Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topoisomerase I inhibitors are a new therapeutic class whose clinical evaluation began a few years ago; Irinotecan (CPT-11) gave interesting results in colon cancer; side effects were neutropenia, diarrhea, vomiting and a cholinergic syndrome. Topotecan was useful in lung and ovarian cancer; side effects were mostly hematologic. Undergoing studies concern dose optimization, mode of administration and therapeutic associations.
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PMID:[Topoisomerase I inhibitors. Review of phase II trials with irinotecan (CPT-11) and topotecan]. 749 18

Intraperitoneal (IP) administration of fluorinated pyrimidines has been evaluated for ovarian and gastrointestinal malignancies in phase I, II, and III trials. The tolerance and pharmacokinetic profile of IP 5-fluoro-2'-deoxyuridine(FUDR) alone and with (R,S)-leucovorin ((R,S)-LV) have each been evaluated in previous phase I studies. FUDR doses of 3 g per day with and without (R,S)-LV doses up to 640 mg per day given IP are well tolerated. The current phase I study was designed to determine the pharmacokinetic profiles and clinical tolerance of escalating doses of the pure biologically active S-isomer of leucovorin ((S)-LV) given IP with the same dosing schedule of FUDR. A group of 16 patients with disease confined to the abdominal cavity were treated in this study. Pharmacokinetic studies of blood and peritoneal fluid, toxicity profiles, and clinical response for the first three cycles are reported here. The toxicity profile did not significantly differ from the prior two studies. All non-hematologic toxicities, such as fatigue, nausea, vomiting, diarrhea, and abdominal discomfort were less than grade 4, and most were less than grade 3. Neutropenia and thrombocytopenia were uncommon and observed only in patients with compromised bone marrow reserve. The pharmacokinetic profiles were also congruent with the previous studies and indicate a three-log advantage for FUDR. The (S)-LV profiles in the peritoneal cavity paralleled those of FUDR. Antitumor effects or absence of progression until after cessation of therapy were documented in 11 patients. At a median follow-up of 18 months 44% of patients were alive. IP administration of 3-g of FUDR and up to 640 mg (S)-LV daily for three days was well tolerated. The tolerance and antitumor effects observed during IP FUDR and LV in these studies encourage further exploration of this regimen against ovarian and gastrointestinal malignancies. The actual role and optimal dose of LV as an enhancer of the antitumor actions of FUDR administered by this route remain unknown.
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PMID:Intraperitoneal 5-fluoro-2'-deoxyuridine (FUDR) and (S)-leucovorin for disease predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study. 749 94

A dose escalation study of teniposide (VM-26) plus cisplatin (CDDP) was carried out using recombinant human granulocyte colony-stimulating factor (rhG-CSF) in 46 previously untreated patients with advanced small cell lung cancer (SCLC). The dose of CDDP was 80 mg/m2/day intravenously (i.v.) (day 1) and VM-26 was escalated from 60 mg/m2/day to 80, 100 and 120 mg/m2/day i.v. x 5 days for four cycles. The dose of rhG-CSF was 90 micrograms/m2/day subcutaneously for 13 days. The feasibility of the regimen at the starting dose level of VM-26 with or without rhG-CSF was initially examined in 10 patients chosen through random allocation. WHO grade 4 neutropenia was observed in 17% (three out of 18 courses) of patients in the rhG-CSF group and in 63% (12 out of 19 courses) of the control group (P < 0.01). The number of patients with febrile episodes (> 38 degrees C) over the four courses of chemotherapy was 1 in the rhG-CSF group and 4 in the control group. According to these results, all 36 patients received rhG-CSF in the dose escalation stage. The incidence of WHO grade 4 neutropenia at the dose levels of 60, 80, 100 and 120 mg/m2/day of VM-26 was 66, 57, 76 and 85%, respectively (P > 0.1). The incidence of grade 4 thrombocytopenia was 19, 31, 18 and 46%, respectively (P > 0.1). The overall response rate was 100% in patients with limited stage SCLC and 83% in patients with extensive stage SCLC. The actual administered VM-26 dose per week at the dose level of 100 mg/m2/day was 1.6-fold higher than the planned starting dose (60 mg/m2/day) per week. At the dose level of 120 mg/m2/day, 50% of patients developed WHO grade 4 leucopenia, which lasted longer than 1 week and 67% of the patients had WHO grade 3 or 4 diarrhoea. At this same dose, all patients had at least one febrile episode (> 38 degrees C), and 1 patient died of cerebral bleeding with severe thrombocytopenia. The median survival time of all patients was 451 days (411 days, extensive disease; 497 days, limited disease). VM-26 plus CDDP with rhG-CSF was active in previously untreated patients with SCLC. The recommended dose of VM-26 in combination with CDDP for a phase II study is 100 mg/m2/day for 5 days with rhG-CSF support.
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PMID:A study of dose escalation of teniposide (VM-26) plus cisplatin (CDDP) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) in patients with advanced small cell lung cancer. 751 56

The objective of this phase I trial was to determine the maximal tolerated dose (MTD) of Taxol and doxorubicin administered as a simultaneous intravenous infusion over 72 hours every 21 days. Granulocyte-colony stimulating factor (G-CSF) 10 micrograms/kg, was administered on days 4-18 of each cycle. The treated population consisted of metastatic breast cancer patients previously untreated with chemotherapy for metastatic disease, who had not received doxorubicin in the adjuvant setting and who had bidimensionally measurable disease. The MTD was determined to be 75 mg/m2 of doxorubicin and 160 mg/m2 of Taxol. The dose-limiting toxicity of the combination was clinical typhlitis in three of three patients. Other significant toxicities included grade 3 diarrhea at the higher dose levels and grade 4 neutropenia in all patients. Eighteen patients were treated on this initial phase I study. The overall response rate was 62%, with 6% complete responses and 56% partial responses. The combination of doxorubicin and Taxol by 72-hour continuous infusion with G-CSF is an active regimen in patients with metastatic breast cancer.
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PMID:Phase I study of Taxol, doxorubicin, plus granulocyte-colony stimulating factor in patients with metastatic breast cancer. 751 54

The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5-2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily x5 schedule has been developed further with dose escalation using granulocyte-colony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.
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PMID:Camptothecin analogues: studies from the Johns Hopkins Oncology Center. 752 Aug 44

In a phase II Eastern Cooperative Oncology Group trial, single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was administered to 26 patients with advanced urothelial cancer who had not received prior systemic chemotherapy. Paclitaxel was given at a dose of 250 mg/m2 by 24-hour continuous infusion along with prophylactic granulocyte colony-stimulating factor. Despite a 23% incidence of grade 3 or 4 neutropenia, only two patients developed febrile neutropenia; other hematologic toxicity was mild and not dose limiting. Nonhematologic toxicity included grade 3 neurologic toxicity in three patients, grade 3 mucositis in three patients, and grade 4 diarrhea in one patient. Eleven of 26 (42%) patients had an objective response (seven clinical complete responses, four partial responses), two had stable disease as their best response, and 13 patients progressed while on therapy. Preliminary response data suggest significant single-agent activity for paclitaxel in transitional cell carcinoma of the bladder. Future studies will evaluate paclitaxel-containing combination regimens as first-line therapy for advanced disease and define the role of paclitaxel in salvage therapy following conventional chemotherapy.
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PMID:Preliminary experience with paclitaxel in advanced bladder cancer. 754 Nov 50

Paclitaxel (Taxol), the prototype of a new class of plant-derived antineoplastic compounds, is a natural product isolated from the Pacific yew. Docetaxel (Taxotere) is a hemisynthetic product derived from the European yew. These agents share a unique mechanism of cytotoxic action by promoting assembly of microtubules and rendering the microtubules resistant to depolymerization. In vitro studies suggest a possible role for radiation sensitization. In Phase I trials, the dose-limiting toxicity was neutropenia for both agents. Other toxicities include infusion-related hypersensitivity reactions, alopecia, neurotoxicity, mucositis, diarrhoea and myalgias. To prevent infusion-related reactions, routine premedication is recommended. Noncumulative cardiac toxicity has been observed with paclitaxel. Fluid retention and rash have been reported with docetaxel. In Phase II studies of paclitaxel in advanced non-small cell lung cancer, response rates of 21% and 24% were observed. In Phase II studies of docetaxel in similar patients, response rates ranging from 28-38% were reported, including patients previously treated with cisplatin. The most common toxicity in these studies was neutropenia. Combination studies with cisplatin and other agents are in progress. Paclitaxel and docetaxel are among the most active chemotherapeutic agents for non-small cell lung cancer patients. Their testing will dominate trials of new therapies in this disease for years to come.
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PMID:Paclitaxel (Taxol) and docetaxel (Taxotere): active chemotherapeutic agents in lung cancer. 755 25

Camptothecin is a natural product derived from the Oriental tree Camptotheca acuminata which has shown activity in a number of experimental tumors. Its clinical development was halted in the early-70s owing to its unpredictable and formidable toxicities. Two water-soluble camptothecin analogs have been synthesized recently and are currently in clinical trials: topotecan and CPT-11. Camptothecin and its derivatives are unique in that they represent the only family of topoisomerase I inhibitors. Topoisomerase I is a nuclear enzyme which modulates the topological structure of DNA by making transient single-stranded breaks. Pre-clinical studies have shown that CPT-11 and topotecan possess high and broad antitumor activity against a variety of experimental tumors including both non-small cell lung cancer (NSCLC) and small cell lung cancer. Lack of cross-resistance with most classical anticancer agents has been also demonstrated. Phase I studies have identified neutropenia to be the dose-limiting toxicity for topotecan while, for CPT-11, either neutropenia or diarrhoea were dose-limiting. Maximum Tolerated Doses (MTD) of both agents are greatly dependent upon the schedule used. A Phase II Japanese study of CPT-11 in advanced untreated NSCLC has been recently published. Given at the dose of 100 mg/m2 as a 90-min infusion, CPT-11 produced a 32% objective response rate out of 72 assessable untreated patients. Similar studies are in progress with topotecan. The same Japanese group has completed Phase I-II studies on the combination of CPT-11 with cisplatin. The optimal dose of CPT-11, which can be safely combined with cisplatin 80 mg/m2, was found to be 60 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Camptothecin analogues in the treatment of non-small cell lung cancer. 755 27

The combination of 5-fluorouracil (5-FU) and folinic acid (FA) has demonstrated activity in colorectal cancer (CC). Cisplatin is reported to have synergistic activity with 5-FU. We examined the combination FA + 5-FU + cisplatin in patients who had previously received chemotherapy with FA + 5-FU and relapsed. Two months after the last dose of FA + 5-FU and documentation of relapse, patients continued with the regimen consisting of cisplatin 20 mg/m2 in 15 min i.v. infusion followed by FA 500 mg/m2 in 1 h i.v. infusion, in the middle of which 5-FU 500 mg/m2 i.v. bolus was administered, with adequate post-hydration. This was repeated weekly for 4 weeks followed by a 2 week rest, for a maximum of six cycles. A total of 30 patients with CC that had relapsed to the combination of FA + 5-FU were treated; 23 had previous surgery and none had radiotherapy. Local recurrence was found in eight patients, metastases in the liver in 21, in lymph nodes in six, lung six and peritoneal metastases in seven. Seven patients responded partially. Toxicity requiring dose reduction or discontinuation of treatment included neutropenia 42% (grade 3:7%), mucositis 28% (grade 1:2), diarrhea 63% (Grade 3:10%), nausea-vomiting 55% (Grade 3:10%), increased creatinine value in three patients and peripheral neuropathy in two patients. We conclude that evaluation of this regimen shows substantial toxicity, with satisfactory response as a second line chemotherapy in these heavily pretreated patients.
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PMID:5-Fluorouracil, folinic acid and cisplatin in advanced colorectal cancer: a pilot study. 757 65

Neutropenic enteropathy and multiple myeloma. Neutropenic enteropathy (NE) is an acute entity with an aggressive clinical behavior. The most common reported association of NE is with neutropenic children under chemotherapy for leukemias and lymphomas, other less common causes include: neutropenic adults with treatment for autoimmune diseases, aplastic anemia, cyclic benign neutropenia or solid-neoplasms. There are two cases of NE associated to multiple myeloma (MM). There was a 62 year old man with MM diagnosed ten months earlier and under chemotherapy. He developed abdominal pain, nausea, vomiting, diarrhea and rectal bleeding three days before death. The autopsy study revealed ulcers and thickening of the colonic wall in 40% of the entire surface, and in 5% of the ileum. The microscopic analysis revealed mucosal and submucosal ischemic necrosis, and bacterial invasion without acute inflammatory response. As the two previously reported cases, he received vincristine and steroids a few days before developing neutropenia. This report shows the clinical and morphologic findings of the third case of the association of NE and MM, and the first one illustrated in Mexico.
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PMID:[Neutropenic enteropathy associated with multiple myeloma]. 763 36


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