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Povzetek: Background. Human breast cellular model, comprising four cell lines originating from spontaneously immortalized human breast epithelial MCF10A cell line, its c-Ha-ras transfectant, MCF10AT, and two tumourigenic derivatives, cultured from two sequential mouse xenographs, MCF10AT-Ca1a and MCF10AT-Ca1d, were used to compare the relative protein concentration of cathepsins and stefins in single cells. Methods. The relative protein concentration of cathepsins and stefins in single cells was analysed by confocal microscopy, and compared to their protein expression in cell homogenates. Results. The most invasive, MCF10AT cell line contained several fold higher protein concentration of cathepsin B and increased levels of stefins, but similar levels of cathepsin L, compared with the parental MCF10A cells. This was associated with five fold higher endocytosis of Matrigel-DQ-collagen IV (DQC) and a simultaneous increase in signal overlap between DQC and cathepsin L as well as DQC and stefin B, but a decrease in that of DQC and cathepsin B overlap in the MCF10AT cells. Simultaneously, increased signal overlaps between both cathepsins and between cathepsins-stefins pairs, were observed in this cell line. Conclusions. These results suggest that the increased collagen endocytosis and degradation in theinvasive phenotype significantly affect also the subcellular localization of cysteine cathepsins and stefins. Based on these and the reports of other authors, we hypothesize that the intracellular degradation may also be assoeiated with cathepsin L, whereas cathepsin B in the ras transformed breastcells is involved in both, the intracellular and pericellular degradation of extracellular matrix during cell migration and invasion.
Ključne besede: breast neoplasms, tumor cells cultured, neoplasms invasiveness, cathepsins, extracellular matrix
Objavljeno v DiRROS: 15.02.2024; Ogledov: 122; Prenosov: 35
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Povzetek: Background: Increasing the dose intensity of cytotoxic therapy by shortening the intervals between cycles, or by giving individual drugs sequentially at full dose rather than in lower-dose concurrent treatment schedules, might enhance efficacy. Methods: To clarify the relative benefits and risks of dose-intense and standard-schedule chemotherapy in early breast cancer, we did an individual patient-level meta-analysis of trials comparing 2-weekly versus standard 3-weekly schedules, and of trials comparing sequential versus concurrent administration of anthracycline and taxane chemotherapy. The primary outcomes were recurrence and breast cancer mortality. Standard intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded dose-intense versus standard-schedule first-event rate ratios (RRs). Findings: Individual patient data were provided for 26 of 33 relevant trials identified, comprising 37,298 (93%) of 40,070 women randomised. Most women were aged younger than 70 years and had node-positive disease. Total cytotoxic drug usage was broadly comparable in the two treatment arms; colony-stimulating factor was generally used in the more dose-intense arm. Combining data from all 26 trials, fewer breast cancer recurrences were seen with dose-intense than with standard-schedule chemotherapy (10-year recurrence risk 28.0% vs 31.4%; RR 0.86, 95% CI 0.82-0.89; p<0.0001). 10-year breast cancer mortality was similarly reduced (18.9% vs 21.3%; RR 0.87, 95% CI 0.83-0.92; p<0.0001), as was all-cause mortality (22.1% vs 24.8%; RR 0.87, 95% CI 0.83-0.91; p<0.0001). Death without recurrence was, if anything, lower with dose-intense than with standard-schedule chemotherapy (10-year risk 4.1% vs 4.6%; RR 0.88, 95% CI 0.78-0.99; p=0.034). Recurrence reductions were similar in the seven trials (n=10,004) that compared 2-weekly chemotherapy with the same chemotherapy given 3-weekly (10-year risk 24.0% vs 28.3%; RR 0.83, 95% CI 0.76-0.91; p<0.0001), in the six trials (n=11,028) of sequential versus concurrent anthracycline plus taxane chemotherapy (28.1% vs 31.3%; RR 0.87, 95% CI 0.80-0.94; p=0.0006), and in the six trials (n=6532) testing both shorter intervals and sequential administration (30.4% vs 35.0%; RR 0.82, 95% CI 0.74-0.90; p<0.0001). The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant (p<0.0001) in oestrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumour characteristics. Interpretation: Increasing the dose intensity of adjuvant chemotherapy by shortening the interval between treatment cycles, or by giving individual drugs sequentially rather than giving the same drugs concurrently, moderately reduces the 10-year risk of recurrence and death from breast cancer without increasing mortality from other causes.
Ključne besede: breast neoplasms, women, drug therapy, clinical protocols, meta-analysis, breast cancer, chemotherapy, treatment schedule, randomized trials
Objavljeno v DiRROS: 22.10.2020; Ogledov: 1287; Prenosov: 1089
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