Chemotherapy use and risk of bone marrow suppression in a large population-based cohort of older women with breast and ovarian cancer
ABSTRACT We studied 65,521 women with breast cancer and 7,420 women with ovarian cancer aged ≥ 65 identified from the 16 areas of the Surveillance, Epidemiology and End Results program linked with Medicare data during 1991-2002. Bone marrow toxicity associated with chemotherapy was defined using diagnosis codes from Medicare inpatient, outpatient and physician claims. The time to event Cox regression was utilized to estimate the risk of bone marrow toxicity. Use of anthracyclines, taxanes or platinums was associated with increased risks of short- (≤3 months) and long-term (>3 months) anemia and neutropenia in patients with breast cancer. Alkylating agents or antimetabolites were additional significant predictors of anemia in women with ovarian cancer. Patients who received chemotherapy (irrespective of regimens) were twice (breast cancer) or three times (ovarian cancer) as likely to develop thrombocytopenia compared to those not receiving chemotherapy. Among women with breast cancer, patients receiving cyclophosphamide, methotrexate and fluorouracil regimens (hazard ratio=19.0, 95% CI=11.2-32.5), platinum/taxane therapy (21.9, 11.9-40.4) or the cyclophosphamide, adriamycin and fluorouracil regimen (32.5, 19.6-53.9) were strongly associated with risk of aplastic anemia. There was a dose-response relationship between the use of taxane or platinum and the risk of bone marrow suppression, whereas the increased risk of bone marrow toxicity was consistently higher in those with use of alkylating agents or anthracycline-based regimens irrespective of the increasing number of cycles received. In conclusion, there was an association between chemotherapy use and clinical manifestations of bone marrow toxicities in a population-based setting.
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ABSTRACT: This study examined the effects of daunorubicin and glutaraldehyde on some parameters of erythrocytes. The aim of the article was to present the results of research aiming to identify the level of glutaraldehyde at which the hemoglobin oxidation, externalization of phosphatidylserine and the changes in the viability (hemolysis) of erythrocytes are not statistically significant and therefore this level of glutaraldehyde can be used for the drug carriers' preparation. Glutaraldehyde was used as a crosslinking agent to enhance the uptake of the drug within red blood cells and to prevent its leakage from the cells. Fluorescence microscopy, flow cytometry and fluorimetric measurements confirmed higher levels of the drug in glutaraldehyde-treated human erythrocytes. Unfortunately, substantial damage to the red blood cells was also noted. DNR increased oxidative processes in the cell, which in turn led to an increase in the reactive oxygen species (ROS) level. When the red blood cells were also treated with glutaraldehyde, ROS production was significantly higher. We also observed loss of both the reduced and the total glutathione. Moreover the decreased activity of glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) was also observed. As hemoglobin, the erythrocytes' main component plays an essential role in the erythrocytes, the level of its oxidized form (metHb) in the erythrocytes and the phosphatidylserine exposure on the erythrocyte surface were also investigated. When higher concentrations of glutaraldehyde (0.0025-0.005%) were used for the uptake of DNR the elevated level of metHb was observed. Only at 0.0005% the level of oxidized form of Hb was within the physiological level and at that level the increase in the exposure of phosphatidylserine at the cell surface was not observed to be statistically significant. Moreover the percent of released hemoglobin was less than 1%. Based on these results it was concluded that glutaraldehyde can be used as a cross-linker between the drug (DNR) and the erythrocytes only at low concentration of about 0.0005%.04/2013; 36(1):171-181. DOI:10.1016/j.etap.2013.03.020
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ABSTRACT: Epothilones are a new group of compounds with action mechanisms similar to taxanes. The aim of this study was to compare the effects of epothilone A (Epo A) and epothilone B (Epo B) on ovarian cancer cell line SKOV-3 with those of paclitaxel (PTX), a classic taxane. We evaluate glycoprotein P (P-gp) activity in the ovarian cancer cell line. Apoptotic and necrotic cell levels were measured by double staining with Hoechst 33258 and propidium iodide (PI) as well as Annexin V staining. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential (ΔΨm) in cells exposed to Epo A, Epo B and PTX were studied using specific fluorescence probes, DCFH(2)-DA (2',7'-dichlorodihydrofluorescein diacetate) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine). The cytotoxic activity of the drugs was determined by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) test. All probes were analyzed in both the presence and absence of the antioxidant N-acetylcysteine (NAC). The results obtained demonstrated that the antiproliferative capacity of Epo A and Epo B in SKOV-3 cell line (measured as IC(50) after 72h continuous treatment) was six and five times greater than that of PTX's respectively. Epothilones induced timecourse-dependent apoptosis and necrosis. Apoptotic and necrotic events were partially blocked by NAC, indicating ROS played a substantial role in epothilone-induced apoptosis. Cell death was also associated with a decrease in mitochondrial membrane potential, which was more pronounced after treatment with epothilones as compared to paclitaxel.Toxicology in Vitro 09/2012; 27(1). DOI:10.1016/j.tiv.2012.09.006 · 3.21 Impact Factor
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ABSTRACT: Myelosuppression and drug resistance are common adverse effects in cancer patients with chemotherapy, and those severely limit the therapeutic efficacy and lead treatment failure. It is unclear by which cellular mechanism anticancer drugs suppress bone marrow, while drug-resistant tumors survive. We report that due to the difference of glucosylceramide synthase (GCS), catalyzing ceramide glycosylation, doxorubicin (Dox) eliminates bone marrow stem cells (BMSCs) and expands breast cancer stem cells (BCSCs). It was found that Dox decreased the numbers of BMSCs (ABCG2(+)) and the sphere formation in a dose-dependent fashion in isolated bone marrow cells. In tumor-bearing mice, Dox treatments (5mg/kg, 6 days) decreased the numbers of BMSCs and white blood cells; conversely, those treatments increased the numbers of BCSCs (CD24(-)/CD44(+)/ESA(+)) more than threefold in the same mice. Furthermore, therapeutic-dose of Dox (1mg/kg/week, 42 days) decreased the numbers of BMSCs while it increased BCSCs in vivo. Breast cancer cells, rather than bone marrow cells, highly expressed GCS, which was induced by Dox and correlated with BCSC pluripotency. These results indicate that Dox may have opposite effects, suppressing BMSCs versus expanding BCSCs, and GCS is one determinant of the differentiated responsiveness of bone marrow and cancer cells.The international journal of biochemistry & cell biology 06/2012; 44(11):1770-8. DOI:10.1016/j.biocel.2012.06.010 · 4.24 Impact Factor