Induction Of Osteosarcoma Research Articles

Induction of Osteosarcoma and Biochemical Effects in Rats Treated with Benzopyrene

Osteosarcoma accounts for 20% of all sarcomas, affects children and young adults, usually originating in lower limb bones and possibly ending in amputation. The murine models identify the molecular and pathophysiological basis of diseases and allow the development of new therapies for their treatment. Benzopyrene (BZP) is an aromatic polycyclic hydrocarbon, reported as a potent cancer inducer.

On the Interpretation of Rat Carcinogenicity Studies for Human PTH(1-34) and Human PTH(1-84)

On the Interpretation of Rat Carcinogenicity Studies for Human PTH(1-34) and Human PTH(1-84)

Parathyroid Hormone and Teriparatide for the Treatment of Osteoporosis: A Review of the Evidence and Suggested Guidelines for Its Use

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.

The specific induction of osteosarcomas in different mouse strains after injections of 239Pu citrate.

Lifetime bone tumor induction by the injection of a bone-seeking alpha emitter, 239Pu citrate, was compared among 630 female mice from three strains (C3H/He, C57BL/6 and B6C3F1) showing different genetic backgrounds for carcinogenesis. Bone tumors, mostly osteosarcomas, appeared early during the period from 200 to 600 days after the injection, showing an almost similar dose responsiveness with a peak incidence of 50% to 63% at skeletal doses of 2-3 Gy, in all mouse strains. The primary sites of bone tumors from these strains were also predominantly distributed in 80% to 90% of the skeletal bones, which had well-developed trabecular bone surfaces and large vascular sinusoids. The frequency of lymphoid neoplasms was significantly lower than the control values, and some appeared earlier at the higher injected doses than those of the controls. Fewer or no myeloid leukemias were found in all the control and injected animals, and the incidences of other solid tumors decreased, reaching zero at doses where the maximum incidences of bone tumors were noted. These findings indicate that osteosarcoma is the only specific tumor commonly observed among different mouse strains following the injection of soluble plutonium compounds.

Fatigue microdamage in the radial predilection site for osteosarcoma in dogs.

To evaluate whether body size and anatomic site influence the quantity of bone microdamage in dogs without osteosarcoma (OS). Pairs of radii were collected from 10 small dogs (< 15 kg) and 10 large dogs (> 25 kg). Specimens were stained in basic fuchsin for bone microdamage. Transverse sections were cut from each proximal and distal radial metaphysis at 15 and 85% of bone length. The following variables were determined for each region: mean microcrack length (CrLe, microM), microcrack density (CrDn, microcracks/mm2), microcrack surface density (CrSDn, microm/mm2), and estimated activation frequency (Acf, microcracks/mm2/y). Metaphyseal region did not significantly influence CrDn, CrLe, and CrSDn. The CrDn and CrSDn were influenced by body size, with microdamage being increased in large dogs, compared with small dogs. However, mean CrLe was not significantly influenced by body size. Acf significantly decreased with age and was significantly decreased in large dogs and in the distal radial metaphysis, compared with small dogs and the proximal radial metaphysis, respectively. Our data did not reveal an increase in microdamage or remodeling at the OS predilection site (ie, the distal metaphysis of the radius), suggesting that induction of microdamage and an associated increase in bone remodeling are unlikely to be an important risk factor for induction of OS.

Induction of osteosarcoma and acute myeloid leukaemia in CBA/H mice by the alpha-emitting nuclides, uranium-233, plutonium-239 and amercium-241

Purpose : To compare tumour induction in CBA/H mice, principally osteosarcoma and acute myeloid leukaemia, resulting from exposure to the alpha-emitting nuclides, uranium-233, plutonium-239 and americium-241, and to relate differences between the three nuclides to the pattern of dose delivery within tissues. Materials and methods : Each nuclide was administered intraperitoneally in citrate solution to three groups of adult male CBA/H mice at levels of activity which gave estimated life-time average skeletal doses of about 0.25-0.3 Gy, 0.5-1 Gy and 1-2 Gy. Animals were carefully monitored and sacrificed as soon as they showed signs of ill health; tumours were identified by standard histopathological techniques. Results : Statistical modelling by Cox regression showed that, considering all three nuclides together, there was a highly significant increase in risk of death from osteosarcoma or myeloid leukaemia with increasing dose rate. For osteosarcoma, the effect was significantly greater for 239 Pu than 241 Am, while separate analysis for 233 U showed no significant increase with increasing dose rate. For example, the increase in relative risk of death from osteosarcoma for an increase in life-time average dose rate to bone of 1 mGy d -1 was 4.2 (2.7-6.5) for 239 Pu, 2.3 (1.4-3.4) for 241 Am and 1.1 (0.4-3.1) for 233 U. For myeloid leukaemia, there was no significant difference between 239 Pu and 241 Am in the effect of dose rate. The increase in relative risk from myeloid leukaemia for an increase in average dose rate of 1 mGy d -1 was 1.8 (1.1-2.8) for 239 Pu, 2.0 (1.4-2.9) for 241 Am and 1.5 (0.8-2.7) for 233 U. Significant increases in renal and hepatic carcinomas were also recorded in animals exposed to 233 U and 241 Am, respectively. Studies of the distribution of the nuclides within the skeleton, published separately, have shown differences in their retention in individual bones and within bone. The proportions of decays occurring near to endosteal bone surfaces and throughout bone marrow were in the order: 239 Pu > 241 Am > 233 U. Conclusions : For osteosarcoma, the relative effectiveness of the nuclides in terms of average bone dose, in the order 239 Pu > 241 Am > 233 U, is consistent with the proportion of dose delivered near to endosteal surfaces. For myeloid leukaemia, the greater effectiveness of 239 Pu and 241 Am than 233 U is consistent with their accumulation in marrow.

Tumorigenic target cell regions in bone marrow studied by localized dosimetry of 239 Pu, 241 Am and 233 U in the mouse femur

Purpose : To study the temporal change in microdistribution of plutonium-239, americium-241 and uranium-233 in the mouse distal femur and to compare and combine calculated radiation doses with those obtained previously for the femoral shaft. Also, to relate doses to relative risks of osteosarcoma and acute myeloid leukaemia. Materials and methods : Computer-based image analysis of neutron-induced and α -track autoradiographs of sections of mouse femora was used to quantify the microdistribution of 239 Pu, 241 Am and 233 U from 1 to 448 days after intraperitoneal injection. Localized dose-rates and cumulative doses over this period were calculated for different regions of the marrow spaces in trabecular bone. The results were then combined with previous data for doses to the cortical marrow of the femoral shaft. A morphometric analysis of the distal femur was carried out. Results : Initial deposition on endosteal surfaces and dose-rates near to the trabecular surfaces at 1 day were two to four times greater than corresponding results for cortical bone. Burial was most rapid for 233 U, about twice the rate in cortical bone. As in cortical bone, subsequent uptake into the marrow was seen for 239 Pu and 241 Am but not 233 U. Cumulative doses to 448 days for different regions of trabecular marrow were greater than corresponding values for cortical marrow for each radionuclide. Combined doses reflected the greater overall volume of cortical marrow. Conclusions : Cumulative radiation doses to the 10 μ m thick band of marrow adjacent to all endosteal surfaces were in the ratio of ~7:3:1 for 239 Pu: 241 Am: 233 U. This ratio is not inconsistent with observed incidences of osteosarcoma induction by the three nuclides. Analysis of doses to different depths of marrow, however, showed that although ratios were probably not significantly different to that for a 10 μ m depth, better correlations with osteosarcomagenic risk were obtained with 20-40 μ m depths. For acute myeloid leukaemia, the closest relationship between relative risk and doses was obtained by considering only the central 5-10% of marrow, which gave a dose ratio of ~12:11:1 for 239 Pu: 241 Am: 233 U respectively.

Temporal Change in Microdosimetry to Bone Marrow and Stromal Progenitor Cells from Alpha-Particle-Emitting Radionuclides Incorporated in Bone

The microdistributions of the alpha-particle-emitting bone surface-seeking radionuclides (239)Pu, (241)Am and (233)U in the mouse femoral shaft have been studied using computer-based image analysis of neutron-induced and alpha-particle track autoradiographs, prepared from femora of CBA/H mice which had been injected with 40 kBq kg(-1) of radionuclide (as citrate solution) at times from 1 to 448 days previously. Employing dosimetric methods, radiation dose rates and cumulative radiation doses to regions of the bone marrow thought to contain hemopoietic and stromal progenitor cells susceptible to neoplastic transformation to leukemia and osteosarcomas have been calculated. It has been shown that the three radionuclides differ in their relative deposition on the bone surfaces, and that patterns of changing redistribution with time are also varied. For stromal progenitor cells, which are thought to be targets for induction of osteosarcoma and are found in proximity to the bone surfaces, cumulative doses showed the trend (239)Pu > (241)Am > (233)U, correlating well with incidences of osteosarcoma observed in mice. Cumulative doses to the primitive hemopoietic stem cells, concentrated in the central marrow and thought to be susceptible to neoplastic transformation to myeloid leukemia, were considerably lower and also showed the trend plutonium > americium > uranium.

Consideration of tissue response in the application of the two-mutation model to radiation carcinogenesis

The Moolgavkar-Venzon-Knudson (MVK) twomutation model of carcinogenesis is an analytical model that predicts the variation of cancer yield-rate with time, and with dose of a carcinogen. The model is biologically based, and assumes that a specific mutation in a stem-cell will increase its rate of proliferation compared with that of unmutated cells, so that a clone of pre-malignant cells develops; a second specific mutation in any one of these will make it malignant, and a cancer will start to grow. The model has been used in recent years to analyse a number of sets of epidemiological data on carcinogenesis. The purpose of this paper is to point to a problem in the use of this model for radiation-induced carcinogenesis, namely that ionizing radiation causes reproductive death of stem cells, which leads to regenerative division and hence a change in the number of stem-cells at risk. The possible effects of such changes on the predictions of the model are discussed. At low dose-rates of continuous or chronic irradiation and at low doses of acute irradiation, it is expected that pre-malignant cells will be killed along with the unmutated cells, and that the regenerative division of the surviving pre-malignant cells will restore the numbers of both stem cells and pre-malignant cells to what they would have been in the absence of cell killing; hence, no net effect of the tissue regeneration is expected. At high dose-rates, the initial delay in regenerative division and subsequent faster proliferation are expected to lead to an initial reduction in tumour yield-rate with time (compared with that predicted by the MVK model) followed by a faster increase. For acute irradiation, in the particular case of beta -particle irradiation of the skin, at high doses where there are practically no surviving cells in the irradiated area, repopulation by unirradiated cells from the margin is predicted to lead to a decrease in tumour yieldrate with dose. The predictions have been compared with published data on the induction of osteosarcoma in mouse by repeated injection of 89Sr, the induction of skin tumours in rat by acute and chronic irradiation with electrons, and the induction of skin tumours in mouse by acute irradiation with beta -particles. At low doses and dose-rates the basic MVK model fitted the data well. At higher doses and dose-rates the expected effects of tissue regeneration were observed qualitatively, although there were some discrepancies in detail; these are discussed.

Experimental induction of osteosarcoma by subperiosteal radioactive phosphorus injections in rats

In search of a predictable experimental model for the study of therapeutic modalities for osteosarcoma, a group of rats had injections of phosphorus-32 (P-32) colloid subperiostally and were followed for the occurrence of malignant bone tumors until death or for 18 months. Of 50 rats, 26 died of unrelated causes and only 24 were included in the study. Two cases of osteosarcomas, one occurring in month 16 and the other at month 18 were induced; one case demonstrated multiple lung metastases. Clear evidence of the sarcoma inducing effect of P-32 has been obtained in this study. However, a high yield experimental osteosarcoma model was not produced.

Long-term effects on tumour incidence and survival from 241Am exposure of the BALB/c mouse in utero and during adulthood.

BALB/c mice were given 100, 500 or 1500 Bq/g 241Am at day 14 of pregnancy. The offspring were separated from the mothers at birth and followed until death. In addition, adult females and one group of males were also studied for the effects of 241Am following treatment with 45-213 Bq/g. Adults treated with 241Am showed significantly shortened survival and increased incidence of osteosarcoma (to 40 - 50%). The data also suggest that the female mouse is more susceptible to induction of osteosarcoma than the male. There was also a significant increase in osteosarcoma, all bone tumours, all sarcomas, and all leukaemias in the offspring from the contaminated mothers, although this appeared to occur independently of dose. Calculations of the number of osteosarcomas induced per Gy varied for contamination of adult mice between 0.2 and 0.01 and for the offspring between 6 and 0.6. Thus, offspring seemed to be about 10 times more at risk if osteosarcomas induced per mouse Gy are compared. Surprisingly, offspring from mothers treated with 241Am displayed a longer survival time than controls, possibly due to fewer deterministic lung diseases appearing early in life.

The Influence of Selenium, Vitamin E, and Oestrogen on the Development of Tumours in Mice Exposed to90Sr

The primary object of this experiment was to evaluate the potential role of the antioxidants, selenium and vitamin E, in the anti-tumour defence of mice internally irradiated with 90Sr. Comparison in terms of neoplastic response was made between mice kept on a selenium and vitamin E deficient diet and mice given the same deficient diet but administered selenium and/or vitamin E in a controlled manner. The influence of simultaneous oestrogen treatment, known to promote radiogenic osteosarcoma induction, was also investigated. Non-irradiated mice were used as controls. Results are presented as crude and actuarial tumour incidence. No significant difference in tumour yield or actuarial tumour incidence was found when the differently treated mouse groups were compared, and accordingly no support was gained for the theory that the antioxidants selenium and vitamin E constitute a critical part of the complex defence system against neoplasms.

Negative regulation of human c-fos expression by thes retinoblastoma gene product

Inactivation of the retinoblastoma susceptibility gene (RB-1) has been associated with the aetiology of many types of human cancers, leading to the classification of RB-1 as an anti-oncogene or tumour suppressor gene. Given that the protein product of RB-1 (Rb) has a nuclear localization and DNA-binding activity in vitro, it is possible that Rb regulates transcription of certain genes. The promoter of the c-fos gene might be a target for regulation by Rb, because both v-fos and RB-1 are associated with the induction of osteosarcomas in mice and humans, respectively. Also, fos expression is thought to be required for quiescent cells to enter the cell cycle, making the fos promoter an attractive target for suppressors of cell growth. Here we report that Rb can repress c-fos expression and AP-1 transcriptional activity in both serum-induced and cycling 3T3 cells. We have mapped a cis-acting element in the human c-fos promoter that can confer repression by Rb to a heterologous promoter. We have the termed the cis-acting sequence regulated by Rb the retinoblastoma control element.

Osteosarcoma Risk after Simultaneous Incorporation of the Long-Lived Radionuclide 227 Ac and the Short-Lived Radionuclide 227 Th

The effect of injection of 1.85 kBq/kg of the long-lived radionuclide 227Ac on the induction of osteosarcomas in female NMRI mice by different dose levels (18.5, 74, and 185 kBq/kg) of the short-lived radionuclide 227Th was investigated. The highest absolute osteosarcoma incidence was observed with the highest doses of 227Th. Addition of 227Ac resulted in an additional osteosarcoma incidence only at the lowest dose of 227Th and did not affect the osteosarcoma incidence resulting from higher doses of 227Th. The longest times to tumor appearance were observed with 227Ac alone. The latent period in two different age groups (4 weeks and 10-12 weeks) appeared to be similar following injection with combined doses of 227Th and 227Ac but different after injection of each radionuclide alone.

Induction of osteosarcoma after radiation

Induction of osteosarcoma after radiation

In vitro induction of osteosarcoma by transformation of cartilage precursor cell with murine sarcoma virus

In vitro induction of osteosarcoma by transformation of cartilage precursor cell with murine sarcoma virus

Tissue and cell type-specific expression of two human c-onc genes.

Cellular genes containing nucleotide sequences homologous to retroviral oncogenes (v-onc) have been identified in the genomes of a variety of species of both the vertebrate and invertebrate phyla. Expression of such genes, termed c-onc genes, has been shown to be tissue-specific in chickens and mice and to be modulated during murine development and differentiation of human haematopoietic cells. We report here that the level of the c-fos gene transcripts is 100-fold greater in human term fetal membranes than in other normal human tissues and cells. These levels of c-fos expression in human amniotic and chorionic cells are close to the level of v-fos expression that results in the induction of osteosarcomas in mice and transformation of fibroblasts in vitro. This observation suggests that the induction of neoplastic transformation by the FBJ murine osteosarcoma virus may require the expression of the fos gene product at high levels in an inappropriate cell type. In contrast, the human c-fms gene is expressed at high levels specifically in term placenta and trophoblastic cells. The tissue and cell type-specific patterns of c-fos and c-fms expression suggest that the physiological function of the c-fos and c-fms encoded proteins may be associated with those embryo-derived cells whose primary functions are protection and nourishment of the human fetus.

The Role of Time-factor and Rbe for the Induction of Osteosarcomas by Incorporated Short-lived Bone-seekers

The Role of Time-factor and Rbe for the Induction of Osteosarcomas by Incorporated Short-lived Bone-seekers

The Role of Time-factor and Rbe for the Induction of Osteosarcomas by Incorporated Short-lived Bone-seekers

In a large series of experiments, fractionate-d injections of short-lived bone-seekers have been shown in many cases to cause a remarkable increase of the osteosarcoma incidence compared with a single administration of the same total skeletal dose. This effect has been observed with both alpha- and beta-emitters. In addition the latency period was shortened by protracting the dose. The total skeletal doses investigated ranged between 0.9 and 20 Gy for alpha-emitters (224Ra and 227Th) and between 28 and 112 Gy for the beta-emitter (177Lu). In all cases the protracted dose had higher or at least equal effects when compared with a single application. Reference experiments with long-lived alpha- and a-emitting bone-seeking nuclides (226Ra and 90Sr) showed that the incidence of osteosarcomas per Gy was sometimes lower than that observed when the same skeletal dose was applied by protraction of short-lived radionuclides. The dependence of osteosarcoma incidence on dose-time distribution, duration of internal irradiation, and radiation quality is discussed. In this context the possibility that the critical initial dose rate may be related to the initiating event within the multi-stage hypothesis of carcinogenesis is considered.

Osteosarcomas among Beagles Exposed to 239 Pu

A Weibull distribution was fit to the osteosarcoma death times of beagles given single intravenous injections of /sup 239/Pu. For injected doses in the range 0-1..mu..Ci/kg the osteosarcoma incidence rate h(t) at t days after injection can be fit by a quadratic function of injected dose d: h(t) = 2.61 X 10/sup -18/ d/sup 2/t/sup 4.91/. The best-fitting linear function was rejected by the data (P < 0.001). A different formula for h(t), derived from a multistage theory for osteosarcoma induction, was also fit to these data. For this purpose microdosimetry calculations were used to estimate the dose to the cells at risk in the endosteal layer (endosteal dose). According to the best fit, h(t) is a quadratic function of endosteal dose at low doses. A linear dose-response relationship was again rejected. The absence of a linear component at low doses might be explained by the fact that 108 of the 185 animals injected at the lowest doses (<0.02 ..mu..Ci/kg) were still alive at the time these data were collected.