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)

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.
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PMID:A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer. 151 22

We have evaluated the effect of Interleukin-2 [IL-2] after Cyclophosphamide (C) chemotherapy in 41 patients with metastatic cancer. IL-2 was given as a continuous infusion priming cycle 36 hours after C at 1 gm/m2 intravenously. In 39 evaluable patients, there were no complete remissions [CR], 2 partial remissions [PR], and 1 had a minor response [MR]. Stable disease for 30 days was seen in 16 patients whereas 20 progressed. The durations of partial and minor responses were brief, ranging from 1-6 months. Grade 3-4 neutropenia was seen in 41%. This was more severe than seen with IL-2 alone or IL-2 combined with lower doses of C. The marrow suppression was due to the chemotherapy. This combination of IL-2 and C appears to be reasonably well tolerated by patients, but toxicity is greater and the response rate is no better than results achieved by IL-2 alone. Responses of 26 patients with renal cancer appear to be inferior to our historical data using IL-2/LAK cells without C. Immune monitoring demonstrated changes expected with C chemotherapy (i.e., a non-selective decline in immune function). C induced no further differences in IL-2 induced changes in immune function.
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PMID:Continuous infusion of interleukin-2 and cyclophosphamide as treatment of advanced cancers: a National Biotherapy Study Group Trial. 191 Jun 23

In this study, recombinant human IL-1 alpha (rhIL-1 alpha) was used to protect normal and tumor-bearing BALB/c mice from the acute toxicity caused by lethal doses of cyclophosphamide (Cy) and 5-fluorouracil. Pretreatment of mice for 7 days with 10,000 U/day of rhIL-1 alpha protected 70 to 100% of mice from the acute death induced by lethal doses of both Cy (380 mg/kg) and 5-fluorouracil (250 mg/kg). In contrast, post-treatment of mice with single or multiple doses of rhIL-1 alpha was not chemoprotective. Pretreatment of mice with rhIL-1 alpha increased the acute LD90 of Cy from 380 mg/kg to greater than 500 mg/kg in normal mice, an LD90 dose-modifying effect of at least 1.25, was accompanied by a more rapid recovery from neutropenia and a less severe reduction in the number of bone marrow single lineage monocyte, myeloid, or myelomonocytic colonies. Some of the mice (10 to 50%) that were successfully protected by pretreatment with rhIL-1 alpha died after day 50. These mice consistently presented with extensive pulmonary inflammation and fibrosis at death. Mice bearing murine renal cancer (Renca) were also protected from the acute toxic effects of Cy (450 mg/kg) by pretreatment with rhIL-1 alpha. Renca-bearing mice pretreated with rhIL-1 alpha and either sublethal (300 mg/kg) or lethal (450 mg/kg) doses of Cy exhibited enhanced survival times over those of untreated Renca-bearing mice. Interestingly, the cause of death in Renca-bearing mice that ultimately failed treatment with rhIL-1 alpha plus 300 mg/kg Cy was recurrent tumor, whereas most mice treated with rhIL-1 alpha plus 450 mg/kg Cy had no detectable tumor, although several died from late pulmonary inflammation and fibrosis. Thus, the dose escalation of Cy in rhIL-1 alpha-pretreated mice results in greater antitumor effects of Cy. However, the dose escalation of some cytotoxic agents allowed by the use of myelostimulatory agents can result in late fatal complications not detected in acute toxicity testing.
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PMID:Chemoprotective effects of recombinant human IL-1 alpha in cyclophosphamide-treated normal and tumor-bearing mice. Protection from acute toxicity, hematologic effects, development of late mortality, and enhanced therapeutic efficacy. 225 10

Paclitaxel is an antineoplastic agent, first isolated and described in 1971. Despite its novel structure and apparent activity in vitro, little interest was shown in developing the compound because of its scarcity, problems with its formulation and the mistaken assumption that its mechanism of action was similar to that of the vinca alkaloids. Approximately 10 years later, the unique mechanism of action of paclitaxel, its ability to stabilise microtubules, was discovered, and its activity against human tumour xenografts was demonstrated. Interest in the drug was reignited and clinical testing began. Severe hypersensitivity reactions were controlled in the phase II programme with a premedication regimen consisting of dexamethasone, histamine H1-antagonists and H2-antagonists. Neutropenia was dose limiting in all studies conducted in patients with solid tumours. This toxicity was schedule-dependent, and less severe when paclitaxel was administered as a 3-hour infusion regimen. Peripheral neuropathy was mild to moderate in the initial experience, and dose-dependent. However, when bone marrow support with haemopoietic growth factors was used to allow paclitaxel dose intensification, neurotoxicity became dose limiting. To date, substantial clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancers. Response rates were low in initial studies in melanoma, prostate, colon, cervix and renal cancer. In December 1992, US Food and Drug Administration approval was granted for the use of paclitaxel as second-line therapy in ovarian cancer patients. More recently, similar approval was granted for use in recurrent breast cancer. Nevertheless, important questions remain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A preliminary risk-benefit assessment of paclitaxel. 761 31

Eighty patients with measurable metastatic colon or renal cancer, melanoma, or sarcoma entered these Phase II studies. A dose of 25 mg/m2/day of Pirarubicin (THP) for 3 consecutive days every 4 weeks for the first patients, and then 20 mg/m2/day for 3 days every 3 weeks was given by i.v. push. These patients received 225 cycles for a median cumulative dose of 165 mg/m2 (range: 55-630). The mean number of cycles given was 2.8 (range: 1-8). Only 3 partial responses and 18 stable disease (22%) were observed. Hematologic toxicity was the main problem; it was responsible for one death and a 19% and 44% incidence of grade 3 and 4 WHO neutropenia, respectively. Alopecia was rare (4%). Chemotherapy was discontinued in three cases because of suspicion of cardiac toxicity, but only one patient had a significant drop in left ventricular ejection fraction at a cumulative THP dosage of 120 mg/m2. A lack of efficacy in renal and colon cancer and melanoma was presupposed and confirmed by these trials. Due to pretreatment with anthracycline in most patients, definite evaluation of THP in soft tissue sarcoma could not be given.
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PMID:Phase II trials of tetrahydropyranyl-adriamycin (Pirarubicin) on renal and colon carcinoma, melanoma, and soft tissue sarcoma. 845 5

Pyrazine diazohydroxide (PZDH) is a novel antitumor agent that forms DNA adducts via the reactive pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al, Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in renal cancer (15 patients, 2 with liver metastases) and in 5-fluorouracil-refractory colorectal cancer (14 patients, 13 with liver metastases) to determine efficacy in each disease and to correlate safety and tolerance of the drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either tumor type. The primary toxicity of PZDH was myelosuppression with neutropenia (absolute neutrophil count, < 1000/microl) and thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum chloride or blood pH levels. The colorectal patients experienced significantly more thrombocytopenia than did the renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior 5-fluorouracil and leucovorin reduced bone marrow reserve or that colorectal patients with liver metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum chloride and thrombocytopenia. Curiously, an increase in alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an antineoplastic agent, further studies of these relationships are suggested.
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PMID:Phase II and pharmacodynamic studies of pyrazine diazohydroxide (NSC 361456) in patients with advanced renal and colorectal cancer. 956 86

A Phase I dose escalation trial of i.v. administered recombinant human interleukin 12 (rhIL-12) was performed to determine its toxicity, maximum tolerated dose (MTD), pharmacokinetics, and biological and potential antineoplastic effects. Cohorts of four to six patients with advanced cancer, Karnofsky performance >/=70%, and normal organ function received escalating doses (3-1000 ng/kg/day) of rhIL-12 (Genetics Institute, Inc.) by bolus i.v. injection once as an inpatient and then, after a 2-week rest period, once daily for five days every 3 weeks as an outpatient. Therapy was withheld for grade 3 toxicity (grade 4 hyperbilirubinemia or neutropenia), and dose escalation was halted if three of six patients experienced a dose-limiting toxicity (DLT). After establishment of the MTD, eight more patients were enrolled to further assess the safety, pharmacokinetics, and immunobiology of this dose. Forty patients were enrolled, including 20 with renal cancer, 12 with melanoma, and 5 with colon cancer; 25 patients had received prior systemic therapy. Common toxicities included fever/chills, fatigue, nausea, vomiting, and headache. Fever was first observed at the 3 ng/kg dose level, typically occurred 8-12 h after rhIL-12 administration, and was incompletely suppressed with nonsteroidal anti-inflammatory drugs. Routine laboratory changes included anemia, neutropenia, lymphopenia, hyperglycemia, thrombocytopenia, and hypoalbuminemia. DLTs included oral stomatitis and liver function test abnormalities, predominantly elevated transaminases, which occurred in three of four patients at the 1000 ng/kg dose level. The 500 ng/kg dose level was determined to be the MTD. This dose, administered by this schedule, was associated with asymptomatic hepatic function test abnormalities in three patients and an onstudy death due to Clostridia perfringens septicemia but was otherwise well tolerated by the 14 patients treated in the dose escalation and safety phases. The T1/2 elimination of rhIL-12 was calculated to be 5.3-9.6 h. Biological effects included dose-dependent increases in circulating IFN-gamma, which exhibited attenuation with subsequent cycles. Serum neopterin rose in a reproducible fashion regardless of dose or cycle. Tumor necrosis factor alpha was not detected by ELISA. One of 40 patients developed a low titer antibody to rhIL-12. Lymphopenia was observed at all dose levels, with recovery occurring within several days of completing treatment without rebound lymphocytosis. There was one partial response (renal cell cancer) and one transient complete response (melanoma), both in previously untreated patients. Four additional patients received all proposed treatment without disease progression. rhIL-12 administered according to this schedule is biologically and clinically active at doses tolerable by most patients in an outpatient setting. Nonetheless, additional Phase I studies examining different schedules and the mechanisms of the specific DLTs are indicated before proceeding to Phase II testing.
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PMID:Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. 981 99

We performed a phase I study combining gemcitabine and interferon (IFN)- 2b in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and recommended doses for phase II trials. Five dose levels of gemcitabine (mg/m )/IFN- (x10 IU) were planned: 500/5, 1000/5, 1000/7, 1000/10 and 1200/10. Gemcitabine was given once weekly and IFN 3 x weekly for 3 consecutive weeks followed by 1 week of rest (28-day cycles). Between February 1997 and June 1999, 21 patients with advanced pancreatic ( =3), ovarian ( =1), renal ( =10) and non-small cell lung cancer (NSCLC; =7) were enrolled. The MTD was reached at gemcitabine 1000 mg/m and IFN- 7 x 10 IU, with two of three patients having dose-limiting toxicity (thrombocytopenia). The predominant hematologic toxicities (grade 3/4) were neutropenia and thrombocytopenia (13 and five patients, respectively). Three patients had moderate neutropenic fever and one had grade 4 AST/ALT; none required hospitalization. Of the 18 evaluable patients, responses included one partial response (NSCLC) and 10 stable diseases (eight renal cancer). We conclude that the recommended phase II study regimen is gemcitabine 1000 mg/m and IFN- 5 x 10 IU, every 28 days. The results, particularly those in metastatic renal carcinoma, are encouraging and worthy of further evaluation in phase II trials.
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PMID:Gemcitabine and interferon-alpha 2b in solid tumors: a phase I study in patients with advanced or metastatic non-small cell lung, ovarian, pancreatic or renal cancer. 1239 52

Triapine is a novel small molecule ribonucleotide reductase inhibitor that showed activity in renal cell carcinoma (RCC) cell lines. Evaluating new agents with novel mechanisms remains of interest for patients with incurable RCC. This was a single-arm, multicentre phase II trial where Triapine was given at a schedule of 96 mg/m2 2-h infusion daily x 4 repeated every 2 weeks in patients with recurrent RCC. A median of four cycles of Triapine was administered to 19 eligible patients. One response was seen (7%.) Median time to progression was 3.6 months. Common adverse events (AEs) were grade 1-2, with fatigue in 74%, nausea in 68% and vomiting in 58%. However grade 3/4 neutropenia was seen in 79% and acute reactions of hypoxia, hypotension, methemoglobinemia were seen. Dose reductions/delays due to AEs were common with only 47% of patients receiving > 90% of planned dose intensity. The study closed, at the end of stage 1 as it did not meet the minimal efficacy criteria to proceed. Further evaluation of Triapine at this dose and schedule in patients with advanced kidney cancer is not recommended.
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PMID:Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). 1739 73

Polymeric micelles are ideally suited to exploit the EPR effect, and they have been used for the delivery of a range of anticancer drugs in preclinical and clinical studies. NK012 is an SN-38-loaded polymeric micelle constructed in an aqueous milieu by the self-assembly of an amphiphilic block copolymer, PEG-PGlu(SN-38). The antitumor activity was evaluated in several orthotopic tumor models including glioma, renal cancer, stomach cancer, and pancreatic cancer. Two independent phase I clinical trials were conducted in Japan and the USA. In the preclinical studies, it was demonstrated that NK012 exerted significantly more potent antitumor activity with no intestinal toxicity against various orthotopic human tumor xenografts than CPT-11. In clinical trials, predominant toxicity was neutropenia. Non-hematologic toxicity, especially diarrhea, was mostly Grade 1 or 2 during study treatments. Total 8 partial responses were obtained. According to data of preclinical studies, NK012 showing enhanced distribution with prolonged SN-38 release may be ideal for cancer treatment because the antitumor activity of SN-38 is time dependent. Clinical studies showed that NK012 was well tolerated and had antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing in patients with colorectal cancer in Japan and in patients with triple negative breast cancer and small cell lung cancer in the USA.
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PMID:Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. 2056 51


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