Abstract
Doxorubicin (DOX) is widely used in combination cocktails for treatment of childhood hematological cancers and solid tumors. A major factor limiting DOX usage is DOX-induced cardiotoxicity. However, it is not known whether protectants like dexrazoxane (DXR) and amifostine (AMF) can prevent DOX-mediated bone damage. The present study investigated whether administration of AMF alone or in combination with DXR would prevent any DOX-mediated bone damage. Male rat pups were treated with DOX, DXR, AMF, and their combinations. On neonate day 38, the bone mineral density (BMD), bone mineral content (BMC) and the micro-architecture of the lumbar vertebrae were analyzed. We have shown that when male rats are treated with DOX, DXR, DOX+DXR, AMF, DOX+AMF or DOX+DXR+AMF, there is a decrease in lumbar vertebral BMD (p<0.05). Furthermore, the relative bone volume (BV/TV) was decreased by DXR, DOX+DXR, and DOX+AMF treatments. Interestingly, DOX+AMF significantly increased BV/TV when compared to DXR treatment (p<0.04). The trabecular number (Tb.N) decreased with DXR and DOX+DXR and increased with DOX+AMF treatments. This information will be useful in designing better cancer combination therapies that do not lead to vertebrae deterioration.
Highlights
IntroductionThe strength of adult bone reflects factors that regulate bone quality (architecture) and density (bone mass or quantity of calcium deposited/unit of bone) acquired during childhood and adolescence
The strength of adult bone reflects factors that regulate bone quality and density acquired during childhood and adolescence
We have previously shown a significant decrease in the right femoral and lumbar vertebral Bone mineral density (BMD) of female rats treated with AMF, AMF+DOX or AMF+DXR+DOX [22]
Summary
The strength of adult bone reflects factors that regulate bone quality (architecture) and density (bone mass or quantity of calcium deposited/unit of bone) acquired during childhood and adolescence. Chemotherapies administered to children with cancer have the potential for long-term negative effects on bone [6] and can cause osteopenia during treatment [7]. The reduced height and mineralization, and the increased bone fragility found in cancer survivors can be caused by several factors that include nutritional deficiencies, the malignancy itself, radiation, corticosteroids, and direct action of anti-cancer drugs on bone [7, 8]. Current treatments of childhood hematological cancers and solid tumors can involve the anthracycline antibiotic doxorubicin (DOX, AdriamycinTM) in combination cocktails [9, 10]. DOX-induced cell killing is due to increases in oxidative stress causing apoptosis, as well as to its ability to bind and
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