Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gallium nitrate is the anhydrate salt of the naturally occurring heavy metal. It has demonstrated antitumor activity in a variety of murine tumor models, including Walker carcinosarcoma 256, fibrosarcoma M-89, leukemia K-1964, adenocarcinoma 755, mammary carcinoma YMC, reticulum cell sarcoma A-RCS, lymphoma P1798, and osteosarcoma 124F. Preclinical studies performed in rats, rabbits, dogs, and monkeys showed the dose-limiting toxicity to be renal. The hepatic, pulmonary, gastrointestinal, hematologic, and integumentary systems were also involved. The major route of elimination is the kidneys, with 35%-71% of the infused dose excreted within 24 hours. Three phase I studies suggested the following phase II doses: 700-750 mg/m2 by short infusion, once every 2-3 weeks; 300 mg/m2/day by short infusion for 3 consecutive days, to be repeated every 2 weeks; and 300 mg/m2/day by continuous infusion for 7 consecutive days, to be repeated every 3-5 weeks. The major organ toxicity reported was renal; however, this can be adequately controlled either by hydration and osmotic diuresis or by use of continuous schedule. (Either maneuver appears to allow delivery of the recommended phase II dose with a less than 30% risk of change in serum creatinine.) In limited phase II evaluation, the drug has shown antitumor activity in patients with either refractory lymphomas or small cell lung carcinoma, with total objective response rates of 28% and 11%, respectively. In addition, it has been effective in the treatment of patients with cancer-related hypercalcemia by having an inhibitory effect on calcium reabsorption from bone. Single-agent phase II studies are planned in all major tumor types. Some are already ongoing in patients with genitourinary malignancies (renal, bladder, prostate, testicular), small cell lung carcinoma, and multiple myeloma. Metabolic studies are in progress at Memorial Sloan-Kettering Cancer Center to further elucidate the mechanism or mechanisms of the hypocalcemic effects.
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PMID:Gallium nitrate: the second metal with clinical activity. 353 51

Carboplatin has been developed for clinical trials as a less nephrotoxic, less emetogenic analog of cisplatin. In preclinical tumor models it was less potent than the parent compound on a molar basis, but reduced toxicity allowed comparable antitumor doses to be given. In phase I studies its dose-limiting toxicities were reversible myelosuppression, especially thrombocytopenia. Leucopenia and anemia occurred to a lesser degree. Other reported toxicities included nausea, vomiting, malaise, myalgia, arthralgia, ototoxicity, hypomagnesemia, and proteinuria. Nausea and vomiting occurred frequently, but was much less severe than that observed with cisplatin. The incidence of serum creatinine elevations was low. The increase was usually reversible and occurred only in association with administration of aminoglycosides, or abnormal pretreatment renal function. Recommended phase II doses by schedule are: bolus every 4 weeks, 400-500 mg/m2 (560 mg/m2 in children); 24 hour continuous infusion every 4 weeks, 320-400 mg/m2; weekly bolus for 4 consecutive weeks with 2 weeks rest, 100-125 mg/m2 (175 mg/m2 in children); bolus for 5 consecutive days every 4 weeks, 77-95 mg/m2. Objective responses were observed during these phase I studies in adult patients (head and neck, breast, renal carcinomas) and children (osteosarcoma, brain stem lesions). In addition to phase II evaluations in all major tumor types, plans for phase III studies in selected tumors are underway.
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PMID:Results of NCI-sponsored phase I trials with carboplatin. 391 Feb 21

Urinary glycosaminoglycan and hydroxyproline excretion was studied in 11 patients with clear evidence of Paget's disease of bone. Urinary hydroxyproline, cetyl pyridinium chloride (CPC)-precipitable uronic acid and CPC-precipitable hexosamine were expressed as ratios to urinary creatinine. Urine samples were concentrated x 1000 by vacuum dialysis and the glycosaminoglycans examined by electrophoresis on cellulose acetate followed by staining with alcian blue. All the cases studied showed markedly raised hydroxyproline excretion, whereas the uronic acid excretion was normal or only slightly raised in 10 of the 11 cases studied. One patient who had a raised uronic acid and raised hydroxyproline concentration was shown to have osteosarcoma as a complication of Paget's disease. THE VERY HIGH HYDROXYPROLINE: creatinine ratio in all cases of Paget's disease (mean 241.8 mmol hydroxyproline/mol creatinine) contrasted sharply with the cases of disseminated neoplasm, where the ratio was either normal or slightly raised (mean 29.3 mmol hydroxyproline/mol creatinine). The ratio of hydroxyproline to CPC-precipitable uronic acid was also markedly raised in cases of Paget's disease (mean 77.3 mmol hydroxyproline/mmol uronic acid) and was lower in the neoplastic group (mean 14.1 mmol hydroxyproline/mmol uronic acid) but showed no advantage over the hydroxyproline: creatinine ratio in differentiating the two groups. THE URINARY HYDROXYPROLINE: creatinine ratio promises to be of value in differentiating between Paget's disease of bone and neoplastic invasion of bone. A marked rise in CPC-precipitable uronic acid excretion alone is more suggestive of neoplastic invasion of bone, and if associated with a marked increase in hydroxyproline excretion, it raises the possibility of neoplastic change in Paget's disease of bone. The results of this study also suggest that bone collagen, rather than bone tissue in general, is primarily affected in Paget's disease.
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PMID:Urinary excretion of glycosaminoglycans and hydroxyproline in Paget's disease of bone, compared with neoplastic invasion of bone. 730 92

We attempted to ascertain renal, hematologic, and neurologic tolerance to ifosfamide (IFX) in pediatric patients previously treated with large single and cumulative doses of cis-Diamminedichloroplatinum-II (CDP) for osteosarcoma (OS). Twenty OS patients were treated with CDP: initially 150 mg/m2 was administered every 2 weeks for a maximum of seven courses. Later, other agents, including additional CDP, were also administered. Twelve patients were treated with intra-arterial CDP, one with intra-arterial, and later intravenous CDP, and seven with intravenous CDP. Patients who relapsed were treated with IFX. Renal function was monitored by measuring creatinine clearance, serum electrolytes, total protein, albumin and CO2 content, and urine analysis during IFX therapy. Prior to initiation of IFX, creatinine clearance was above 60 ml/min/m2 in all except one patient who had developed a hemolytic uremic syndrome (HUS). Cumulative CDP doses ranged from 300 to 22,500 mg/m2, and cumulative IFX doses 12 to 128 gm/m2. Myelosuppression was monitored by obtaining routine hemograms midway between each course of treatment. Neurologic tolerance was assessed by reviewing the medical records for any abnormality. The interval between CDP and IFX ranged from 1 to 64 months. All patients experienced a progressive reduction in creatinine clearance with CDP. The reduction in creatinine clearance, measured from base-line after three to four courses varied from 10 to 53.7%, after four to seven courses from 19 to 78%, and after seven courses from 12 to 80.5%. In all patients except five, including the HUS patient, creatinine clearance remained above 60 ml/min/m2 during IFX therapy. Twelve patients developed hypo-magnesemia in the vicinity of 1.4 to 1.6 mg/dl during CDP treatment and required magnesium supplementation. They were asymptomatic and the abnormality did not affect IFX tolerance. Fourteen patients intermittently displayed variable degrees of glycosuria, phosphaturia, and/or proteinuria during IFX therapy. This was considered to be a forma frustre type of Fanconi's syndrome. Approximately 80% of courses of IFX were associated with reversible myelosuppression. No neurologic abnormalities were detected. The abnormalities detected during IFX treatment were not major, did not give rise to symptomatology, and did not require discontinuation of therapy. Renal abnormalities were considered a forma frustre type of Fanconi's syndrome. Provided a creatinine clearance of 60 ml/min/m2 is accepted as a prerequisite for treatment, and no major preexisting renal disease is present, IFX is well tolerated by most patients previously exposed to very high cumulative doses of CDP.
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PMID:Ifosfamide tolerance in osteosarcoma patients previously treated with cis-diamminedichloroplatinum-II: renal, hematologic, and neurologic observations. 749 10

The acute renal effects of chemotherapy are known, but long-term nephrotoxicity has rarely been investigated. The aim of the present study was to assess long-term renal function in children and adolescents who received at-risk chemotherapy, including cisplatin, ifosfamide, and methotrexate, to treat an osteosarcoma. Renal function tests [creatinine clearance, microalbuminuria, and renal excretion of sodium, potassium, chloride, calcium, magnesium (Mg), phosphorus (P), and uric acid] were prospectively performed 5.4+/-2.2 (+/-SD) years after chemotherapy (total cumulative dose: methotrexate 41+/-31 g/m2, ifosfamide 39+/-14 g/m2, cisplatin 674+/-188 mg/m2) in 18 children and adolescents. The results were compared with 13 normal volunteers matched for age and sex. Creatinine clearance, which was greater than 80 ml/min per 1.73 m2 in all patients, correlated with the total dose of ifosfamide (r=0.55, P<0.05) and cisplatin (r=0.48, P<0.05). Microalbuminuria was noted in 4 patients. Hypomagnesemia was present in 4 and hypercalciuria in 3 patients; renal excretion of P, Mg, and uric acid was higher in patients than in controls. Glomerular function was not significantly altered and only mild tubular dysfunction was present. Since renal excretion of P and Mg were increased in patients compared with normal volunteers and hypercalciuria was occasionally seen, divalent ion disorders are the most-likely potential complications.
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PMID:Long-term nephrotoxicity of cisplatin, ifosfamide, and methotrexate in osteosarcoma. 976 57

Interleukin (IL)-6 promotes osteoclastogenesis and is thought to play a role in the bone loss that follows estrogen withdrawal. In vitro studies have demonstrated that IL-6 is produced in response to PTH by cells in the osteoblast lineage and that PTH-induced bone resorption is inhibited by a neutralizing antibody to the IL-6 receptor. In addition, we have recently reported that IL-6 plays a role in PTH-induced bone resorption in humans with chronic PTH excess and in experimental animals during the short-term infusion of PTH. In the current study, we examined whether estrogen withdrawal augments PTH-induced IL-6 production. When cultured in the absence of estrogen, human osteosarcoma cells (Saos-2) treated with PTH demonstrated significantly greater release of IL-6 than cells grown under estrogen-replete conditions, 30-fold vs. 15-fold (P = 0.005). A similar effect but of lesser magnitude was seen with primary human osteoblasts. In vivo, PTH induced IL-6 production was also increased in the estrogen-deficient state (ovx) such that at the end of a 5-day PTH infusion, the mean circulating level of IL-6 was significantly higher in ovx vs. sham/ovx mice (60.1 vs. 16.9 pg/ml; P < 0.0001). The greater increase in circulating levels of IL-6 in PTH-treated ovx mice was paralleled by a greater rise in bone resorption markers with the mean level of urine collagen cross-links in the PTH-treated ovx group being more than 2.5-fold higher than in the PTH-treated sham/ovx animals (236 vs. 88.5 microg/mmol creatinine, P < 0.0001). Mean serum collagen cross-link values were 17.4 microg/liter in PTH-treated ovx vs. 7.4 microg/liter in PTH-treated sham/ovx animals (P < 0.0001). Treatment of animals with estrogen prevented the exaggerated response to PTH infusion such that the increase in both circulating levels of IL-6 and bone turnover markers in estrogen-treated animals were similar to those observed in sham/ovx animals and significantly lower than those in PTH-treated ovx animals. These findings may help to explain the increased skeletal sensitivity to the resorbing effects of PTH seen in the estrogen-deficient state.
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PMID:Estrogen modulates parathyroid hormone-induced interleukin-6 production in vivo and in vitro. 1087 54

Glucocorticoids have an essential role in skeletal development and function but are detrimental in excess. In several tissues, glucocorticoid action is dependent upon the expression of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes, which interconvert active cortisol (F) and inactive cortisone (E). We previously demonstrated the expression of 11beta-HSD isozymes in human osteosarcoma cell lines, osteoblast cultures, and fetal bone. We now characterize 11beta-HSD expression in adult human bone using specific antihuman 11beta-HSD antibodies, riboprobes, and enzyme activity studies. In addition, the effect of 11beta-HSD on bone metabolism in vivo was assessed using the 11beta-HSD inhibitor carbenoxolone in eight normal male volunteers. In fresh normal human bone tissue, both 11beta-dehydrogenase (cortisol-to-cortisone conversion) and reductase (cortisone-to-cortisol conversion) activities were demonstrated. There was considerable interindividual variation in the dehydrogenase, but not reductase, activity. In bone homogenates, activity was NADP-dependent with a K(m) for F of 4.8 +/- 1.2 micromol/L, suggesting the presence of 11beta-HSD1. This was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Immunohistochemistry and in situ hybridization studies demonstrated 11beta-HSD1 isozyme expression in cells of the osteoblast lineage and in osteoclasts. The 11beta-HSD2 isozyme was expressed, but only in osteoblasts and at a low level. Ingestion of 300 mg of carbenoxolone by eight normal volunteers for 7 days resulted in a significant decrease in the bone resorption markers, pyridinoline (Pyr) and deoxypyridinoline (DPyr) (change in urinary Pyr/creatinine -1.55 +/- 0.55 [mean +/- SE], for DPyr/creatinine -0. 4 +/- 0.14 nmol/mmol; p < 0.05 for both), with no overall change in the bone formation markers C- and N-terminal propeptides of type I collagen (PICP and PINP). These data suggest that local tissue metabolism of glucocorticoids is likely to be important in determining the sensitivity of both osteoblasts and osteoclasts to glucocorticoids. In particular, variation in 11beta-HSD isozyme expression and activity may explain individual variation in susceptibility to glucocorticoid-induced osteoporosis.
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PMID:Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone. 1096 48

Amifostine protects normal tissue from the cytotoxic damage induced by radiation and chemotherapy. In this study, 39 consecutive newly diagnosed children with osteosarcoma were assessed; 20 received amifostine and 19 did not. The chemotherapy regimen included an induction phase of three cycles of cisplatin (100 mg/m2), carboplatin (500 mg/m2), and doxorubicin (60 mg/m2), followed by surgery. Alternating cycles of cisplatin/ifosfamide (9 mg/m2), ifosfamide/doxorubicin, carboplatin/doxorubicin, and ifosfamide/carboplatin were administered every 3 weeks to complete 26 weeks of treatment. Amifostine was administered 15 minutes before the infusions of cisplatin and carboplatin in a total of 193 infusions. Side effects during infusions and renal, hearing, and bone marrow toxicities were evaluated and compared between the two groups. Hypotension was observed in 28 (14.5%) infusions. No patient required discontinuation of therapy. Fewer than two episodes of vomiting occurred in 130 (71%) infusions and two to five episodes occurred in 51 (28%) infusions, and no patient had grade 4 toxicity. There was no difference between the two groups regarding renal toxicity (creatinine clearance). Neutropenia and leukopenia were significantly less frequent in the amifostine group. No difference was observed in platelet and hearing toxicities. Amifostine was well tolerated in doses of 740 mg/m2 in children and adolescents, and myelotoxicity was less severe in the amifostine group. This was a pilot study for further evaluation in a larger randomized trial.
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PMID:Use of amifostine in the therapy of osteosarcoma in children and adolescents. 1199 Mar 4

We retrospectively studied 790 patients with osteosarcoma treated by neoadjuvant chemotherapy at a single institution between 1983 and 2000 according to different protocols, all including a high dose of methotrexate (HDMTX), to determine the incidence of delayed clearance of HDMTX, and identify patients at high risk for this kind of toxicity. Chemotherapy was administered according to 7 different protocols, successively activated, in which HDMTX was associated with other drugs (cisplatin, adriamycin, ifosfamide) in different combinations. The doses of MTX ranged between 7.5 to 12 g/m(2) and patients received from 1 to 10 cycles with MTX for a total number of 4219 cycles. The incidence of delayed clearance of MTX (plasma values of the drug at 24 h >5 microM/l) was 8.6% per patient and 1.6% per cycle of treatment. In 51 cases the delayed clearance of MTX was "mild" (plasma values of MTX at 24 h between 5 and 19 microM/l) and in 18 cases "severe" (plasma values of MTX at the 24 h >20 microM/l). The delayed clearance of MTX was significantly correlated with the age of patients (16% for patients over 20 vs. 6% for younger patients: p=0.0001) and was significantly more frequent during the first cycles of chemotherapy (7% during the first 3 cycles of treatment vs. 2% during subsequent cycles). There was also a significant correlation (p=0.0001) between the plasma values of MTX at the end of the infusion and at 18 h and the delayed clearance of the drug. In addition to support treatment by increased hydration and sodium bicarbonate, all patients who experienced the delayed clearance of MTX were treated solely with a high dose of leucovorin (HDLV), which was started at the first 18 h. Significant neutropenia and/or thrombocythopenia, increase of serum creatinine, mucositis of varying degrees and vomiting occurred in most cases of severe delayed clearance of MTX, but all patients completely recovered. We conclude that in spite of adequate hydration and urine alkalinization and the use of pharmacokinetically guided leucoverin rescue, delayed clearance of MTX may still occur and that its incidence is higher in older patients and during the first cycles of treatment. However, if "rescue" treatment is started early, the consequent morbility is tolerable and these patients can be rescued using only HDLV, without the need for extracorporeal removal.
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PMID:Delayed methotrexate clearance in osteosarcoma patients treated with multiagent regimens of neoadjuvant chemotherapy. 1279 34

Hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) are markers of collagen absorption and LP is specific for collagen type I in bone. In the present study we evaluated the concentration of HP and LP in urine of patients with osteosarcoma ( n=20; age range 16-49 years) and chondrosarcoma ( n=15; age range 18-70 years). The values were compared with those obtained from 74 healthy controls (age range 16-83 years). The range and upper limit of normal values (HP(max) and LP(max)) were measured in our control group. High performance liquid chromatography (HPLC) was used to determine concentrations of HP and LP (nmol/mmol creatinine). The average urinary HP concentrations were significantly increased in patients with osteosarcoma ( p=0.001) and chondrosarcoma ( p<0.001), whereas HP remained within the normal range in approximately half of the patients. The average urinary LP concentrations were not increased in osteosarcoma and chondrosarcoma patients as compared with the control group. Further studies in a large group of patients are necessary to evaluate whether HP might be a valuable marker of prognosis, and if its urinary concentration can be correlated to tumour burden.
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PMID:Differential enhancement of collagen crosslink excretion in cases of osteosarcoma and chondrosarcoma. 1451 70


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