Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

Chen, Xian; Cool, Johanna C.; Gangelen, Jeffery van; Foster, Bruce K.; Howarth, Gordon S.

doi:10.4161/cbt.6.2.3576

Cited by 27 publications

(26 citation statements)

References 37 publications

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“…The groups of CTX-treated mice had a shorter femur than controls. This seems to be due to a CTXinduced stromal collagen, as well as calcified matrix, apoptosis which affects elongation and trabecular thickness, as reported in previous studies [Xian et al 2007]. In our study, we cannot assume malnutrition from CTX as a cause of defective bone development, since we observed a similar BMI in all groups.…”

Section: Discussionsupporting

confidence: 82%

“…Animal studies have been instrumental in learning that CTX causes apoptosis of various cell types, including ovarian and bone. In the ovary, CTX causes apoptosis of granulosa cells and oocytes, while in the bone it causes apoptosis in the metaphyseal growth plate and trabecular bone, thus affecting bone elongation potential [Oktem and Oktay 2007a;Meirow et al 1999;Xian et al 2007]. While it is known that uterine irradiation at a young age hampers the final adult uterine development [Critchley and Wallace 2005], the impact of chemotherapy on uterine development is uncertain despite reports of a higher incidence of fetal growth restriction and preterm delivery among those exposed.…”

Section: Introductionmentioning

confidence: 99%

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Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age

Detti

Williams

et al. 2013

Systems Biology in Reproductive Medicine

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Disruption in the normal timing of female puberty, such as in pre-pubertal cancer treatments, can cause abnormal somatic development. We sought to evaluate the impact of cyclophosphamide (CTX) on the somatic, uterine, and ovarian, development of pre-pubertal mice. Pre-pubertal (day 18 of life) C57BL/ 6J female mice were randomized to receive placebo (group 1A and 1B), 200 mg/kg CTX (group 2A), or 120 mg/kg CTX (group 2B). Mice were euthanized on day 56 (A groups) or 95 (B groups) of life. Body weight and length, uterine and ovarian weight and right femur length and weight were measured, and ovarian insufficiency was assessed. Data were analyzed using ANOVA and t-test. Body weight and length did not differ among groups at time of euthanasia. The femur was shorter and weighed less in mice treated with CTX than in controls. Uterine weight was lower in group 2B than 1B (46.1 mg, 95% CI: 42.9-49.4, vs. 62.2 mg, 95% CI: 58.5-65.8, respectively; p = 0.005) and was lower in mice that developed ovarian insufficiency than in mice that did not ( p < 0.05). Ovarian weight was lower in mice treated with CTX, regardless of whether they developed ovarian insufficiency. Even with no observable effect on adult body length and weight, CTX treatment in prepubertal mice appears to negatively affect femur, uterine, and ovarian development. However, uterine development seems to be dependent on the hormonal status created by CTX more than on its direct effect.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age

Detti

Williams

et al. 2013

Systems Biology in Reproductive Medicine

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“…EO supplementation significantly preserved the osteoblast density especially on day 3 after H 2 O ϩ 5-FU administration and prevented 5-FU-induced higher osteoclast density in the metaphysis. Although the mechanisms for EO-induced preservation of osteoblast density remain to be studied, it is known that a constant supply of osteoblasts is required for normal bone formation and homeostasis, and any significant reduction in osteoblast numbers and activity can result in reduced bone formation and lead to osteoporosis (8,49,51). Although the underlying mechanisms for EO's antiosteoclastic effects remain to be defined, consistent with its effects in suppressing 5-FU-induced osteoclastogenesis, our gene expression studies suggest that EO supplementation can suppress the induction of proinflammatory cytokines, particularly TNF␣ and osteoclast receptors RANK and OSCAR, which were upregulated by (53).…”

Section: Discussionmentioning

confidence: 99%

“…Stained sections were used for morphometric measurements of growth plate total heights, heights of primary spongiosa, and bone volume of primary and secondary spongiosa metaphyseal bone using image analysis software AnalySIS (Olympus). Briefly, the entire height of the growth plate along an axis oriented 90°to the transverse of the growth plate and parallel to the longitudinal axis of the tibial bone was measured (12,48,49,51,52). Similarly, the average primary spongiosa zonal height at the metaphysis was also obtained using the same software (12,48,49,51,52).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the entire height of the growth plate along an axis oriented 90°to the transverse of the growth plate and parallel to the longitudinal axis of the tibial bone was measured (12,48,49,51,52). Similarly, the average primary spongiosa zonal height at the metaphysis was also obtained using the same software (12,48,49,51,52). At both primary (0.1 mm above the primary-secondary transitional line) and secondary spongiosa (1 mm below the transitional line), total areas were measured and all trabecular cores traced, and the data were used to work out the ratio of bone volume to total tissue volume (BV/TV%), as described (12,48,49,51,52).…”

Section: Methodsmentioning

confidence: 99%

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Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

Nadhanan

Abimosleh

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Raghu Nadhanan R, Abimosleh SM, Su YW, Scherer MA, Howarth GS, Xian CJ. Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss. Am J Physiol Endocrinol Metab 302: E1440 -E1449, 2012. First published March 20, 2012; doi:10.1152/ajpendo.00587.2011Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml·day Ϫ1 ·rat Ϫ1 ) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O ϩ Sal, H2O ϩ 5-FU, EO ϩ 5-FU, and EO ϩ Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O ϩ 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNF␣, osteoclast marker receptor activator of nuclear factor-B, and osteoclast-associated receptor. Therefore, this study demonstrated that EO can counter 5-FU chemotherapy-induced inflammation in bone, preserve osteoblasts, suppress osteoclast formation, and potentially be useful in preventing 5-FU chemotherapy-induced bone loss.receptor activator of nuclear factor-B ligand; tumor necrosis factor-␣; anti-inflammatory ANTI-CANCER CHEMOTHERAPY can cause significant adverse effects on tissues, including the bone, in both pediatric and adult cancer patients (25). Short stature, low bone mass or osteoporosis, and/or fractures are some skeletal side effects that are due to chemotherapy among pediatric patients and adult survivors (32, 38, 46). Experimental studies in rats have also shown that drugs such as methotrexate (MTX), cisplatin, doxorubicin, etoposide, cyclophosphamide, and 5-fluorouracil (5-FU) can cause a reduction in bone growth and bone mass (50 -52). 5-FU is an antimetabolite drug commonly used to treat adult patients suffering from colorectal and breast cancer, whereas in children 5-FU is used to treat childhood solid tumours (27, 36). 5-FU inhibits thymidylate synthase, an enzyme required to synthesize thymine nucleotide, which is important for synthesis of DNA and RNA (27). In an acute 5-FU chemotherapy model in rats, reduced primary spongiosa heigh...

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Follow‐Up of Children after Hematopoietic Stem Cell Transplantation: growth and Development

Hardy

Jacobsohn

Perez-Albuerne

2013

Blood and Marrow Transplantation Long‐Term Management

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Effects of etoposide and cyclophosphamide acute chemotherapy on growth plate and metaphyseal bone in rats

Cited by 27 publications

References 37 publications

Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age

Somatic and reproductive outcomes in mice treated with cyclophosphamide in pre-pubertal age

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

Follow‐Up of Children after Hematopoietic Stem Cell Transplantation: growth and Development

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