Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase I represents a unique new target that can be exploited for development of new antineoplastic agents. There are now two new topoisomerase I inhibitors that are in early clinical trials that have generated a tremendous amount of interest. Topotecan (SKF 104864-A) is a topoisomerase I inhibitor that has been explored in phase I trials using a variety of dosages and schedules. The dose-limiting toxicity of the agent is neutropenia. Other toxicities include alopecia, very mild nausea and vomiting, anemia, and occasional fever. Responses have already been noted in patients with advanced, refractory ovarian cancer and non--small-cell lung cancer. The drug is currently undergoing intense phase II testing. Irinotecan (CPT-11) is also a topoisomerase I inhibitor, which has already undergone extensive phase I and early phase II clinical testing in both Japan and the United States. Dose-limiting toxicities of the agent have included neutropenia and diarrhea. Responses have been noted in patients with refractory colorectal cancer, non--small-cell lung cancer, lymphoma, ovarian cancer, head and neck cancer, pancreatic cancer, and breast cancer. There is no doubt both of these agents will be important additions to our chemotherapy armamentarium.
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PMID:Clinical trials with the topoisomerase I inhibitors. 133 79

Irinotecan (CPT-11) is a novel water-soluble, semisynthetic derivative of camptothecin, with inhibitory effects on mammalian DNA topoisomerase I, high cytotoxic activity in vitro and anticancer activity in animal models. Fifty-nine patients, with cancer refractory to conventional therapy, were entered in this phase I study, using a weekly schedule administration. A total of 304 weekly doses were administered at dose levels ranging from 50 to 145 mg/m2 (30-90 min i.v. infusion). Leukoneutropenia and diarrhea were the dose-limiting toxicities and appeared to be dose related, reversible and noncumulative. However, interpatient variability of toxic effects was substantial. Prolongation of the infusion time from 30 min to 90 min appeared to decrease the diarrhea. Other toxicities included moderate emesis, asthenia, alopecia, abdominal pain, and anemia. CPT-11 plasma disposition was bi- or triphasic with a terminal half-life of 9.3 h. CPT-11 area under the plasma concentration versus time curves increased linearly with dose (r = 0.47, P < 0.01). The active metabolite area under the plasma concentration versus time curve correlated significantly with that of CPT-11, but not with that of CPT-11 dose. Both CPT-11 and 7-ethyl-10-hydroxycamptothecin areas under the plasma concentration versus time curve correlated significantly with leukoneutropenia and diarrhea. One partial and 4 minor responses were observed at dose levels of 130 and 145 mg/m2. Using this weekly schedule, recommended doses for phase II studies are 100 mg/m2 in high risk patients and 115 mg/m2 in others.
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PMID:Phase I and pharmacokinetic study of the camptothecin derivative irinotecan, administered on a weekly schedule in cancer patients. 804 82

A late phase II study of CPT-11 for advanced breast cancer was conducted at 27 institutions. Seventy-nine patients were enrolled, 75 were eligible for the study, and 65 were evaluable for efficacy. One complete response and 14 partial responses were obtained, and the response rate was 23%. The response rate of patients with prior endocrine therapy and prior chemotherapy including adriamycin or other anthracycline drugs was 27% (11/41) and 26% (12/46), respectively. The response rate for patients with estrogen receptor-negative tumors and premenopausal patients was 32% (6/19) and 27% (4/15), respectively. Responses were observed not only for soft tissue lesions such as lymph nodes (5/17), but also for distant metastases in the lungs (8/28) and bone (1/18). The major adverse reactions were myelosuppression and gastrointestinal symptoms. The incidence of Grade 2 or higher leukopenia, anemia, nausea/vomiting, anorexia, diarrhea and alopecia was 68%, 31%, 67%, 59%, 37%, and 30%, respectively. These results suggested that CPT-11 was a promising drug for advanced breast cancer.
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PMID:[A late phase II study of CPT-11 (irinotecan) in advanced breast cancer. CPT-11 Study Group on Breast Cancer]. 821 Feb 51

A multi-institutional collaborative late phase II study of irinotecan hydrochloride (CPT-11) was performed on patients with advanced gastric cancer. CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion or as 150 mg/m2 fortnightly. Of 81 registered patients, 77 cases were eligible and 60 cases were evaluable for response. The overall response rate for evaluable cases was 23.3% (14/60), and the response rate was 16.1% (9/45) for the patients who had received prior chemotherapy. The primary tumor showed a 4.5% response, while metastatic lesions in the lymph-nodes, lungs, and liver showed response rates of 36.4%, 33.3%, and 17.4%, respectively. The major toxicities (> or = Grade 3) were leukopenia (41.2%), anemia (28.9%), diarrhea (22.4%) and anorexia (19.7%). These toxicities were generally reversible. CPT-11 showed activity against advanced gastric cancer, suggesting that further clinical studies of CPT-11 combined with other active chemotherapy agents are warranted.
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PMID:[Late phase II study of irinotecan hydrochloride (CPT-11) in advanced gastric cancer. CPT-11 Gastrointestinal Cancer Study Group]. 821 Feb 54

A late phase II study of CPT-11 was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with advanced pancreatic cancer as a cooperative study of 19 institutions. From February 1990 to June 1992, 61 patients with advanced pancreatic cancer were enrolled in this study. Fifty-seven patients were evaluable for toxicity and 35 for response. CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion (regimen A) or as a 150 mg/m2 every two weeks (regimen B). The response rate was 11.4% (4/35). The primary tumor showed a 10.3% (3/29) response and the liver metastases showed a 10.5% (2/19) response. The major toxicities were myelosuppression and gastrointestinal symptoms. The incidences (> or = Grade 2) of leukopenia, anemia, anorexia, nausea/vomiting, alopecia and diarrhea were 61.4% (35/57), 56.1% (32/57), 70.2% (40/57), 56.1% (32/57), 40.4% (23/57) and 36.8% (21/57), respectively. The incidence of diarrhea was higher with regimen A than with regimen B, but the antitumor activity was no different between the two regimens. These results suggested that CPT-11 has some antitumor activity against advanced pancreatic cancer.
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PMID:[A late phase II study of CPT-11, irinotecan hydrochloride, in patients with advanced pancreatic cancer. CPT-11 Study Group on Gastrointestinal Cancer]. 821 Feb 55

An early phase II study of irinotecan (CPT-11) in patients with advanced or recurrent breast cancer was undertaken by a cooperative study group of 15 institutes in Japan. CPT-11 was administered by intravenous drip-infusion. The administration schedules were 100 mg/m2 weekly (regimen A), 150 mg/m2 biweekly (regimen B), and 200 mg/m2 every 3-4 weeks (regimen C). There were 4 partial responses (PRs), 12 cases with no changes (1 minor response) and 9 cases of progressive diseases with a response rate of 16% (4/25). One out of 7 patients on regimen A and 3 patients out of 15 patients on regimen C achieved PR with a response rate of 14% and 20%, respectively. In three out of 4 PRs, prior chemotherapy, endocrinotherapy or radiotherapy had failed. Major adverse reactions were leukopenia 28/33 (85%), neutropenia 19/25 (76%), anemia 15/33 (46%), nausea/vomiting 28/33 (85%), anorexia 25/33 (76%), diarrhea 22/33 (67%) and alopecia 20/33 (61%). The incidence of leukopenia and thrombocytopenia seemed to be higher in regimen C than regimen A, and diarrhea was also more severe in regimen C than regimen A. The recovery of leukopenia was delayed in some patients on regimen C. The results suggested that CPT-11 was effective against advanced or recurrent breast cancer. The recommended administration schedule for a late phase II study was thought to be 100 mg/m2 weekly, considering efficacy and safety.
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PMID:[An early phase II study of CPT-11 (irinotecan hydrochloride) in patients with advanced breast cancer]. 829 19

The efficacy and safety of irinotecan (CPT-11) combined with cisplatin (CDDP) were assessed in 24 previously untreated patients with primary non-small cell lung cancer. CPT-11 (60 mg/m2) and CDDP (30 mg/m2) were administered in combination at weekly intervals, on days 1.8, and 15 of the treatment course. During treatment, the patients were evaluated for adverse drug reactions and response. The response rate was 58.3% for all patients and 60.9% for the patients who completed the full treatment course. The median survival time was 13.0 months. The major adverse reactions were myelosuppression and gastro-intestinal disorders, but no treatment-related deaths were observed. Myelosuppressions included grade 3 or 4 leukopenia (25.0%) and anemia (33.3%). Grade 3 and higher gastro-intestinal reactions included nausea and vomiting (8.3%), diarrhea (12.5%), and anorexia (16.7%). These results suggest that combined weekly CPT-11 and CDDP therapy is capable of achieving a favorable tumor response with less toxicity, and thus worth consideration as a treatment option. Given that only 33.3% of the patients finished the full treatment course, further study should be devoted to the subject of CDDP and/or CPT-11 dosages.
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PMID:[Clinical evaluation of irinotecan combined with cisplatin by divided administration in patients with untreated primary non-small cell lung cancer]. 986 79

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The patients' median age was 57 years (range 35-75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16-62 days). The median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.
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PMID:Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced or recurrent cervical cancer. 1064 38

Based upon the results of phase I study of irinotecan (CPT-11) combined with cisplatin (CDDP) on non-small cell lung cancer (NSCLC), a combination phase II study on NSCLC was carried out from Feb., 1992 to Sep., 1992. CPT-11 (60 mg/m2) and CDDP (80 mg/m2) were administered by i.v. drip infusion, with administration schedules of Days 1, 8, 15 and only Day 1, respectively. This therapy course was repeated every 4 weeks. Subjects were NSCLC patients of stage III B or IV disease. Those without prior chemotherapy (Group A) and those with prior therapy (Group B) were enrolled separately. Seventy patients were entered into Group A and 32 patients into Group B. One of the patients of Group A was ineligible. The characteristics of the eligible cases of Group A were: male/female, 51/18; median age, 61 years old; PS 0/1/2, 18/39/12; stage IIIB/IV, 26/43; and adeno/squamous/large, 51/15/3. Those of group B were: male/female, 20/12; median age, 62 years old; PS 0/1/2, 5/18/9; stage I/IIIB/IV, 1/7/24, adeno/squamous/large/ad-sq, 28/2/1/1. Thirty-three patients (47.8%) responded in Group A and B patients (25.0%) responded in Group B. Major adverse reactions (grade 3 or higher) of Group A/Group B were neutropenia (80.3%/73.3%), anemia (35.3%/34.4%), diarrhea (18.8%/28.1%) and nausea/vomiting (34.8%/34.4%). Median survival times for Group A and Group B were 308 and 295 days, respectively. CPT-11 in combination with CDDP is effective against NSCLC, suggesting that further studies are needed to determine the usefulness of this therapy.
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PMID:[A phase II study of irinotecan combined with cisplatin in non-small cell lung cancer. CPT-11 Lung Cancer Study Group]. 1074 Jun 35

The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT-11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration-time curve (AUCP) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 micrograms/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (i.p.) administration of topotecan has been studied in a phase I trial as a 24-hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose-limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second-order kinetics with elimination half-lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.
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PMID:Alternative administration of camptothecin analogues. 1119 99


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