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)

The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital. The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 mumol/l) than in the patients who relapsed (571.9 mumol/l) (p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 mumol/l. In fact, according to the mean MTX concentrations, the patients with less than 700 mumol/l showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700 mumol/l MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Serum methotrexate (MTX) concentrations and prognosis in patients with osteosarcoma of the extremities treated with a multidrug neoadjuvant regimen. 851 97

To improve the final treatment results in children with osteosarcoma, we applied after French DD-11 protocol HD MTX increasing with the younger age of patients, modified next on the basis of maximal serum drug concentrations (Cmax) as feed-back dosing. Toxic side effects were analysed according to WHO grading correlated with MTX elimination. We administered 39 HD MTX courses in 13 patients with osteosarcoma: aged 7-20 yrs (median 12 yrs). We performed 301 measurements of MTX concentration using the method of fluorescence polarisation. Therapeutic Cmax of 1000 microM/L and higher were obtained in 20 courses, the mean of lower values was 770 microM/L. We modified the next MTX doses in 23.7% of courses. Drug elimination was good in the majority of cases: in 34 of 39 courses at 24 hrs, in 36 of 39 at 48 hrs. Nevertheless, III and IV degree toxic side-effects accompanied about half of the courses and could not be predicted by MTX serum level measurements. HD MTX therapy with monitoring MTX serum levels proved feasible with acceptable toxicity. Therapeutic MTX levels were obtained in about 60% of cycles in patients with a favourable course of the disease in comparison with 25% in patients with an unfavorable course but the beneficial effect of age-tailored MTX and feed-back dosing on the treatment results will be possible to assess in the next 3 years.
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PMID:[Preliminary evaluation of individualized use of large doses of methotrexate for treatment of osteosarcoma in children and adolescents]. 867 59

In cancer chemotherapy, routine monitoring of drug concentrations has been practical only for methotrexate (MTX). The primary setting for pharmacokinetic monitoring of MTX is its use in high doses (HDMTX) for adjuvant therapy of osteosarcoma, for single-agent treatment of intracranial lymphomas, and in combination therapy of childhood leukemia as well as adult and pediatric non-Hodgkin lymphomas. Typically, HDMTX is infused in doses of 3-15 g/m2 over a period of 6-24 h. Precautions must be taken to ensure a high urine flow and an alkaline urine pH, so as to prevent precipitation of MTX in urine. Patients with decreased renal function, advanced in age, and taking nonsteroidal anti-inflammatory drugs or nephrotoxic agents are at increased risk of developing renal dysfunction during MTX infusion, thus being placed at high risk for toxicity. At the end of HDMTX infusion, and periodically thereafter for 24-48 h, drug concentrations are measured to assure that the disappearance rate of MTX from plasma is occurring at a normal rate. Also, at the end of HDMTX infusion, the patient is given leucovorin (5-formyl-tetrahydrofolic acid; LV), which replenishes intracellular stores of reduced folate and attenuates the toxicity secondary to HDMTX. In the presence of inappropriately high concentrations of MTX, routine doses of LV will be ineffective; the dose of LV required must be increased in proportion to the MTX concentration it faces in plasma. In practice, routine monitoring of plasma MTX concentrations allows early detection of abnormal clearance, as well as institution of early and effective countermeasures, including the use of increased and prolonged LV rescue.
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PMID:Concepts in use of high-dose methotrexate therapy. 869 6

Methotrexate is a therapeutic agent used widely for osteosarcoma. We used an extremely sensitive high-performance liquid-chromatography assay to evaluate 112 urine samples obtained from 28 hospital employees during high-dose therapy with methotrexate and during routine care of patients. The highest cumulative urinary excretion was observed when methotrexate infusions were handled in a workbench from which a portion of filtered air was emitted into the room. Remarkable urine contaminations were identified for personnel, including 1 administrative employee who had "stood by" for 2 h in the room where infusions were prepared. Lower methotrexate concentrations were detected in the urine of nurses whose exclusive function was to care for patients. The urine burden in oncologic nurses decreased after a central pharmacy unit was installed. Methotrexate was excreted in the sweat of patients who were under high-dose therapy, and its elimination half-life was 11.1 h (mean maximal concentration = 1.7 micrograms/ml [n = 51). The maximal burden in spontaneous vomit from these patients was 441.5 micrograms/ml, and it declined to 0.24 micrograms/ml 19.5 h after infusion was completed. No methotrexate was detected in personnel who prepared 20-g methotrexate infusions in the central pharmacy unit. We demonstrated that occupational safety depended not only on technical precautions, but on the skills of specifically trained personnel.
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PMID:Exposure of oncologic nurses to methotrexate in the treatment of osteosarcoma. 875 11

Intra-arterial (IA) and intravenous (IV) cisplatinum (CDP) were studied in a multiagent regimen of neoadjuvant chemotherapy for osteosarcoma of the extremities. Preoperatively two cycles of high-dose methotrexate (HDMTX) were administered, followed 5 days later by CDP and Adriamycin (ADM). MTX and ADM were administered IV, and CDP was delivered IA or IV. Postoperatively, good responders received 3 more cycles of the same drugs, while poor responders had a longer chemotherapy including ifosfamide. The rate of good histological response to chemotherapy was significantly higher in patients treated intraarterially (78% vs 46%: P < .004), while no significant differences in terms of disease-free survival were observed between patients who received CDP IA and patients who received CDP IV (55% vs 51%). In the IA group, however, there was only one local recurrence vs 5 in the IV group. The IA infusion of CDP is more active on the primary tumor than the IV infusion.
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PMID:Intra-arterial versus intravenous cisplatinum (in addition to systemic Adriamycin and high dose methotrexate) in the neoadjuvant treatment of osteosarcoma of the extremities. results of a randomized study. 883 14

Methotrexate (MTX) is a clinically important antifolate that has been used in combination with other chemotherapeutic agents in the treatment of malignancies including acute lymphocytic leukemia, osteosarcoma, carcinomas of the breast, head and neck, choriocarcinoma and non-Hodgkin's lymphoma. The primary target of MTX is the enzyme dihydrofolate reductase (DHFR) which catalyzes the reduction of folate and 7,8-dihydrofolate to 5,6,7,8-tetrahydrofolate. Understanding of MTX action has revealed how cells acquire resistance to this drug. The four known mechanisms of MTX resistance are a decrease in the uptake of the drug, a decrease in the retention of the drug due to defective polyglutamylation or an increase in polyglutamate breakdown, an increase in the enzyme activity and a decrease in the binding of MTX to DHFR. The molecular basis for some of these mechanisms has been elucidated in MTX resistant cell lines; in particular the occurrence of gene amplification resulting in increased DHFR and point mutations resulting in altered DHFR with reduced affinity for MTX. Cloning of the human folylpolyglutamate synthase gene and the reduced folate transport gene have been reported recently and should facilitate the identification of the molecular basis of these resistant phenotypes. DHFR protein has been shown to regulate its synthesis by exerting an inhibitory influence on its own translation. Addition of MTX relieves this inhibition thus providing a possible molecular explanation for the rapid rise in DHFR activity noted in some cells after MTX administration. Alterations in genes involved in regulating the cell cycle such as cyclin D1 and the retinoblastoma (Rb) gene have also been shown to influence cellular response to MTX. Overexpression of cyclin D1 in HT1080, a human fibrosarcoma cell line, results in decreased MTX sensitivity. The molecular basis of this observation is under investigation. Abnormalities in the Rb gene may also have profound effects on MTX sensitivity. Rb interacts with the family of transcription factors called E2F reducing transcription of genes that contain E2F binding sites in the promoter regions e.g. DHFR. When Rb is deleted or rendered nonfunctional levels of "free" or unbound E2F are high resulting in enhanced transcription of genes such as DHFR. This results in increased DHFR protein and may lead to MTX resistance. As the knowledge regarding mechanisms of resistance increases newer approaches to circumvent such resistance or to target resistant cells can be undertaken.
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PMID:Molecular mechanisms of resistance to antifolates, a review. 885 36

Since its discovery in 1948 the clinical applications of methotrexate have widened; and in order to overcome resistances to methotrexate, the concept of high-dose methotrexate has been proposed. The use of rescue by folinic acid, as well as rapid dosage of MTX coupled with pharmacokinetic studies, have permitted us to administer an optimum dose of drug, with maximum therapeutic effects, but with reduced toxicity. Individual adaptation of posology, calculated using the test dose or according to population pharmacokinetic with a Bayesian method of parameter estimation (which allows us to adjust the dose of high-dose methotrexate during its infusion) permits control of inter and intra-individual variations of this drug. After analysis of the different methods proposed, we now present the results of 778 courses of treatment by high-dose methotrexate (while separating 238 courses for osteosarcoma as these formed a homogeneous group of patients). Theoretical maximum concentration and length of infusion were decided by physicians, followed by individual adaptation of posology by pharmacologists at the sixth hour of infusion of methotrexate. This treatment unites maximum security for the patient with no serious side effects (no grade 4 toxicity according to WHO classification), while receiving an optimum dose of methotrexate. In courses of MTX for osteosarcoma, the dose of MTX can be further intensified without risk, by administering on average 65% more than the usual dose in adults (8 g/m2) and 10% more than the usual dose in children (12 g/m2).
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PMID:[Individual dose adjustment of high-dose methotrexate in clinical practice]. 888 Dec

High-dose methotrexate (HDMTX), adriamycin (ADR), and cisplatinum (CDDP) are effective agents in the treatment of osteogenic sarcoma (OS). Individual patient doses are determined by prior successful clinical trials but may be reduced due to ongoing toxicities. It is unknown whether individualized dose reductions of these drugs influence disease outcome. We retrospectively studied 27 consecutively enrolled children treated with HDMTX, ADR, and CDDP as adjuvant chemotherapy for OS, for correlations between disease outcome and several characteristics of drug dosings the cumulative MTX, CDDP, and ADR doses administered and the mean MTX blood levels for each patient. With a median follow-up of 59 months, the actuarial overall and disease-free survival rates were 70% and 59%, respectively. Factors which favorably influenced prognosis on univariate analysis were a cumulative ADR dose of > 300 mg/m2 (P = 0.0002) and a cumulative MTX dose > 114 gm/m2 (P = 0.0048). By multivariate analysis only the cumulative ADR dose > 300 mg/m2 retained prognostic value. We conclude that adjuvant chemotherapy dosages may need to be adjusted for therapeutic efficacy in addition to adjustments made for toxicity. The effect of different cumulative HDMTX and ADR dosages on prognosis in osteosarcoma patients needs to be evaluated in a prospective trial.
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PMID:Prognostic significance of chemotherapy dosage characteristics in children with osteogenic sarcoma. 902 12

Methotrexate is commonly used in the treatment of rheumatoid arthritis. An osteopathy has been described in children treated with methotrexate for leukaemia, consisting of bone pain, osteoporosis and fractures. Animals given short-term high-dose and long-term low-dose methotrexate have both reduced bone formation and increased resorption on histomorphometry. As patients with rheumatic diseases have numerous risk factors for osteoporosis, possible additional risk from low-dose methotrexate is of relevance to the rheumatologist. To investigate further the mechanism of osteoporosis in animals and man, in vitro studies were carried out on an osteoblast cell line, using concentrations found in patients with rheumatic disease. UMR 106 rat osteoblast-like osteosarcoma cells were incubated with methotrexate, and also with sulphasalazine, an anti-rheumatic drug with no known effect on bone, for comparison. A dose-dependent toxic effect of methotrexate on the cell line was observed using concentrations found in patients with rheumatic disease. This was not observed with sulphasalazine. The reduced bone formation observed in animals and man may be due to a direct effect of methotrexate on the osteoblast.
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PMID:Effect of methotrexate and sulphasalazine on UMR 106 rat osteosarcoma cells. 913 25

The effect of intra-arterial versus intravenous infusion of cisplatinum on the histological response of osteosarcoma of the limbs was evaluated based on the results of three studies in which CDP was preoperatively associated with MTX and ADM (1st study), and with MTX, ADM, and IFO (2nd and 3rd studies). In the chemotherapeutic protocol that involved 3 drugs the percentage of "good histological responses to chemotherapy" (defined as tumor necrosis > 90%) was significantly higher in the 40 patients who were administered CDP by intra-arterial infusion as compared to that observed in the 39 patients treated with CDP by intravenous route (78% versus 46%: P .004). In the two sequential studies where 4 drugs were used, the percentage of good histological responses was essentially the same for patients treated with CDP administered intravenously, and for those treated with CDP administered intra-arterially (78% versus 84%). Regardless of the route of infusion used to administer cisplatinum the percentage of "good" histological responses was significantly higher in the 109 patients treated with the 4-drug protocol as compared to the 79 patients treated with the 3-drug protocol (82% vs 62%; P .04). This difference may essentially be attributed to the higher percentage of good responses observed in the 4-drug protocol in patients treated with CDP administered intravenously (78% vs 46% for patients treated i.v. with the 3-drug protocol; P .006). For the patients instead treated with CDP administered intra-arterially the percentage of good responses was essentially the same with the 4-drug protocol and with the 3-drug protocol (84% vs 78%; P ns). These data lead us to conclude that in the neoadjuvant treatment of osteosarcoma of the limbs a preoperative 4-drug protocol (MTX, CDP, ADM, IFO) is more effective than a 3-drug protocol (MTX, CDP, ADM), and that in a 4-drug preoperative chemotherapy protocol intra-arterial infusion of CDP does not offer particular advantages as compared to intravenous infusion.
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PMID:The effect of intra-arterial versus intravenous cisplatinum in the neoadjuvant treatment of osteosarcoma of the limbs: the experience at the Rizzoli Institute. 914 28


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