Summary Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein-expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL-60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5-1 µM and delayed mitotic cell death at 0.1 µM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50-100 µM daunorubicin and mitotic cell death at 10 µM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias.Keywords: drug resistance; P-glycoprotein; cell death; daunorubicin; myeloid leukaemia; response prediction 1090British Journal of Cancer (1999) 79(7/8), 1090-1097 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 25 February 1998 Revised 11 May 1998 Accepted 12 June 1998 Correspondence to: AK Larsen apoptotic morphological features and only very low levels of internucleosomal DNA fragmentation in the KG1 and KG1a cell lines (Quillet-Mary et al, 1996). Both KG1 and KG1a cells overexpress the MDR-1 gene as well as functional P-glycoprotein and are naturally resistant to daunorubicin compared with HL-60 or U937 cells. It has also been reported that another anthracycline, doxorubicin, induces internucleosomal fragmentation in parental P388 leukaemia cells but not in resistant P388/ADR cells that express the P-glycoprotein (Ling et al, 1993). These results can be interpreted in different ways. It is possible that P-glycoprotein expression and an altered cell death process represent two independent resistance mechanisms, which can occur together. Alternatively, the lack of apoptosis in MDR cells might be causally linked to the transport abnormalities as a minimum intracellular concentration of anthracycline may be required to trigger apoptosis...

Previously it was demonstrated that intravenously administered morphine produced greater analgesic but lower hyperthermic responses to morphine in 24-week-old rats in comparison to 8-week-old rats. The differential pharmacological responses to morphine could not solely be attributed to the pharmacokinetic parameters, namely area under the serum morphine concentration-time curve, serum levels of morphine extrapolated to zero time, half-life, mean residence time, apparent volume of distribution at the steady state, terminal rate constant and total body clearance of morphine in serum. In order to determine whether the differences in pharmacological responses to morphine in rats from two age groups are related to differential distribution of morphine in the central nervous system, in the present study, the time course of the distribution of morphine in brain regions (hypothalamus, hippocampus, cortex, pons and medulla, amygdala, midbrain and corpus striatum), spinal cord and serum following intravenous injection of 10 mg/kg dose to 8- and 24-week-old male Sprague-Dawley rats was determined. Morphine injected intravenously produced a greater analgesic but less intense hyperthermic effect in 24-week-old rats in comparison to 8-week-old rats. In most of the brain regions and spinal cord, with few exceptions, the concentration of morphine was found to be greater in 24-week-old rats than in 8-week-old rats. Similarly, the ratio of the concehtration of morphine in brain region or spinal cord to serum was significantly higher in rats from the older age group. The studies demonstrate that the altered pharmacological responses to intravenously administered morphine to rats of differing ages may be related to the higher concentration of morphine in the central nervous system of older rats, which in turn may be related to the differences in the blood-brain barrier to morphine in the two age groups.

Prophylactic mastectomies are more and more frequent. As a result, breast reconstruction is also more frequent and mammary lipofilling often used to improve the aesthetic results. Contradictory cliniacal data have been published concerning the risk of breast cancer after using this technique. It is possible that Adipose-Derived Stem / Stromal Cells (ADSC or ASC), present in the lipofilling may interact with normal or tumoral epithelial mammary cells. In this context, we studied the effect of conditioned media of human ASC on different tumor breast lines (MCF7, T47D, ZR75-1, SKBR3, SUM159). The ASCs were extracted from non-cancer patients with identical body mass index (BRCA1 and BRCA2 mutated or wild-type). We observed that the conditioned media of ASC induced the proliferation of luminal, Her2 and basal-like tumor breast lines. This proliferative effect is more important when ASCs are differentiated and the BRCA mutation status has no impact on it. Finally, we have demonstrated an estrogen signaling within the ASCs which is set up during their differentiation. Differentiated ASCs express ERα and produce 17β-estradiol (E2). This estrogenic pathway seems to be established independently of the BRCA mutational status. The proliferative effect on luminal mammary lines induced by conditioned media of ASC could pass through this estrogenic signaling, but remains to be confirmed. These data highlight the fact that adipose-derived stem cells in mammary lipofilling should only be used after a cancer has been eliminated, as there are still some uncertainties concerning their implication on carcinogenesis. Citation Format: Benderra M-A, Zaoui M, Atlan M, Ferrand N, Denis JA, Leban M, Lamari F, Larsen AK, Sabbah M, Gligorov J. Interactions between adipocyte stem cells and normal or tumoral mammary epithelial cells. Potantial role of BRCA status and estrogen pathway [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-07-05.

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