Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In 20 patients with non-Hodgkin lymphoma or breast cancer, high-dose cyclophosphamide induced, during the post-nadir period of rapid leucocyte recovery, on median day 19 about a 30-fold increase in the peak concentration of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells, and an even higher increase in the more immature pluripotent progenitors (CFU-Mix, 72-fold). After infusion of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), peak concentration was reached earlier (median day 15) and with further enhancements (159, 116 and 283-fold respectively, in the number of CFU-GM, BFU-E and CFU-Mix). Most CFU-GM were immature, lacking the differentiation antigen CD15, and gave rise to large myeloid colonies, reflecting a high proliferative capacity of the founder cells. Very immature maphosphamide-resistant progenitors were detectable. The marked expansion in the circulating pool was predictable and reliable, allowing harvesting, after two or three leukaphereses, of sufficient haematopoietic progenitors for autologous bone-marrow reconstitution.
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PMID:Peripheral blood expansion of early progenitor cells after high-dose cyclophosphamide and rhGM-CSF. 182 35

Activation of ras protooncogenes by any of several possible mutations in codons 12, 13 or 61 has been demonstrated in a variety of human malignancies, including acute non-lymphoblastic leukemia (ANLL). In situ staining for the ras gene product, p21, has been demonstrated in carcinomas of several sites. High levels of p21 expression have been associated with histologic anaplasia in prostate cancer and regional lymph node metastasis in breast cancer. We examined 16 marrow aspirates and blood smears from patients with acute leukemia, predominantly ANLL, and eight controls. Marrow aspirates or blood were smeared on glass slides and fixed immediately in 10% buffered formalin. p21 was examined with avidin-biotin linked immunoperoxidase visualization. Particular attention must be paid to antibody selection and fixation protocol to demonstrate p21, owing to its rapid degradation ex vivo. Three of 16 patients exhibited occasional high p21 expression primarily in leukemic blasts, but in no case were more than 10% of blast cells positive. Normal reticuloendothelial and myeloid cells occasionally exhibited mild to moderately heavy staining, but megakaryocytes, erythroid precursors, lymphocytes and plasma cells were consistently negative. Most patients, 5 normal volunteers and 3 patients with non-malignant disease, exhibited no reactivity, or only a faint blush. These data suggest that while point mutation and concomitant activation of c-N-ras occurs regularly in ANLL, high levels of ras p21 expression are rarely found with this technique.
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PMID:Ras gene product expression in blood and marrow smears of patients with acute leukemia: importance of fixation. 223 1

A human in vivo somatic cell assay based on the enumeration of variant erythrocytes lacking expression of an allelic form of the cell-surface sialoglycoprotein, glycophorin A, was applied to the study of blood samples from patients obtained prior to, during, and following chemotherapy for malignant disease in order to determine the effect of mutagenic chemical agents on the frequency of variant cells. In 22 patients assayed prior to therapy, the mean variant cell frequency was 11.9 per million, which was not significantly different from that observed in healthy controls. In an initial cross-sectional survey, blood samples were obtained at various times during and after therapy from 30 patients diagnosed with a variety of malignancies who were treated with one or more known mutagenic agents including adriamycin, bleomycin, cis-platinum, cyclophosphamide, dacarbazine, etoposide, lomustine, mechlorethamine, melphalan, mitomycin C, and procarbazine. Significant elevations in the mean frequency of variant cells over pre-therapy and normal levels were observed in samples obtained during and after therapy. In a time-series study, 14 breast cancer patients treated with CAF (cyclophosphamide, adriamycin, 5-fluorouracil), CMF (cyclophosphamide, methotrexate, 5-fluorouracil), or VMF (vinblastine, methotrexate, 5-fluorouracil) adjuvant chemotherapy were sampled repeatedly during and after therapy. For the CAF and CMF patients an increase in the frequency of variant cells was observed with a lag in the appearance of induced variants after initiation of therapy; variant frequencies gradually increased during therapy reaching a maximum at or shortly after the end of therapy, then declined to near pre-therapy levels within 6 months. The maximum level of induced variants ranged from 2- to 7-fold over pre-therapy or normal levels depending on the combination of agents used. The breast cancer patients treated with both adriamycin and cyclophosphamide showed consistent elevations in the frequency of variant cells; patients treated only with cyclophosphamide showed lower and more variable elevations. The data demonstrate that mutagenic chemotherapy agents induce elevated levels of glycophorin A variant erythrocytes consistent with the hypothesis that variant cells result from somatic mutation. The elevations in variant cells were transient, suggesting that these agents primarily affect the rapidly cycling committed erythroid cell population.
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PMID:The effect of chemotherapy on the in vivo frequency of glycophorin A 'null' variant erythrocytes. 231 10

Twenty percent (n = 6) of Stage III or IV breast cancer patients (n = 30) had bone marrow metastases detected in bilateral bone marrow biopsy/aspiration preparations using standard histologic preparations. Each metastasis was also detected by four separate monoclonal antibodies (MAbs) which recognize breast carcinoma associated antigens (DF3, anti-EMA, HMFG-2, and CAM5.2). These MAbs were then utilized to stain other bone marrow preparations (n = 81) to determine their utility for the detection of micrometastatic breast carcinoma. MAbs HMFG-2, anti-EMA, and DF3 were each strongly reactive with bone marrows containing histologically-evident metastatic breast carcinoma (18/18). These anti-epithelial membrane antigen MAbs, however, were also reactive with rare plasma cells and immature cells (as well as cell clusters) in some of the control bone marrow samples tested, including those from normal patients and patients with hematologic disorders. They also reacted with some of the preparations from patients with leukemia and lymphoma, and with uninvolved marrows from patients with non-epithelial malignancies. The anti-keratin MAb CAM5.2, in contrast, reacted with 83% (15/18) breast cancer metastases and failed to stain any cells in the various categories of control marrow preparations. These data suggested that MAb CAM5.2 might be utilized to immunohistochemically differentiate micrometastatic breast carcinoma from immature myeloid or erythroid elements. Each MAb was then reacted with histologically uninvolved marrow preparations from the remaining 24 of 30 breast cancer patients in an attempt to identify occult breast carcinoma metastases. While MAbs HMFG-2, DF3, and anti-EMA demonstrated reactive cells in some of these marrows, this reactivity was similar to that seen with control preparations. MAb CAM5.2, in contrast, was negative with all specimens. These data suggest that MAb CAM5.2 may be a useful immunologic probe for the detection and confirmation of metastatic breast carcinoma in bone marrow, while more caution must be employed in the interpretation of results obtained using MAbs anti-EMA, DF3, and HMFG-2.
Breast Cancer Res Treat 1988 May
PMID:Comparison of monoclonal antibodies for the detection of occult breast carcinoma metastases in bone marrow. 245 2

Monoclonal antibodies which bind to breast cancer have been used to evaluate the detection of metastatic disease in axillary lymph nodes. Three monoclonal antibodies (H59, H71, and H72) were reacted with tissue sections of primary tumors and axillary nodes from 24 mastectomy specimens and four specimens from glandular mastectomies for benign disease. All three antibodies had been shown to react with subsets of normal and malignant breast tissue; did not bind erythroid, myeloid, or lymphoid tissue; and recognized antigens in paraffin-embedded tissue. The antibodies recognized cell surface antigens, and H59 and H72 bound to glycoproteins which are either sloughed or secreted. Primary tumors and tumors in lymph nodes from the same specimen were always bound by the same antibodies. Antibodies detected unrecognized microscopic tumor in nodes from one previously node-negative specimen and two specimens with positive nodes. This suggests that monoclonal antibodies may be useful for detecting metastatic breast cancer in nodes which by light microscopy are negative. Moderate binding of H59 and H72 antibodies to sinus histiocytes and perivascular cells was observed in all uninvolved nodes with sinus hyperplasia obtained from benign and malignant specimens. Thus, breast antigens can be identified in hyperplastic nodes in patients with no evidence of breast cancer. The antigens are detected predominately in the lymphoid sinuses and are bound to nonneoplastic cells. Therefore, breast antigens are regularly being processed and presented by normal lymphoid cells within the sinus. The binding of these monoclonal antibodies to axillary lymph nodes does not necessarily indicate the presence of metastatic disease. Dense binding to paracortical single cells was observed in tumor-containing lymph nodes and in uninvolved nodes obtained from mastectomy specimens with breast cancer. These cells are infrequent, and their number in an uninvolved node correlates with the pathological stage. They represent either binding to isolated lymphoid cells or metastatic tumor. Studies are under way to determine the origin of these cells.
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PMID:Presence of breast cancer antigens in uninvolved axillary lymph nodes. 400 59

We examined the effects of recombinant human interleukin 11 (rhIL-11) on in vivo human hematopoiesis. Twelve women with advanced breast cancer and no evidence of bone marrow (BM) involvement were treated with 10, 25, 50, or 75 micrograms/kg/day of rhIL-11 administered subcutaneously for 14 consecutive days. Examination of bone marrow trephine biopsies obtained before and after rhIL-11 treatment revealed unchanged BM cellularity at all doses, and a statistically significant increase in megakaryocyte (MK) frequencies (from 0.5 +/- 0.1% to 1.0 +/- 0.3%) following administration of the two highest doses (p < 0.001). The BM biopsies also showed an increased proportion of immature myeloid and erythroid precursors following 14 days of treatment in all cases. The mean proportion of marrow cells stained with PC10, a monoclonal antibody (mAb) that recognizes the proliferating cell nuclear antigen (PCNA), increased from 16.3 +/- 5.7% to 45.8 +/- 17.1% (p < 0.001) following the two highest treatment doses. Most of the PC10+ cells were promyelocytes and proerythroblasts. In this same group, the proportion of PC10+ MKs increased from 28.3 +/- 11.5% to 56.8 +/- 24.3% (p < 0.01) after treatment, while megakaryocyte ploidy analysis revealed a greater number of higher ploidy (64N) megakaryocytes following rhIL-11 treatment (p < 0.012). Numbers of BM and peripheral blood (PB) CD34+, CD34+DR+, and CD34+DR- cells did not change following rhIL-11 treatment. Following rhIL-11 therapy at the highest dose studied, a 3- and 10-fold increase in the number of committed BM MK progenitor cells (CFU-MK) was observed in two of three patients, while no change was seen in the number of the other BM or PB progenitor cells examined. rhIL-11 administration was also associated with an increase in BM reticulin content (fibrosis grade 1-2) in 7 patients. These results indicate that the administration of rhIL-11 to patients with normal hematopoiesis stimulates MK endoreduplication, PCNA expression, and, at high doses, increases MK and CFU-MK progenitor cell numbers. In addition, rhIL-11 was able to stimulate precursor cells of different marrow lineages without affecting the number of assayable progenitor cells.
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PMID:Effects of recombinant human interleukin-11 (Neumega rhIL-11 growth factor) on megakaryocytopoiesis in human bone marrow. 886 39

The effect of granulocyte-macrophage colony stimulating factor (GM-CSF) on reticulocytes, haemoglobin and haematocrit levels of patients receiving chemotherapy for solid tumours was assessed. Forty-two patients were randomized into two groups who either did or did not receive GM-CSF 300 U/d on days 8 and 15 post-chemotherapy for neutropenia prophylaxis. Patients were stratified according to tumour type (non small-cell lung cancer, small-cell lung cancer, ovarian and breast cancer). Eight patients with progressive disease were excluded. The 34 patients evaluated completed six chemotherapeutic cycles of 21 days. They did not receive transfusions or erythropoietin. The estimated dose intensities (mg/m2/d) for each drug used were significantly higher in the group on GM-CSF compared to the group without. Haemoglobin and haematocrit were measured by the H * 1 (Bayer) haematology analyser and reticulocyte counts by the flow-cytometric reticulocyte analyser, R-1000 (Sysmex). Measurements were conducted on days 1 and 12 of every cycle for six cycles. At the beginning of therapy there were no significant differences between the two groups. However, red cell and reticulocyte counts fell significantly in the group without GM-CSF compared to the group on GM-CSF. Reticulocyte differences preceded those of haemoglobin and haematocrit. The data indicate a positive in vivo effect of GM-CSF on the erythroid tissue of patients receiving chemotherapy for solid tumours.
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PMID:The effect of GM-CSF on reticulocytes, haemoglobin and haematocrit in patients receiving chemotherapy for solid tumours. 911 14

Interleukin (IL)-3 is a multipotent hematopoietic growth factor produced by activated T cells, monocytes/macrophages and stroma cells. The human IL-3 gene is located on chromosome 5 near segment 5q31. The high-affinity receptor for human IL-3 is composed of alpha and beta subunits. IL-3 shares a common beta subunit with granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-5; this subunit has been mapped to chromosome 22q13.1. The biological effects of IL-3 have been studied in human and murine hematopoietic cell lines and normal human marrow cells. Addition of IL-3 to the culture medium induces proliferation, maturation and probably self-renewal of pluripotent hematopoietic stem cells and cells of myeloid, erythroid and megakaryocytic lineages. Human IL-3 was cloned in 1986, and since then various clinical trials have assessed the in vivo potential of recombinant human (rhIL-3). Initial results of phase I/II studies of IL-3 at a dose of 5-10 microg/kg subcutaneously daily for 5-10 days in patients with relapsed lymphomas, small-cell lung cancer, breast cancer and ovarian cancer showed that post-chemotherapy application of IL-3 reduces chemotherapy delays and induces faster regeneration of granulocytes and platelets. However, these results were not confirmed in phase III studies. The role of IL-3 alone in the treatment of myelodysplastic syndromes (MDS), aplastic anemia (AA) and other bone marrow failure disorders have also been disappointing. However, preliminary studies of IL-3 in combination with chemotherapeutic agents and immunosuppression have demonstrated encouraging results in patients with MDS and AA respectively. The therapeutic potential of IL-3 in peripheral blood stem cell (PBSC) harvesting and priming of stem cells before harvest is beginning to be identified. Initial results of IL-3 combination with GM-CSF or later-acting growth factors such as granulocyte colony-stimulating factor (G-CSF) have yielded larger amounts of PBSC during harvesting. In recent years, the availability of synthetic IL-3 receptor (IL-3R) agonists and similar chimeric molecules with greater in vitro biological activity and fewer inflammatory side-effects has extended our options to employ and compare these molecules and rhIL-3 for the prevention of chemotherapy-induced myelosuppression. The role of IL-3 and IL-3R agonists in ex vivo expansion of stem cells, dendritic cell development and gene transfer requires further evaluation. It appears that future application of IL-3 in combination with other cytokines is an attractive way forward in the prevention of treatment-related mortality and morbidity in oncology patients. It also shows prospects for the development of new therapeutic strategies for dose escalation and immune modulation for cancer patients with relapsed and resistant disease.
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PMID:Interleukin-3 in hematology and oncology: current state of knowledge and future directions. 1051 81

A series of novel nitroheterocyclic phosphoramidates has been evaluated for antitumor activity in murine and xenograft tumor models and for toxicity in mice. Significant increases in lifespan and long-term survivors were noted in L1210 leukemia and B16 melanoma models, and both complete and partial tumor regressions were observed in the MX-1 breast cancer xenograft model. All compounds exhibited some degree of toxicity to granulocyte/macrophage progenitors in the bone marrow of mice. Two drugs were selected for further toxicologic, histopathologic, and pharmacokinetic evaluations. Toxicity of potential clinical significance was observed only in the bone marrow at the highest drug dose; otherwise no significant abnormalities in blood chemistries or organ histopathology were noted. The bone marrow lesions consisted of reduced numbers of progenitor cells in the myeloid and erythroid series; platelets were not affected. The compounds were eliminated rapidly by first-order kinetics, with half-lives in the 4-12 min range. The best of these compounds exhibits excellent antitumor activity and minimal toxicity at therapeutically effective doses in mice.
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PMID:Antitumor activity and toxicity of novel nitroheterocyclic phosphoramidates. 1114 Oct 90

Administration of stem cell factor (SCF) has been proven to enhance cytokine-induced mobilization of CD34+ hematopoietic progenitor cells (HPC) into the peripheral blood (PB). The aim of the present study was to explore in a homogeneous group of 22 uniformly treated breast cancer patients: (1) the kinetics of mobilization into PB of both CD34+ and CD34- cell subsets, including dendritic cells, in sequential samples obtained from day +7 up to day +12 after mobilization; and (2) the composition of the CD34+ and CD34- cell subsets present in the two leukapheresis products obtained for each patient. The following CD34+ and CD34- subsets were analyzed: early CD34+ HPC, erythroid-, myeloid- and B-lymphoid-committed CD34+ precursor cells, mature T, B and NK cells, monocytes, neutrophils, eosinophils, basophils, and dendritic cells (DC) including three subsets of lin-/HLADR+DC (CD16+, CD33high and CD123high). Our results show that the absolute number of PB CD34+ HPC progressively increases from day +7 onwards. As far as the CD34- PB leukocyte subsets are concerned, monocytes (CD14+) displayed the earliest recovery after mobilization predicting neutrophil recovery 1 day in advance. The number of CD34+ HPC collected in a single leukapheresis product was always > or = 1.4 x 10(6) cells/kg body weight. No significant changes were observed between the two leukapheresis sessions either as regards their composition in CD34+ HPC subsets or their CD34- leukocyte populations except for a higher ratio of both CD34+ erythroid/CD34+ myeloid HPC (0.35 +/- 0.13 vs 0.30 +/- 0.13; P = 0.04) and neutrophils/monocytes (1.58 +/- 2.1 vs 0.69 +/- 0.27; P = 0.009) found for the first leukapheresis. Interestingly, the overall number of dendritic cells (DC) was higher in the second leukapheresis (1.06 +/- 0.56 vs 1.9 +/- 0.46; P = 0.02) due to a selective increase of the CD16+ antigen-presenting cells. In summary, our results show that the combination of cyclophosphamide, G-CSF and SCF is highly effective for stem cell mobilization, with differences observed in the mobilization kinetics of the different hematopoietic cell subsets analyzed.
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PMID:Sequential analysis of CD34+ and CD34- cell subsets in peripheral blood and leukapheresis products from breast cancer patients mobilized with SCF plus G-CSF and cyclophosphamide. 1123 67


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