Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer chemotherapy and HIV-1 viral infection (AIDS) can result in respective transient or irreversible losses of up to 40-50% of circulating lymphocytes. The relationship of lymphopenia on tumor immunosurveillance and the control of opportunistic infections has yet to be established. The objective of this study was to characterize the changes in natural killer (NK) and lymphokine activated killer (LAK) cell function associated with cytotoxic drug therapy, breast cancer and HIV-1 infection. NK and LAK activities were measured at multiple effector to target ratios. Exponential regression analysis of target cell lysis determined the maximal % target kill and the lytic potential of effector cells. Flow cytometric analysis of lymphocyte subsets in seropositive populations was performed to determine the % of NK(CD56+) cells. Taken together, our findings indicate that cytotoxic NK pool sizes increased in breast cancer patients, diminish consequent to chemotherapy. The functional capacity of individual NK and LAK cells remains intact. In contrast, the diminution of NK and LAK functional responses in HIV-1 seropositive individuals is associated with reductions in cytotoxic NK and LAK pool sizes, as well as marked reductions in cytolytic function of individual cells. Zidovudine (AZT) treatment did not affect LAK activity in HIV+ subgroups. Our findings indicate that NK and activated LAK functions are affected both by chemotherapy and disease etiology.
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PMID:Different effects of breast cancer, HIV-1 infection and chemotherapy on inducible natural immunity. 815 88

Patients with advanced renal cell carcinoma, previously failed maximal treatment with standard chemo-hormonal-radiation therapies, were treated with plant lectin phytohemagglutinin (PHA)-stimulated autologous peripheral blood lymphocytes in a 10-year study with a 16-year follow up period. In a phase I-II setting, 52 patients were given subcutaneously 40-80 x 10(6) PHA-stimulated lymphocytes weekly for 3 weeks and then escalated to a maximum number of 80 x 10(9) lymphocytes over the next 9 weeks at 3 week intervals. In vitro blastogenesis under study conditions (10 micrograms/ml PHA for 72 hr) measured by [3H]thymidine uptake was optimal with lymphocyte stimulating indexes approaching 300. Lymphocytes obtained from patients with breast cancer, melanoma and renal cell carcinoma responded to PHA similarly to those from normal volunteers. All patients that responded developed erythematous reactions at the sites of injection; malaise, joint paint and chill-fever for 24-48 hr. The patients that responded the best were those with at least 1 positive reaction out of 4 skin tests (tuberculosis, yeast, dermatophytin, mumps) prior to therapy. All toxicity was transient and did not exceed Grade I based on criteria of the Southwest Oncology Group. The majority of patients developed a lymphopenia in the first 24 hr followed by a lymphocytosis 48-72 hr later. For some patients the lymphocytosis was as much as 30% atypical lymphocytes. Of 41 evaluable patients, there were 5 complete responses, 8 partial responses, 3 stable diseases, and 25 progressive disease. The overall response rate was 32% and the median survival was 2.8 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adoptive immunotherapy of advanced renal cell cancer using PHA-stimulated autologous lymphocytes. 826 79

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.
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PMID:Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone. 950 93

BBR 2778 is a novel aza-anthracenedione with no cardiotoxicity in preclinical models. This Phase I dose escalation trial of BBR 2778 was conducted to determine the maximum tolerated dose, the dose-limiting toxicity, and the pharmacokinetic profile of BBR 2778 in patients with advanced solid tumors. BBR 2778 was given in three consecutive weekly 30-min i.v. infusions over a 4-week cycle (cy). Thirty patients (pts) were treated with BBR 2778 at doses ranging from 5 to 150 mg/m2/week. The dose levels 5, 10, 16.5, 25, 37.5, 75, 112.5, and 150 mg/m2/week were investigated in 4 pts (9 cy), 3 pts (3 cy), 3 pts (5 cy), 6 pts (9 cy), 1 pt (1 cy), 4 pts (9 cy), 6 pts (18 cy), and 3 pts (4 cy), respectively. The dose-limiting toxicity was neutropenia, typically occurring at day 14. Other toxicities were mild to moderate and were principally thrombocytopenia, lymphopenia, alopecia, nausea, and vomiting and blue coloration of the skin and urine. No significant cardiac toxicity was observed. The plasma dose concentration curve fitted a biexponential profile, with a rapid distribution phase followed by a prolonged elimination phase (mean t1/2,z, 12 h). BBR 2778 displayed a large volume of distribution (range, 9.7-29.7 l/kg) with a high plasma clearance rate (0.75-1.31 l/h/kg). Less than 10% of the dose was recovered in urine as unchanged drug. The maximum tolerated dose was 150 mg/m2/week for 3 weeks, every 4 weeks. On the basis of this study, the recommended dose for Phase II studies is 112.5 mg/m2/week days 1 and 8 with individual optional administration at day 15, every 4 weeks. Antitumor activity was observed in patients with breast, small cell lung carcinoma, and facial cylindroma. This trial showed that BBR 2778 has a manageable toxicity profile on a weekly schedule. This lead compound of the aza-anthracenedione family shows promising antitumor activity and deserves Phase II investigation in patients with high risk of cumulative cardiotoxicity, such as anthracycline-pretreated breast cancer patients.
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PMID:A phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies. 1120 16

The aim of this study was to evaluate the possible role of apoptosis-related proteins (ARP: Fas and Fas ligand, bcl-2, p53) in the progress of tumorigenesis in breast cancer. Epithelial tumor cells and lymphocytes were analyzed immunohistochemically for the rate of lymphoid infiltration and presence of ARP in 50 human breast tumors of different types. The tumors included: i) fibrocystic disease (n=12); ii) benign fibroadenoma (n=11); iii) carcinoma in situ (n=8); iv) invasive ductal carcinoma with high lymphoid infiltration (n=12); and v) invasive ductal carcinoma with lymphoid depletion (n=7). Both fibrocystic disease and fibroadenomas had low amounts of lymphocytes and very little lymphoid infiltration. In cancer in situ, expansion of lymphoid infiltrates and increased density of lymphocytes resulted in a rise in the total number of lymphocytes, reflecting intensification of the immune response. In carcinomas with high lymphoid infiltration, a significant increase in the number of Fas and FasL and p53-positive cells was found. The number of bcl-2-positive tumor cells in these tumors was not changed, whereas the number of bcl-2-positive lymphocytes decreased. In carcinomas with lymphoid depletion, the opposite picture was found as a result of deep subcompensation of the lymph system. ARP are present in a significantly higher number of lymphocytes than of the epithelial tumor cells. This indicates that the cells initiating apoptosis in tumors are themselves damaged by the process. The intense apoptosis in lymphocytes in malignant tumors may be one of the reasons for the progress of breast tumors.
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PMID:Apoptosis-related proteins (Fas, Fas ligand, bcl-2 and p53) in different types of human breast tumors. 1216 58

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).
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PMID:Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. 1251 69

We studied the safety, activity and peripheral blood progenitor cell mobilizing capability of a dose-dense combination of vinorelbine (VNB) and paclitaxel (PTX) as first-line chemotherapy for patients with metastatic breast cancer (MBC). Forty-three MBC patients were submitted to four cycles of VNB 30 mg/m2 and PTX 175 mg/m2 intravenously, every 2 weeks, as the first induction step of a tandem high-dose chemotherapy program. Granulocyte colony-stimulating factor (G-CSF) 5 microg/kg was administered daily from day +5 to +10 in order to accelerate hematopoietic recovery, or 48h after the last VNB-PTX when a leukapheresis was planned (after the third or fourth cycle). A total of 172 cycles were administered. The mean delivered dose-intensity of VNB and PTX was 14.7 and 86 mg/m2/week, respectively (98% of the planned dose-intensity). The main per-patient toxicities were: peripheral neurotoxicity (G1/2 60%, G3 5%), constipation (G1/2 10%), oral mucositis (G1/2 20%), and asthenia (G1/2 35%). Hematological toxicity was unremarkable, except for anemia with hemoglobin (Hb) values < 10 g/dl (28%), and lymphopenia with lymphocyte counts < 1000/mm3 (28%). Two complete (5.1%) and 24 partial (61.5%) responses were observed in 39 assessable patients, for an overall response rate of 66.6% (95% CI 51.6-80.9). A median of one apheretic procedure (range 1-3) was required to achieve the target number of 6 x 10(6)/kg CD34+ cells. The median number of CD34+ harvested per patient was 15 x 10(6)/kg (range 6.4-36.5). Four cycles of dose dense VNB and PTX showed a favorable toxicity profile, a relevant anti-tumor activity and a high peripheral blood progenitor cell mobilizing activity.
Breast Cancer Res Treat 2003 Dec
PMID:Dose-dense vinorelbine and paclitaxel with granulocyte colony-stimulating factor in metastatic breast cancer patients: anti-tumor activity and peripheral blood progenitor cell mobilization capability. 1470 65

The evidence of lymphocytopenia has been demonstrated to predict a poor prognosis in terms of survival in advanced cancer patients. This finding is not surprising because of the fundamental role of lymphocytes in mediating tumor cell destruction. Despite the importance of lymphocytes in the pathogenesis of cancer, there are only few data about the profile and the function of lymphocytes during the various antitumor therapies, and in particular the relation between lymphocyte pretreatment number and response to chemotherapy remains to be established. The present study was performed to evaluate whether the evidence of lymphocytopenia before the onset of treatment may influence the efficacy of chemotherapy in metastatic cancer patients affected by the most frequent tumor types. The study included 183 patients (lung cancer: 89; colorectal cancer: 63; breast cancer: 31), 95 of whom had been previously treated with chemotherapy. The chemotherapeutic regimens consisted of oxaliplatin plus 5-fluorouracil and folates in untreated colorectal cancer, weekly irinotecan in pretreated colorectal cancer, cisplatin plus gemcitabine or etoposide in untreated lung cancer, weekly vinorelbine in pretreated lung cancer, and taxotere in breast cancer patients who had been previously treated with anthracyclines. Lymphocyte count was considered to be abnormally low for values below 1500/mm3. Lymphocytopenia was found in 79/183 (43%) patients, without any significant differences in relation to tumor histology. A complete response (CR) was achieved in 6/104 patients with a normal lymphocyte count and in none of the 79 lymphocytopenic patients. A partial response (PR) was obtained in 39 patients with a normal lymphocyte count and in only eight patients with a low lymphocyte count prior to therapy. Therefore, irrespective of the type of chemotherapy, the objective tumor response rate (CR + PR) in lymphocytopenic patients was significantly lower than in patients with normal pretreatment lymphocyte counts (8/79 vs 45/104; p < 0.001). This study shows that the evidence of lymphocytopenia prior to chemotherapy is associated with a lower efficacy of treatment in terms of objective tumor regression rates in patients with metastatic solid tumors, and suggests that the action of chemotherapy may depend at least in part on an interaction with the antitumor immunity. Pretreatment lymphocyte count may represent a new, simple biological marker to be taken into consideration by oncologists in the chemotherapeutic treatment of metastatic cancer.
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PMID:Efficacy of cancer chemotherapy in relation to the pretreatment number of lymphocytes in patients with metastatic solid tumors. 1525 46

Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of approximately 10-25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.
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PMID:IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. 1678 2

The purpose of this study was to evaluate the immune status of women with stage I-III breast cancer after receiving external beam radiotherapy (RT). Fourteen stage I-III, estrogen or progesterone receptor-positive or-negative (FER/PR +\-), postsurgical breast cancer patients undergoing a standard course of chemotherapy and radiation were studied. Complete blood counts (CBC) with differential, phagocytic activity, natural killer (NK) cell functional activity, and tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma cytokine activity were measured immediately before and for the six weeks following the completion of radiation therapy. Fatigue levels after completion of RT were measured using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Nonparametric statistical methods (Wilcoxon rank and Spearman correlations) were used to analyze the data. Compared with postchemotherapy, following the completion of RT, these breast cancer patients showed lymphopenia, low functional activity of natural killer lymphocytes, decreased monocyte phagocytic activity, and decreased TNF-alpha production but no neutropenia, no anemia, and no change in interferon-gamma production. Lymphocyte count did not return to normal by the end of the 6-week post-RT observation period. The severity of lymphopenia and low natural killer cell activity was related to RT area but not radiation dose. Patients did not report significant fatigue levels for the 6 weeks after completing RT. Significant decreases in the numbers and functions of cells from both the innate and adaptive immune system were detected following a standard course of radiation therapy for the treatment of breast cancer. Immune deficits in lymphocyte populations and TNF-alpha production, should they persist, may have consequences for immune response to residual or recurrent malignancy following completion of conventional treatment. The use of adjunctive immune therapies which target these specific defects may be warranted in the post-treatment period.
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PMID:Immune defects in breast cancer patients after radiotherapy. 1908 68


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