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 nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT; NSC 94600) and its derivatives. This drug has been reported to display effective antitumor effects on a variety of human tumor models xenografted in nude mice. However clinical studies of sodium CPT have revealed that the open-ring form of the drug is a poor inhibitor of topo I and much less potent antitumor agent than CPT lactone. However, the insolubility of CPT lactone makes it difficult to devise a suitable formulation for further clinical testing. In view of these observations, we report here the successful incorporation of CPT into a liposome-based drug delivery system (LCPT) composed of DPPC:Sph:CHOL:PI (2.4:6.6:1.0:0.05 M ratio) that can be used as a suitable formulation for clinical testing of the drug. Higher incorporation efficiency was observed when the total phospholipids:drug ratio = 40 and the cholesterol content = 1%. Image analysis of the CPT-containing liposomes with freeze-fracture electron microscopy has indicated that CPT significantly increased the interlamellar space of the vesicles as a result of its intercalation between lipid bilayers. This has occurred with no major disruptive effects on the bilayer structure. The in vitro drug release study in human serum was characterized by an initial rapid loss-of 50% of contents during 4 h, followed by a slow leakage of the remaining 50% of the total drug over a 20 h period. When tested for its antitumor activity on nude mice xenografted with human malignant melanoma and breast carcinoma, LCPT displayed effective antitumor activity with minimal host toxicity. For example, single i.m. injection of LCPT at 10 mg/kg has produced complete tumor regression to nude mice xenografted with CLO breast carcinoma. Likewise, similar results were obtained with the nude mice xenografted with human malignant BRO cells melanoma. These results appear to suggest that i.m. administration of liposome-incorporated CPT has considerable potential for the treatment of human neoplastic diseases, especially lymph node metastases.
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PMID:Antitumor effect of liposome-incorporated camptothecin in human malignant xenografts. 775 88

Lung cancer remains the most common fatal malignancy, so even modest therapeutic advances are potentially beneficial to large numbers of patients. For patients with regional nodal metastases identified at thoracotomy, adjuvant chemotherapy may be of benefit and additional clinical trials are in progress. Locally advanced disease is present in over a third of patients at diagnosis. For patients with marginally resectable tumors, the preliminary results of the neoadjuvant chemotherapy trials are encouraging and may result in an improvement in the 15% 5-year survival in this group. For patients with locally advanced and unresectable tumors, several but not all studies suggest that the combination of chemotherapy and radiation produces better results than radiation alone. Additional trials are needed to clarify these results. In addition, better methods are needed to maintain local control of unresected tumors. Hyperfractionated radiation schedules and concurrent administration of radiosensitizing chemotherapy drugs appear to be the most promising leads. Effective systemic treatment for patients with disseminated disease remains elusive. Several new classes of drugs, especially taxol and the topoisomerase I poisons, are being introduced and have rekindled hope for improved treatment of this large group of patients.
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PMID:Chemotherapy and radiation for the treatment of non-small-cell lung cancer. A critical review. 838 60

Systemic chemotherapy with currently available agents has not improved survival for patients with hormone refractory prostate cancer (HRPC), consequently, the evaluation of new agents is warranted. Topotecan is a specific inhibitor of topoisomerase I with broad antitumor activity in preclinical studies. The purpose of this phase II trial was to determine the objective response rate of topotecan administered as a 30 minute infusion for five consecutive days in men with metastatic HRPC. Thirty-four evaluable patients were treated with topotecan 1.1-1.5 mg/m2 as a 30 minute infusion daily for five days, repeated every three weeks until disease progression or unacceptable toxicity. Response was assessed with a combination of standard solid tumor response criteria and the serum prostate specific antigen (PSA) for patients with bidimensionally measurable disease, and by serial measurements of the PSA in patients with bone only (evaluable) disease. One of 13 patients (7.6%) with measurable soft tissue disease had a PR in nodal sites. Of 21 patients with only osseous metastases, 1 (4.7%) had improvement in bone scan. Six of the 34 evaluable patients (17.6%) had the serum PSA decrease by > or = 50% and 2 (5.8%) had PSA decreases of > or = 75%. Toxicity was chiefly hematologic with 66% of patients experiencing Grade 3 or 4 granulocytopenia. Thirty-nine percent of cycles required a delay to allow for hematologic recovery and ten patients required red cell transfusions. Non-hematologic toxicity, mainly nausea and alopecia, was mild. Topotecan administered at this dose and schedule has limited activity in patients with HRPC. Further trials of topo I inhibition in HRPC should utilize alternative schedules of topotecan (e.g., prolonged infusion) or other camptothecin analogs with more potent topo I inhibitory activity.
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PMID:Phase II study of topotecan in metastatic hormone-refractory prostate cancer. 872 52

Surgery is currently the first-line treatment option for primary colorectal cancer (CRC) and resectable metastatic disease. Cytotoxic chemotherapy is used for adjuvant treatment as well as for the treatment of advanced disease; the combination of 5-fluorouracil (5-FU) plus leucovorin is currently the standard chemotherapeutic regimen used in most centers. In many countries patients with CRC do not receive chemotherapy because some clinicians perceive that the benefits of such treatment do not compensate for the potential negative effects on patient quality of life in terms of toxicity and inconvenient dosage schedules. However, recent evidence suggests that the use of cytotoxic chemotherapy can lead to an improvement in quality of life and effective palliation in CRC. A number of new treatment options are becoming available for the treatment of this malignancy. These include new anticancer agents such as thymidylate synthase inhibitors, monoclonal antibodies and topoisomerase I inhibitors, and new treatment methods including hepatic arterial or i.p. chemotherapy, cryosurgery and chemo-embolization. With the increased referral of patients to oncologists and the use of a multidisciplinary team approach, these new agents and new methods of treatment can be fully evaluated for the treatment of CRC, and should ultimately improve the treatment and outcome of this common disease.
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PMID:Colorectal cancer--an undertreated disease. 891 29

Colorectal cancer affects around 5% of the population in Westernised countries and is associated with a high level of morbidity and mortality. Overall, around 50% of patients can expect to be fully cured by surgery, along with recent improvements in survival due to the use of adjuvant therapy. However, in patients who develop metastatic disease, the prognosis is poor, and the appropriateness of anticancer chemotherapy in such patients has been controversial. Nevertheless, there is increasing evidence that chemotherapy can extend life expectancy in colorectal cancer and that in metastatic disease patients achieve a significant benefit from early rather than late chemotherapy. For first-line treatment of metastatic colorectal cancer, the best available regimens have been those which include 5-fluorouracil (5-FU) and folinic acid; a meta-analysis of nine randomised clinical studies of such regimens produced a mean response rate of 23%. However, in those who fail or relapse, there has been no established second-line alternative. The development of CPT-11 (Campto, irinotecan), a specific inhibitor of topoisomerase I, represents a significant advance in the management of colorectal cancer. Following encouraging observations of sustained activity in colon cancer cell lines, including those having the MDR phenotype, clinical studies of CPT-11 monotherapy in both chemotherapy-naive and pretreated patients with advanced colorectal cancer demonstrated response rates at least equivalent to those achieved with first-line 5-FU/folinic acid combination therapy. This indicates that CPT-11 does not exhibit cross-resistance with 5-FU, making it the first effective second-line agent in this setting. Further studies are ongoing to define the optimum dosage schedule for CPT-11 and to assess the utility of CPT-11 as a single agent in second-line therapy, or combined with 5-FU and other anticancer agents as first-line therapy. In conclusion, CPT-11 offers a different cytotoxic approach that may complement the use of 5-FU/folinic acid in colorectal cancer in the future.
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PMID:Current status of colorectal cancer: CPT-11 (irinotecan), a therapeutic innovation. 894 58

Topotecan (S-9-dimethyl-10-hydroxycamptothecin hydrochloride SKF 104864-A) is a semisynthetic analog of the alkaloid camptothecin and, similar to the parent compound, a potent inhibitor of topoisomerase I. The cytotoxicity induced by topotecan appears due to interference with the normal breakage reunion reaction of topoisomerase I leading to DNA damage and cell death. Since preclinical studies of topotecan suggested antitumor activity against refractory solid tumors, a phase II trial of the drug was initiated in melanoma patients with recurrent and/or metastatic disease. Topotecan 1.5 mg/m2 was given as a daily 30-min infusion for 5 days and repeated every 21-28 days. Seventeen patients were entered into the treatment program with all evaluable for toxicity but I patient, inevaluable for response. There were no objective responses. Toxicity was predominantly severe myelosuppression, which occurred in 12 of 17 (70%) patients. Topotecan in this dose and schedule is inactive in malignant melanoma.
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PMID:Phase II trial of topotecan in malignant melanoma. 924 52

Colorectal cancer is the third most common cause of cancer-related death in both men and women. Surgery is the primary form of treatment, with greater than 90% of patients surviving 5 years or more. The remaining patients have metastatic disease, for which treatment options are limited. The fluoropyrimidine, 5-fluorouracil, elicits favorable tumor response rates in patients with metastatic disease, but has little impact on survival. Based on the observation that colorectal tumors have increased levels of topoisomerase I relative to normal tissue, investigations have focused on the camptothecin derivatives, particularly topotecan, as an effective treatment. Topotecan demonstrated antitumor activity in preclinical studies, causing significant growth delay of xenografts in thymectomized, irradiated mice. Clinical studies with topotecan have not yielded as promising results, with response rates of approximately 7% to 10%, but modifications in dosing schedule or combinations with other agents may enhance antitumor activity.
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PMID:Topotecan in advanced colorectal cancer. 942 60

Therapeutic options after failure of 5-fluorouracil (5-FU) for the treatment of colorectal cancer include regional treatments, different 5-FU-based regimens, and different chemotherapy regimens. Of the regional treatments, resection of hepatic metastases is the most satisfactory because of the potential for long-term survival; however, the number of candidates for this option is limited. Responses are possible if 5-FU is administered by prolonged infusion, but the addition of other chemotherapeutic agents (eg, nitrosoureas, mitomycin C, or cisplatin) is less likely to induce objective responses. The new topoisomerase I inhibitor irinotecan has promising activity in patients with metastatic colorectal cancer. Depending on the status of the patient population, objective response rates of 15% to 30% have been reported in patients with colorectal cancer that has progressed or rapidly recurred following 5-FU-based treatment.
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PMID:Therapeutic options for the treatment of colorectal cancer following 5-fluorouracil failure. 978 14

Colorectal cancer is one of the most frequent malignancies and one of the greatest causes of cancer death in the Western world. The prognosis is determined by the stage at diagnosis. Patients with metastatic colon cancer have a bad prognosis. Chemotherapeutic treatment with 5-Fluorouracil (5-FU) and folinic acid is actually considered as the standard treatment in patients with metastatic disease. Although the survival benefit is relatively small, many patients can benefit from this treatment in terms of tumor regression or symptom improvement. Several new drugs are actually in development and create hope for improved tumor or symptom control and longer survival. Thymidylate synthase inhibitors (raltitrexed), topoisomerase I inhibitors (irinotecan), the oral 5-FU prodrugs (capecitabine, UFT), ethynyluracil, and oxaliplatin are promising new drugs. The challenge will be to determine the best combination of these new drugs and the exact sequence in which these drugs will be used. Adjuvant post-operative chemotherapy in colon cancer is one of the most important advances in oncology that has been introduced into the clinic during the last years. For rectal cancer, an adjuvant treatment should consist of a combined chemo-radiotherapy. The search for better prognostic factors for recurrence should help to focus on a better adjuvant treatment for patients with the highest risk for recurrence.
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PMID:The medical treatment of colorectal cancer: actual status and new developments. 1037 May 99

J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.
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PMID:In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice. 1059 46


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