Aging is a major risk factor in the development of chronic diseases, especially cardiovascular diseases. Age‐related organ dysfunction is strongly associated with the accumulation of senescent cells. Cardiac mesenchymal stromal cells (cMSCs), deemed part of the microenvironment, modulate cardiac homeostasis through their vascular differentiation potential and paracrine activity. Transcriptomic analysis of cMSCs identified age‐dependent biological pathways regulating immune responses and angiogenesis. Aged cMSCs displayed a senescence program characterized by Cdkn2a expression, decreased proliferation and clonogenicity, and acquisition of a senescence‐associated secretory phenotype (SASP). Increased CCR2‐dependent monocyte recruitment by aged cMSCs was associated with increased IL‐1ß production by inflammatory macrophages in the aging heart. In turn, IL‐1ß induced senescence in cMSCs and mimicked age‐related phenotypic changes such as decreased CD90 expression. The CD90+ and CD90‐ cMSC subsets had biased vascular differentiation potentials, and CD90+ cMSCs were more prone to acquire markers of the endothelial lineage with aging. These features were related to the emergence of a new cMSC subset in the aging heart, expressing CD31 and endothelial genes. These results demonstrate that cMSC senescence and SASP production are supported by the installation of an inflammatory amplification loop, which could sustain cMSC senescence and interfere with their vascular differentiation potentials.
Irinotecan, a DNA‐topoisomerase‐I inhibitor, is active against metastatic colon carcinoma. We investigated the effects of irinotecan and 5FU combinations in human colon‐carcinoma cell line HT‐29, both in vitro and in vivo. Cytotoxicity of 24‐hr exposure was evaluated by SRB technique and the nature of interactions were determined by median‐effect analysis. Strong synergism between irinotecan and 5FU was observed after sequential exposure, and only additivity after simultaneous exposure. At 50% level of kill, the mean sums of fractional effects were 0.13 ± 0.05 and 0.18 ± 0.02 respectively for the 2 sequential schedules, indicating that the combined amount of the 2 drugs necessary to kill 50% cells was only 0.18 and 0.13 times respectively, as much as would be required if they demonstrated purely additive behavior. In nude‐mice xenografts, schedule‐dependent toxicity was observed: the schedule in which irinotecan was administered i.v. 6 hours before 5FU was the most toxic. Higher anti‐tumoral activity was noted when 20 mg/kg/day of each drug was administered sequentially (a delay of 6 hr between the 2 drugs) to mice over 5 days, in comparison with simultaneous administration. In vivo data confirmed those obtained in vitro in the same human colon‐cancer model. These results suggest that irinotecan and 5FU combinations are of clinical interest and that the schedule of administration is a critical parameter for chemotherapeutic efficacy. Int. J. Cancer 73: 729–734, 1997. © 1997 Wiley‐Liss, Inc.
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