Biomedical subjects
J-J Body
Publications and source records attributed to J-J Body.
Steroid-free medium discloses oestrogenic effects of the bisphosphonate clodronate on breast cancer cells.
Tamoxifen is the standard first-line endocrine therapy for breast cancer, but recent data indicate that it is likely to be replaced by the effective aromatase inhibitors (AIs), in both the metastatic and adjuvant settings. Aromatase inhibitors induce complete oestrogen deprivation that leads to clinically significant bone loss. Several ongoing or planned trials combine AIs with bisphosphonates, even more so that recent data reveal that clodronate may reduce the incidence of bone metastases and prolong survival in the adjuvant setting. Bisphosphonates can inhibit breast cancer cell growth in vitro, but they have never been studied in steroid-free medium (SFM), an in vitro environment that mimics the effects of AIs in vivo. Quite surprisingly, in SFM, clodronate stimulated MCF-7 cell growth in a time- and dose-dependent manner by up to two-fold (crystal violet staining assay), whereas it had no mitogenic activity in complete medium. The bisphosphonate similarly increased the proliferation of IBEP-2 cells, which also express a functional oestrogen receptor (ER), while it weakly inhibited the growth of the ER-negative MDA-MB-231 cells. Expectedly, 17beta-oestradiol stimulated the growth of MCF-7 and IBEP-2 cells cultured in SFM, and had no effect on MDA-MB-231 cells. Moreover, partial (4-OH-tamoxifen) and pure antioestrogens (fulvestrant, ICI 182,780), in combination with clodronate, completely suppressed the mitogenic effect of the bisphosphonate, suggesting that it was mediated by an activation of ER. In accordance with this view, clodronate induced ER downregulation, weakly increased progesterone receptor expression, and stimulated the transcription of an oestrogen-responsive reporter gene. In conclusion, we report a previously unknown stimulatory effect of clodronate on MCF-7 cells grown in SFM, in vitro conditions that are potentially relevant to the use of AIs for breast cancer. Moreover, our data suggest that ER is involved in these effects of clodronate on cancer cell growth.
Extracellular calcium downregulates estrogen receptor alpha and increases its transcriptional activity through calcium-sensing receptor in breast cancer cells.
Skeleton is the most common organ targeted by breast cancer cells, especially from estrogen receptor alpha (ER)-positive neoplasms. Metastatic cells can stimulate directly or indirectly osteoclast-mediated bone resorption. Tumor-induced osteolysis is often extensive and leads to the release of large quantities of calcium. Metastatic cancer cells can be thus exposed to high calcium concentrations (40 mM has been reported at the resorption site). However, the effects of Ca2+ on breast cancer cells have been minimally examined. We showed that 20-mM extracellular Ca2+ induced a downregulation of ER protein in MCF-7 cells and caused ER-mediated transactivation of a reporter gene by 55 +/- 10% (mean +/- SD) in MVLN cells (MCF-7 cells stably transfected with ERE and luciferase reporter gene). Moreover, 3 mM Ca2+ increased progesterone receptor (PgR) expression by 45 +/- 8%. Mg2+ tested at up to 20 mM did not exert any effects, while 17beta-estradiol downregulated ER, transactivated the reporter gene, and enhanced PgR expression. The pure antiestrogen ICI 182,780 was able to abrogate the transactivation of the reporter gene and the increase in PgR levels induced by Ca2+, indicating that Ca2+ may exert a weak and specific estrogenic effect in MCF-7 cells. Ca2+ effects on ER probably start at the cell membrane level since a large Ca2+ influx caused by the ionophore A23187 failed to activate ER. We have thus studied the involvement of the membrane calcium-sensing receptor (CaR) that is known to be expressed notably in MCF-7 cells. We first tested the effects of a specific activator of CaR. Exposure to 10(-4) M calcimimetic NPS R-467 mirrored the changes observed with extracellular Ca2+ by inducing a marked decrease in ER protein levels, increasing the transcriptional activity of ER (67 +/- 12%) and stimulating PgR expression (41 +/- 4%). As expected, the NPS S-467 isomer was less effective. Furthermore, a highly selective CaR antagonist partly suppressed the downregulation of ER as well as transactivation of the reporter gene induced by Ca(2+). Our results suggest that the effects of extracellular Ca2+ on ER expression and activity are mediated, at least in part, by the CaR. In summary, calcium released during the process of metastatic bone destruction could modulate the functions of the estrogen receptor, a key receptor involved in breast cancer cells growth and function, and thus participate in the pathogenesis of tumor-induced osteolysis.
Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer.
Bone metastases occur in most women with advanced breast cancer and can lead to considerable morbidity and a rapid deterioration in the patient's quality of life. It was the aim of the present study to assess changes in quality of life and bone pain due to intravenous (i.v.) ibandronate, a potent third-generation bisphosphonate. In a phase III randomised, double-blind, placebo-controlled trial in patients with bone metastases due to breast cancer, 466 women were randomised to receive placebo, 2 mg ibandronate or 6 mg ibandronate for up to 96 weeks. Treatment was administered i.v. at 3- or 4-weekly intervals. Clinical endpoints included the incidence of adverse events, quality of life (assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Scale - Core 30 questionnaire (QLQ-C30)), and bone pain (assessed on a 5-point scale from 0=none to 4=intolerable). Ibandronate was generally well tolerated. Compared with baseline measurements, the bone pain score was increased at the last assessment in both the placebo and 2 mg ibandronate groups, but was significantly reduced in the patients receiving 6 mg ibandronate (-0.28+/-1.11, P < 0.001). A significant improvement in quality of life was demonstrated for patients treated with ibandronate (P < 0.05) for all global health status. Overall, at the last assessment, the 6 mg ibandronate group showed significantly better functioning compared with placebo (P = 0.004), and had significantly better scores on the domains of physical, emotional, and social functioning, and in global health status (P < 0.05). Significant improvements in the symptoms of fatigue and pain were also observed in the 6 mg ibandronate group. I.v. ibandronate treatment leads to significant improvements in quality of life, and is an effective and well-tolerated palliative treatment in patients with bone metastases due to breast cancer.
Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival.
Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone-derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.
Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.
BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.
Investigation of bone disease using isomerized and racemized fragments of type I collagen.
In the collagen type I C-telopeptide an aspartyl-glycine site within the sequence AHDGGR is susceptible to molecular rearrangement. In newly synthesized collagen this site is in the native form, denoted alpha L. During aging a spontaneous reaction occurs resulting in three age-modified forms: an isomerized form (beta L) a racemized form (alpha D), and an isomerized/racemized form (beta D). In this study, we measured the urinary excretion of the four forms of C-telopeptides (CTX) in healthy adults and in patients with bone diseases. Levels of all CTX forms were higher in healthy postmenopausal women (P<0.001) compared with premenopausal controls. Levels decreased within 3 days of bisphosphonate treatment indicating that all CTX forms reflect bone resorption. In hyperthyroidism, characterized by a generalized increased bone turnover, native (alpha L) and age-modified (beta L, alpha D and beta D) forms increased to a similar extent compared to controls, resulting in normal ratios between the alpha L and age-modified forms of CTX. Conversely, in Paget's disease and prostate cancer-induced bone metastases, conditions characterized by focal increased bone turnover, alpha L CTX levels were more elevated than those of age-related CTX forms, resulting in increased ratios between native and age-modified CTX. For example, the ratio alpha L/alpha D was increased 7-fold in Paget's disease (P<0.001) and 2-fold in prostate cancer-induced bone metastases (P<0.002). In conclusion, the study suggests that in conditions with a localized alteration in bone turnover the ratio between alpha L CTX and the age-modified forms is significantly elevated. This may provide a new diagnostic and monitoring tool for diseases such as metastatic bone cancer and Paget's disease.
Calcitonin for the long-term prevention and treatment of postmenopausal osteoporosis.
Calcitonin is a powerful inhibitor of osteoclast activity that exerts a rapid, transient, and reversible inhibition of bone resorption. Prolonged administration of parenteral calcitonin, by injections of 100 IU every 1 or 2 days, can prevent postmenopausal or postovariectomy bone loss, and is also able to increase trabecular bone mass among patients presenting an established osteoporosis. Prolonged treatment with calcitonin injections is, however, difficult to maintain over the long run. In addition to the ease of administration compared with the injectable forms, nasal calcitonin is much better tolerated, the side effects being rare and generally negligible. A prolonged administration of 200 IU intranasal calcitonin acutely inhibits parameters of bone resorption and can increase lumbar spine bone mineral density (BMD) by 1.7%-3.3% after 1 year. Lower doses also appear to be efficient to prevent early postmenopausal bone loss, but the data are conflictual. The results are more consistent in patients who already suffer from established osteoporosis. The increase in lumbar spine BMD is in the order of 1%-2% after 1 year with 200 IU daily. A therapeutic benefit of calcitonin at the level of the cortical bone has been less well demonstrated than for the trabecular bone. As for other antiosteoporotic therapies, the effect of calcitonin on the reduction of fracture risk has been examined less than the beneficial effect on trabecular bone mass. Currently, there is still no prospective, placebo-controlled study with a sufficient number of patients that demonstrates that long-term parenteral calcitonin administration reduces the risk of osteoporotic fractures. The efficacy of nasal calcitonin treatment to reduce vertebral fracture rate has been best examined in the PROOF (Prevent Recurrence of Osteoporotic Fractures) study. This was a prospective 5-year, placebo-controlled, dose-response study of nasal calcitonin (100, 200, or 400 IU daily). The increase in lumbar spine BMD was modest but significant and not clearly dose dependent, as was the reduction in bone turnover. The relative risk of developing new vertebral fractures was reduced by 33% at the end of the study in the 200-IU dose group (relative risk = 0.67, 95% CI 0.47-0.97, p = 0.03). There was also a nonsignificant reduction in the risk of hip fracture in this dose group. The doses of 100 and 400 IU of calcitonin also reduced the vertebral fracture risk, but the difference did not reach the classical level of statistical significance. A possible effect of calcitonin to enhance bone quality, which cannot be assessed by routinely available methods, is currently being investigated in a prospective placebo-controlled trial that could provide a rational explanation for these effects of calcitonin on the reduction in the vertebral fracture rate without much increase in bone mass or a marked reduction in bone turnover.