Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia

To investigate the effects of disease and intensive chemotherapy on bone turnover and growth in children with acute lymphoblastic leukemia (ALL), a longitudinal prospective study was carried out in 22 children, aged 1.2–13.5 yr, enrolled in the Medical Research Council-funded randomized trial of childhood ALL treatment in the UK. We measured lower leg length and markers of bone formation [bone alkaline phosphatase (ALP) and procollagen type I C-terminal propeptide (PICP)], bone resorption [pyridinoline, deoxypyridinoline, and carboxyl-terminal telopeptide of type I collagen (ICTP)], soft tissue turnover [procollagen type III N-terminal propeptide (P3NP)], and the GH axis [IGF-I, IGF-binding protein-3 (IGFBP-3), IGFBP-2, and urinary GH] at 1- to 4-week intervals from diagnosis to week 27 of treatment. In addition, GH-binding protein was measured at diagnosis. <br></br> At diagnosis, mean SD scores were: bone ALP, -1.84; PICP -1.77; pyridinoline, -1.42; deoxypyridinoline, -1.66; ICTP, -0.42; P3NP, +1.45; GH, +24.4; IGF-I, -1.70; IGFBP-3, -0.88; IGFBP-2, +2.42; and GH-binding protein, -0.69. Bone ALP, PICP, and IGFBP-3 were all correlated (P 0.03). During induction and intensification, there was shrinkage of the lower leg, with decreases in PICP, pyridinoline, ICTP, and P3NP (P < 0.05), whereas IGF-I and IGFBP-3 increased (P < 0.05). After prednisolone was discontinued, bone ALP and collagen markers increased markedly (P < 0.01), but there was no significant change in IGF-I and IGFBP-3. In 12 children who received high dose iv methotrexate, postglucocorticoid increases in bone ALP and PICP were less, whereas those in ICTP and P3NP were greater, compared to levels in children who did not receive methotrexate (P < 0.05). <br></br> We conclude that ALL itself caused GH resistance and low bone turnover. During early intensive chemotherapy, further suppression of osteoblast proliferation and osteoclast activity occurred, not mediated through the systemic GH axis, probably by the direct action of prednisolone on bone. The postglucocorticoid increase in bone turnover was also independent of the GH axis and was modulated by high dose iv methotrexate, which depressed osteoblast recovery and enhanced osteoclast activity

Effects of intensive chemotherapy on bone and collagen turnover and the growth hormone axis in children with acute lymphoblastic leukemia

To investigate the effects of disease and intensive chemotherapy on bone turnover and growth in children with acute lymphoblastic leukemia (ALL), a longitudinal prospective study was carried out in 22 children, aged 1.2–13.5 yr, enrolled in the Medical Research Council-funded randomized trial of childhood ALL treatment in the UK. We measured lower leg length and markers of bone formation [bone alkaline phosphatase (ALP) and procollagen type I C-terminal propeptide (PICP)], bone resorption [pyridinoline, deoxypyridinoline, and carboxyl-terminal telopeptide of type I collagen (ICTP)], soft tissue turnover [procollagen type III N-terminal propeptide (P3NP)], and the GH axis [IGF-I, IGF-binding protein-3 (IGFBP-3), IGFBP-2, and urinary GH] at 1- to 4-week intervals from diagnosis to week 27 of treatment. In addition, GH-binding protein was measured at diagnosis. <br></br> At diagnosis, mean SD scores were: bone ALP, -1.84; PICP -1.77; pyridinoline, -1.42; deoxypyridinoline, -1.66; ICTP, -0.42; P3NP, +1.45; GH, +24.4; IGF-I, -1.70; IGFBP-3, -0.88; IGFBP-2, +2.42; and GH-binding protein, -0.69. Bone ALP, PICP, and IGFBP-3 were all correlated (P 0.03). During induction and intensification, there was shrinkage of the lower leg, with decreases in PICP, pyridinoline, ICTP, and P3NP (P < 0.05), whereas IGF-I and IGFBP-3 increased (P < 0.05). After prednisolone was discontinued, bone ALP and collagen markers increased markedly (P < 0.01), but there was no significant change in IGF-I and IGFBP-3. In 12 children who received high dose iv methotrexate, postglucocorticoid increases in bone ALP and PICP were less, whereas those in ICTP and P3NP were greater, compared to levels in children who did not receive methotrexate (P < 0.05). <br></br> We conclude that ALL itself caused GH resistance and low bone turnover. During early intensive chemotherapy, further suppression of osteoblast proliferation and osteoclast activity occurred, not mediated through the systemic GH axis, probably by the direct action of prednisolone on bone. The postglucocorticoid increase in bone turnover was also independent of the GH axis and was modulated by high dose iv methotrexate, which depressed osteoblast recovery and enhanced osteoclast activity

Expression of genes belonging to the IGF-system in glial tumors

The discrepancies arising from conflicting evidence on the results obtained by different laboratories in human gliomas are discussed. Our data highlight the importance of viewing the IGF-related proteins as a complex multifactorial system and show that changes in the expression levels of any one component of the system, in a given malignancy, should be interpreted with caution. As IGF targeting for anticancer therapy is rapidly becoming clinical reality, an understanding of this complexity is very timely.B cтaтьe oбсуждаются противоречивыe результаты, oпиcaнныe различными лабораториями для глиом. Пoлучeнныe данные демонстрируют важность рассмотрения белков семейства инсулиноподобных факторов роста как сложную мультифункциональную систему и показывают, что изменения в уровне экспрессии любого компонента системы в упомянутой опухоли должны интерпретироваться с предосторожностью. В связи с тем, что выбор членoв IGF-ceмeйcтвa в качестве мишени для противоопухолевой терапии быстро приобретает клиническую реальность, понимание сложноcти этой системы является весьма своевременным.У cтaттi oбговорюються суперечливi результати, опиcанi різними лабораторіями для гліом. Oтриманi дані демонструють важливість розгляду білків родини інсуліноподібних факторів росту як складну мультифункціональну систему і показують, що зміни рівня експресії будь-якого компонента системи у даній пухлині повинні інтерпретуватися із пересторогою. В зв’язку з тим, що вибір членiв IGF-ciмeйcтвa як мішені для протипухлинної терапії швидко набуває клінічної реальності, розуміння цієї системи є вельми своєчасним