The use of primary combined chemoradiation to preserve function or to enhance survival in patients with unresectable disease has become a standard approach. As the use of chemotherapy in squamous carcinoma of the head and neck has expanded, investigators have been interested in identifying new active agents. Topoisomerase I inhibitors, a new class of drugs, have been found to be active in a number of solid and hematologic malignancies. Three topoisomerase I inhibitors have been investigated in the treatment of metastatic or recurrent squamous carcinoma of the head and neck: 9-aminocamptothecin (9-AC), topotecan (Hycamtin), and irinotecan (CPT-11, Camptosar). Neither 9-AC nor topotecan has demonstrated clinically significant activity in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. In contrast, irinotecan has demonstrated a modest overall response rate of 21.2% (95% confidence interval [CI] = 9%-38.9%), with a median survival of 214 days and a 1-year survival rate of 30.2%. The response and toxicity appear to be dose dependent. Further investigation of irinotecan in combination with other active agents and radiotherapy is warranted.
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PMID:Topoisomerase I inhibitors in the treatment of head and neck cancer. 1149 32

XR 5000 is one of a series of tricyclic carboxamide-based cytotoxic agents. It binds to DNA by intercalation and stimulates DNA cleavage by inhibition of both topoisomerase I and II, thus possibly overcoming the resistance resulting from downregulation of either enzyme. Twenty patients with advanced or metastatic colorectal cancer, unpretreated for metastatic disease, received XR 5000 at the dose of 3010 mg/m(2) in a 120-h central intravenous (i.v.) infusion every 3 weeks. Response was evaluated every two cycles. No complete (CR) or partial responses (PR) were observed in eligible patients (response rate, 0 of 19, 0%; 95% confidence interval (CI): 0-18%). 5 patients had stable disease, which lasted from 79 to 157 days. Haematological toxicity was low, since only one grade 4 neutropenia and two grade 3 anaemia were observed. Other treatment-related grade 3-4 toxicities were: deep venous thrombosis (2 cases), liver toxicity, diarrhoea, anorexia, dyspnoea, chest pain, infection (1 case each). Despite the good toxicity profile, these results do not support further trials with XR 5000 in metastatic colorectal cancer.
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PMID:Phase II study of XR 5000, an inhibitor of topoisomerases I and II, in advanced colorectal cancer. 1175 Aug 42

Angiogenesis plays a crucial role in tumor growth and metastases. The extent of angiogenesis correlates with the increased invasion and metastasis in a variety of human neoplasms. Vascular endothelial cell proliferation and migration are critical steps in angiogenesis and are regulated by various growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). The topoisomerase I inhibitor topotecan (10-hydroxy-9-dimethylaminomethyl-(S)-camptothecin) is a water-soluble camptothecin analogue and possesses an indirect in vivo antitumor effect mediated through the inhibition of angiogenesis. We found that topotecan inhibited VEGF- and bFGF-induced migration of human umbilical vein endothelial cells (HUVECs) in vitro. The migration of HUVECs was also inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. Thus, we investigated the possibility that topotecan's antiangiogenic property might be mediated by its inhibitory effect on VEGF- and bFGF-induced activation of the PI3K-Akt signaling pathway. We found that topotecan treatment decreased the amount of the phosphorylated (activated) form of Akt, but not the amount of Akt protein, in HUVECs. Moreover, transient transfection of constitutive active akt cDNA into HUVECs reversed the topotecan-mediated decrease in HUVEC migration. These results suggest that the antiangiogenic activity of topotecan is mediated in part by downregulating the PI3K-Akt signaling pathway.
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PMID:Topotecan inhibits VEGF- and bFGF-induced vascular endothelial cell migration via downregulation of the PI3K-Akt signaling pathway. 1185 82

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU). the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen 1, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.
Clin Exp Metastasis 2002
PMID:Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines. 1191 83

A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.
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PMID:Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue. 1193 15

Irinotecan and mitomycin (Mutamycin) possess significant single-agent activity against several tumor types, and mitomycin activates topoisomerase I, the cellular target of irinotecan. We conducted a phase I dose-escalation study of irinotecan and mitomycin in 37 evaluable patients with solid tumors. Antitumor responses included 2 complete responses, 5 partial responses, 10 minor responses, and a CA 19-9 tumor marker response. Responders included 14 patients previously treated with chemotherapy for metastatic disease. No pharmacokinetic interaction between mitomycin and irinotecan was apparent when these agents were given 24 hours apart. Responders (complete and partial responses) demonstrated the largest topoisomerase I induction 24 hours following mitomycin infusion. In addition, since maximum topoisomerase I up-regulation was reached 24 hours after administration of mitomycin, a delay in the administration of irinotecan after mitomycin appeared justified. Based on these encouraging phase I data, phase II clinical trials in breast and esophageal/gastroesophageal junction adenocarcinomas at the recommended doses and schedule are under way.
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PMID:Mitomycin as a modulator of irinotecan anticancer activity. 1219 29


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