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 induction of severe diarrhea limits the usefulness of the DNA topoisomerase I inhibitor irinotecan (CPT-11) in the treatment of advanced colon cancer. We investigated whether oral administration of the new synthetic bacterial lipopeptide, JBT 3002, encapsulated in phospholipid liposomes could prevent damage to the intestinal epithelium and lamina propria and thus allow for the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Treatment of mice with four daily i.p. injections of 100 mg/kg irinotecan was effective against liver metastases but also resulted in loss of body weight and early death. Histopathological examination of the intestines after this treatment revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in S-phase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Studies that used irinotecan administered once a week for 3 weeks after pretreatment with oral JBT 3002 demonstrated significantly intensified eradication of established CT-26 liver metastases compared with treatment with once-weekly irinotecan alone. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. In vitro studies revealed that irinotecan produced direct antiproliferative effects but JBT 3002 did not. Tumor cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data show that oral administration of JBT 3002 can prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, thus allowing for intensification of irinotecan therapy against liver metastases from colon cancer.
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PMID:Prevention of intestinal toxic effects and intensification of irinotecan's therapeutic efficacy against murine colon cancer liver metastases by oral administration of the lipopeptide JBT 3002. 974 19

Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We have investigated the antiangiogenic properties of three camptothecin analogues, 9-amino-20(S)-camptothecin, topotecan, and camptosar (CPT-11), currently under investigation in clinical settings. Angiogenesis was induced by basic fibroblast growth factor in the cornea of inbred Swiss-Webster mice, with the aim of exploring the suppression of neovascularization by the analogues injected into the mice daily over a period of 6 days. The dose range chosen is known to inhibit, in the mouse model, the growth of various human tumor xenografts or murine tumors. The statistical analysis evaluated the association between the area of neoangiogenesis and the dose of the drugs tested and correlated the effects with observed drug toxicity. It was established that, as the drug doses increased, the area of neovascularization decreased, appearing to approximate a negative exponential curve. 9-Amino-20(S)-camptothecin at 6.89 and 8.26 micromol/kg (2.5 and 3.0 mg/kg) and topotecan at 8.31 micromol/kg (3.5 mg/kg), both drugs being delivered over a 6-day period, had statistically significant reduction (47.2-72.5%) of neoangiogenesis and acceptable toxicity. At higher doses of the two analogues, toxic body-weight losses and deaths were observed. CPT-11 showed statistically significant reduction of neoangiogenesis at a dose of 359 micromol/kg (210 mg/kg) delivered over a 6-day course. Unlike camptothecin analogues, the nontoxic dose of vincristine did not induce a statistically significant inhibition of angiogenesis, and there was no dose-dependent escalation of antiangiogenic effects. The results indicate that camptothecins are most likely cytotoxic against two tumor compartments: in addition to tumor cells of epithelial origin, the drugs act against endothelial cells and prevent the growth of the tumor microvessels. We have hypothesized that treatment failure in some patients is due to incomplete or inadequate inhibition of the microvessel growth by camptothecins. Presumably, an intensive inhibition of the remaining tumor microvasculature in such patients could be achieved by combining a camptothecin with another antiangiogenic anticancer agent or with a highly selective angiogenic inhibitor exerting minimal dose-limiting toxicity. Such treatment by a camptothecin plus a less toxic inhibitor of angiogenesis can improve antitumor efficacy. To validate this concept, preclinical studies followed by clinical trials are planned.
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PMID:Antiangiogenic effects of camptothecin analogues 9-amino-20(S)-camptothecin, topotecan, and CPT-11 studied in the mouse cornea model. 991 17

We examined the in vivo anti-tumor activity of the benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido] benzoic acid), for intrahepatic spread of JHH-7 human hepatocellular carcinoma (HCC) cells and its mechanism of action. Oral administration of TAC-101 markedly inhibited liver tumor of JHH-7 cells and prolonged the life-span of tumor-bearing mice without affecting the body weight. The life-prolonging effect of TAC-101 was more effective than that of other anti-cancer agents including CDDP, 5-FU, and CPT-11 (T/C (%) of life-span; 181 to 219, 128, 133, and 142%, respectively). In vitro, TAC-101 at the concentration of more than 10 microM showed direct cytotoxicity against JHH-7 cells caused by induction of apoptosis. Hepatocyte growth factor (HGF) enhanced the invasive ability of JHH-7 cells without affecting the cell viability. Non-cytotoxic concentrations of TAC-101 inhibited the JHH-7 invasion induced by HGF and down-regulated the expression of c-MET protein in a concentration-dependent manner. In summary, these results suggest that TAC-101 would be useful for a new class of therapeutic agents and that it may improve the prognosis of patients with liver-tumors including metastasizing tumor and HCC.
Clin Exp Metastasis 1998 Oct
PMID:4-[3,5-Bis(trimethylsilyl)benzamido] benzoic acid (TAC-101) inhibits the intrahepatic spread of hepatocellular carcinoma and prolongs the life-span of tumor-bearing animals. 993 10

In 1996 two chemotherapy agents were introduced by the U.S. Food and Drug Administration (FDA) with indications for the gastrointestinal malignancies for advanced colon and pancreatic cancers. The agents approved were irinotecan hydrochloride (CAMPTOSAR Injection, Pharmacia & Upjohn Company, Kalamazoo, MI; also investigated under the name CPT-11) for the second-line treatment of metastatic colorectal cancer, recurrent or relapsed, after 5-fluorouracil (5-FU)-based therapy, and gemcitabine hydrochloride (GEMZAR for injection, Eli Lilly and Company, Indianapolis, IN; also referred to as dFdC) for first-line treatment of locally advanced and metastatic cancer of the pancreas. Irinotecan and gemcitabine, with demonstrated activity in colorectal and pancreatic cancer, respectively, are generally well tolerated and can be administered safely on an outpatient basis. Clinically relevant activity is documented for both single agents. Therapy-related side effects are manageable with appropriate monitoring and intervention, and reversible with dose modification or discontinuation. This article is one of a two-part series on new chemotherapeutic agents for gastrointestinal malignancies. The first in the series, this article addresses the agent irinotecan hydrochloride (CAMPTOSAR Injection). The second article, appearing in a subsequent issue, will review gemcitabine hydrochloride (Gemzar for Injection). Both articles review the current clinical use, safety profile, and key patient management guidelines for these new and novel cytotoxics. As clinical and investigational use of irinotecan and gemcitabine increases, the oncology nurse and other members of the health care team will need to anticipate potential treatment associated toxicities and be knowledgeable in their early identification and management. As patient advocates, oncology nurses play a key role in treatment outcome and related quality of life through expert patient education, symptom recognition, and intervention individualized to patient tolerance. This first article of the series addresses irinotecan, which in 1996 was approved for the second-line therapy of metastatic colorectal cancer, recurrent or elapsed, after 5-fluorouracil (5-FU).
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PMID:New agents in gastrointestinal malignancies: Part 1: Irinotecan in clinical practice. 1037 82

This phase I trial combining UFT plus oral calcium folinate (Orzel) with irinotecan (CPT-11) (Camptosar) for the treatment of patients with advanced or metastatic colorectal cancer will open shortly. Eligible patients will have locally advanced or metastatic colorectal cancer, and they may have received adjuvant chemotherapy (provided it has been completed more than 6 months prior to study entry), but will have not received any chemotherapy for advanced or metastatic disease. The primary objectives of this study will be to determine the side-effect profile, dose-limiting toxicities, and the maximum tolerated dose of this combination. A recommended starting dose for future trials will be defined. Response rates will also be observed as a secondary objective. The first cohort of six patients will receive irinotecan 200 mg/m2 by intravenous infusion over 90 minutes on day 1 (the schedule that is in general use in Europe). On days 1 to 14, patients will receive UFT 250 mg/m2/d and calcium folinate 90 mg/d, both divided into three equal doses. This will be followed by a 1-week rest period with treatment for the next cycle resumed on day 22. In subsequent cohorts of six patients, UFT and irinotecan will in turn be escalated provided toxicity is acceptable. The calcium folinate dose will remain fixed at 90 mg/d throughout. The maximum tolerated dose is defined as that at which dose-limiting toxicities occur in more than one third of patients. The cohort of patients treated at the dose below the maximum tolerated dose will be expanded to a total of 20 patients to fully define the pattern of toxicities and activity of the combination.
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PMID:UFT plus calcium folinate/irinotecan in colorectal cancer. 1044 62

When colorectal cancer metastasizes to distant organs, usually multiple sites are involved and treatment consists primarily of systemic chemotherapy and supportive care. Chemotherapeutic agents effective against metastatic colorectal cancer include 5-fluorouracil, often used in combination with leucovorin or methotrexate, and irinotecan (CPT-11). Median survival with optimal chemotherapy regimens ranges from 10 to 15 months. Less frequently, colorectal cancer metastasizes only to the liver or lung. In a minority of these cases, surgical resection can be performed and results in a median survival of 28-46 months for hepatic resections and 24-25 months for pulmonary resections. Five-year survival rates range from 24 to 38% and 21 to 44% for hepatic and pulmonary resections, respectively. For isolated liver metastases that are not surgically resectable, other regional therapies that can be considered are hepatic cryosurgery, radiofrequency ablation, and hepatic arterial infusion chemotherapy. Median survival following cryosurgery is between 26 and 30 months, while median survival following radiofrequency ablation has not been established in large series. Hepatic arterial infusion chemotherapy, especially with newer combination drug regimens, may increase survival in patients with isolated liver metastases compared to systemic chemotherapy, but this must be confirmed in randomized, prospective trials. Colorectal cancer metastases to the brain can be treated with radiation therapy or surgical resection, but median survival with treatment is less than one year.
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PMID:Multidisciplinary management of metastatic colorectal cancer. 1067 70

We attempted a new outpatient treatment using weekly low-dose CPT-11 for advanced colorectal cancer patients. A 73-year-old female with para-aortic lymph node metastases from advanced rectal cancer was given outpatient treatment for more than 5 months with weekly low-dose CPT-11 and HCFU. CPT-11 was given intravenously at a dose of 20 mg/m2 on day 1 every week. On days 2-7, she was treated by oral administration of HCFU (600 mg). Her serum CEA level decreased and continued to do so for more than 5 months. The size of the para-aortic lymph node was reduced by approximately 40%. There were no adverse effects except leukopenia (grade 2). These results suggest that weekly low-dose CPT-11 and oral HCFU may be an effective therapy on an outpatient basis in cases of advanced colorectal cancer.
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PMID:[Weekly low-dose CPT-11 and HCFU for advanced colorectal cancer on an outpatient treatment basis]. 1089 21

Three active antitumor agents, i.e. 5-fluorouracil (5-FU), oxaliplatin and CPT-11, are available for the treatment of advanced colorectal cancer (CRC) patients and have been successfully combined in two-drug regimens. Hence, CRC has become a chemosensitive disease, but the optimal combination of these agents in first-line treatment remains to be determined. We report the first case of the combination of CPT-11 with oxaliplatin, 5-FU and folinic acid (FA) as first-line chemotherapy for a patient with a pre-occlusive sigmoid adenocarcinoma and synchronous bulky liver metastases. CPT-11 was given at 125 mg/m2, prior to the start of a chronomodulated 4-day infusion of oxaliplatin 25 mg/m2/day, 5-FU 800 mg/m2/day and FA 300 mg/m2/day repeated every 2 weeks. The doses could be escalated to 150 mg/m2 for CPT-11 and 900 mg/m2/day for 5-FU. After six cycles of chemotherapy 70% reduction in tumor size was documented in the liver. The primary tumor was no longer detectable by barium enema. The toxicity included three episodes of grade 4 neutropenic fever, and two episodes of severe diarrhea and vomiting with dehydration. A cumulative grade 2 neurosensory toxicity was observed after six cycles. Following surgery of the primary tumor, because of the major hepatic tumor response and of the absence of extra-hepatic metastases, the patient might be registered for a liver transplantation program. This first report of combining the three active agents in CRC every 2 weeks led to a high dose intensity of each agent and was associated with a dramatic tumor response of a very advanced disease in a patient with already altered performance status. The antitumor activity in this patient suggests that a three-drug intensified regimen might be feasible and active. A prospective study appears warranted to further examine the efficacy and toxicity of this therapeutic approach, and to determine whether it may increase the fraction of advanced CRC patients becoming resectable. This aggressive chemotherapy program may contribute to a re-examination of the usefulness of liver transplantation in patients with metastatic CRC confined to the liver.
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PMID:Dramatic tumor response of bulky liver metastases following treatment with CPT-11 and a chronomodulated 4-day infusion of 5-fluorouracil, folinic acid and oxaliplatin every 2 weeks in a colorectal cancer patient. 1089 41

This phase I/II nonrandomized, open-label study was designed to assess the safety and benefit of sequencing irinotecan (Camptosar, CPT-11) plus paclitaxel (Taxol) immediately after cisplatin (Platinol)/etoposide (VePesid, VP-16) or carboplatin (Paraplatin)/etoposide in patients with extensive small-cell lung cancer (SCLC). Ten patients were evaluable in phase I; all had previously been treated with cisplatin and etoposide, and five of the 10 had also previously received carboplatin and paclitaxel. All 10 patients were given a fixed dose of irinotecan (60 mg/m2) and escalating doses of paclitaxel weekly for 3 weeks. Three patients had grade 4 toxicities, one at the lowest dose level of paclitaxel (15 mg/m2). Two patients had grade 3 toxicities. The dose-limiting toxicity occurred at the 60 mg/m2 paclitaxel dose level, when the performance status of both patients in that group decreased to 60 (Karnofsky scale). Two patients had progressive disease after 1 month of treatment and did not receive cycle 2. Three of seven patients evaluable for response had complete remissions. A fourth patient had resolution of lymphangitic metastases and resolution of a partial small bowel obstruction but did not have measurable disease. The fifth patient had a partial remission. The ongoing phase II portion of the study is restricted to previously untreated patients who will receive at least one cycle of either cisplatin or carboplatin in combination with etoposide followed by irinotecan at 60 mg/m2 and paclitaxel at 50 mg/m2 dosed once weekly for 3 weeks.
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PMID:Phase I/II study of weekly irinotecan and paclitaxel in patients with SCLC. 1098 Dec 93

Progress has been made in the adjuvant treatment of colorectal carcinoma. The improvement in survival with the use of adjuvant 5-FU and leucovorin in patients with stage III colon carcinoma has been readily established. However, a survival benefit in stage II patients treated with adjuvant therapy remains unproven. Further evaluation using additional/new prognostic factors may identify a high-risk stage II group that would benefit from adjuvant treatment. Adjuvant chemoradiation has become standard therapy for stage II and III patients with rectal carcinoma. Investigations using preoperative combined-modality therapy are being explored to assess sphincter preservation rates and to evaluate any impact on survival. Radiosensitizing chemotherapeutic agents need to be evaluated in this patient population. Recent advances in metastatic disease have occurred. Frontline therapy remains 5-FU and leucovorin. CPT-11 has demonstrated responses in 5-FU relapsed and refractory patients and is the new standard therapy in these patients. New data recently available also show a survival advantage in patients treated with CPT-11 versus supportive care in 5-FU and leucovorin failures. New agents such as UFT and oxaliplatin have demonstrated activity in colorectal carcinomas and in the future these agents will likely aid in the treatment of this disease.
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PMID:Chemotherapy of Colorectal Cancer. 1109 71


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