Osteosarcoma methotrexate

Recently, Choy et al. also reported that LDHs are an efficient drug reservoir for folate derivatives [187]. Folic acid derivatives, folinic acid and methotrexate (MTX), have been successfully hybridized with Mg/Al LDHs by ion-exchange reactions. Cellular uptake tests with the MTX-LDH hybrids were carried out in the fibroblast (human tendon) and osteosarcoma (SaOS-2) cell lines by in vitro assay. They found that the LDH not only plays a role as a biocompatible delivery matrix for drugs but also facilitates a significant increase in the delivery efficiency. 

Oral and parenteral Leucovorin rescue after high-dose methotrexate therapy in osteosarcoma. 

Metastatic osteosarcoma has a poor prognosis unless the disease is confined to the lungs and is resectable. Palliative chemotherapy can be employed with a number of drugs including doxorubicin, cisplatin, carboplatin, methotrexate, ifosfamide and etoposide. 

A 17-year-old girl with a femoral osteosarcoma received her 11th cycle of methotrexate and simultaneously oral doxycycline 100 mg bd for a palpebral abscess. As in previous cycles, pharmacokinetic monitoring of methotrexate was performed. On this occasion the half-life of methotrexate was more than doubled. She developed hematological and gastroenterological toxicity. 

Methotrexate is a folic acid antagonist that inhibits the enzyme dihydrofolate reductase. This agent is mainly used in the treatment of both cancer [trophoblastic neoplasms, leukemias, breast carcinoma, carcinoma of gastric, esophagus, testes, lymphomas] and non-cancer diseases [psoriasis rheumatoid arthritis]. Recent successful results using high-dose [>lg/ m ] methotrexate followed by leucoverin in the treatment of head and neck carcinomas and osteosarcoma has led to a more widespread use of this therapy in patients with these and other tumors. 

Ferrari S, Sassoli V, Orlandi M, Strazzari S, PuggioH C, Battistini A, et al. Serum methotrexate (MTX) concentrations and prognosis in patients with osteosarcoma of the extremities treated with a multidrug neoadjuvant regimen. J Chemother 1993 5 135-41. 

Leucovorin is used to reduce the toxicity ( rescue ) of high dose methotrexate in osteosarcoma to counteract the action of folic-acid antagonists such as pyrimethamine or trimethoprim and in combination with 4-fluorouracil to prolong survival in patients with advanced colorectal cancer. In this case, leucovorin enhances the toxicity of 5-fluo-rouracil (5-FU), and the doses of 5-FU should be reduced. 

West G W, Weichselbaum R, Little J B (1980). Limited penetration of methotrexate into human osteosarcoma spheroids as a proposed model for solid tumor resistance to adjuvant chemotherapy. Cancer Res. 40 3665-3668. 

When 2 patients with osteosarcoma, treated with high-dose methotrexate 12 give per course, were given ciprofloxacin 500 mg twice daily, either during or 2 days before the start of the methotrexate course, methotrexate elimination was delayed, resulting in raised serum levels, severe cutaneous toxicity and renal impairment. The first patient also had hepatic injury and haematological toxicity. Following increased folinic acid rescue, methotrexate levels normalised after several days. In earlier courses without ciprofloxacin in the first patient and subsequent courses without ciprofloxacin in the second patient, methotrexate elimination was normal. This preliminary report has subsequently been published in full. ... 

An 11-year-old girl with osteosarcoma who developed colitis when treated with high-dose intravenous methotrexate, was subsequently given colestyramine 2 g every 6 hours from 6 to 48 hours after the methotrexate. Serum methotrexate levels at 24 hours were approximately halved. A marked fall in serum methotrexate levels was seen in another patient similarly treated. Colestyramine similarly reduced methotrexate levels in cases of toxicity in another two patients. ... 

A study in a patient with osteosarcoma found that metamizole sodium 4 g daily more than doubled the methotrexate AUC during the first cycle of high-dose methotrexate treatment. ... 

Recently, we looked at the ability of methotrexate, tetrachloroplatinate, a physical mixture of methotrexate and tetrachloroplatinate and a methotrexate-platinum polymers to inhibit various viruses. A related study employing tilorone and a tilor-one derivative and cisplatin polymeric derivatives was carried out. The results will be briefly reported later. For these studies each ceU line is especially chosen to be compatible to support growth for the particular virus. DSC-1 cells are African green monkey kidney epithehal cells, mouse L929 are fibroblast cells, vero cells are African green monkey kidney epithelial cells, and human 143 cells are fibroblast bone osteosarcoma cells. 

Winkler K et al. (1990) Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86). Cancer 66 1703-1710 Witt C et al. (2000) Value of bronchial artery embolisation with platinum coils in tumorous pulmonary bleeding. Eur J Cancer 36 1949-1954... 

Widemann BC, BaUs FM, Bielack-Kempf B, Bielack S, Pratt CB, Ferrari S, Bacci G, Craft AW, Adamson PC. High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma. Cancer 2004 100 2222-32. 

Pe5uiere H, Codglio M, Margueritte G, Vallat C, Blayac JP, Hillaire-Buys D. Optimal management of methotrexate intoxication in a child with osteosarcoma. Ann Pharmacother 2004 38 422-7. 

The use of high-dose methotrexate with leucovorin rescue in such conditions as osteosarcoma has stimulated great interest in the pharmacology and toxicology of this procedure. 

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