Methotrexate: An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of TETRAHYDROFOLATE DEHYDROGENASE and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA.Polyglutamic Acid: A peptide that is a homopolymer of glutamic acid.Antirheumatic Agents: Drugs that are used to treat RHEUMATOID ARTHRITIS.Folic Acid Antagonists: Inhibitors of the enzyme, dihydrofolate reductase (TETRAHYDROFOLATE DEHYDROGENASE), which converts dihydrofolate (FH2) to tetrahydrofolate (FH4). They are frequently used in cancer chemotherapy. (From AMA, Drug Evaluations Annual, 1994, p2033)Tetrahydrofolate Dehydrogenase: An enzyme of the oxidoreductase class that catalyzes the reaction 7,8-dihyrofolate and NADPH to yield 5,6,7,8-tetrahydrofolate and NADPH+, producing reduced folate for amino acid metabolism, purine ring synthesis, and the formation of deoxythymidine monophosphate. Methotrexate and other folic acid antagonists used as chemotherapeutic drugs act by inhibiting this enzyme. (Dorland, 27th ed) EC 220.127.116.11.Arthritis, Rheumatoid: A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated.Aminopterin: A folic acid derivative used as a rodenticide that has been shown to be teratogenic.Antimetabolites, Antineoplastic: Antimetabolites that are useful in cancer chemotherapy.Leukemia L1210Reduced Folate Carrier Protein: A ubiquitously expressed folic acid transporter that functions via an antiporter mechanism which is coupled to the transport of organic phosphates.Trimetrexate: A nonclassical folic acid inhibitor through its inhibition of the enzyme dihydrofolate reductase. It is being tested for efficacy as an antineoplastic agent and as an antiparasitic agent against PNEUMOCYSTIS PNEUMONIA in AIDS patients. Myelosuppression is its dose-limiting toxic effect.Folic Acid: A member of the vitamin B family that stimulates the hematopoietic system. It is present in the liver and kidney and is found in mushrooms, spinach, yeast, green leaves, and grasses (POACEAE). Folic acid is used in the treatment and prevention of folate deficiencies and megaloblastic anemia.gamma-Glutamyl Hydrolase: Catalyzes the hydrolysis of pteroylpolyglutamic acids in gamma linkage to pterolylmonoglutamic acid and free glutamic acid. EC 18.104.22.168.Drug Therapy, Combination: Therapy with two or more separate preparations given for a combined effect.Leucovorin: The active metabolite of FOLIC ACID. Leucovorin is used principally as an antidote to FOLIC ACID ANTAGONISTS.Tetrahydrofolates: Compounds based on 5,6,7,8-tetrahydrofolate.Abortifacient Agents, Nonsteroidal: Non-steroidal chemical compounds with abortifacient activity.Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the LIVER to form the active aldophosphamide. It has been used in the treatment of LYMPHOMA and LEUKEMIA. Its side effect, ALOPECIA, has been used for defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer.Drug Resistance: Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Antineoplastic Combined Chemotherapy Protocols: The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.Sulfasalazine: A drug that is used in the management of inflammatory bowel diseases. Its activity is generally considered to lie in its metabolic breakdown product, 5-aminosalicylic acid (see MESALAMINE) released in the colon. (From Martindale, The Extra Pharmacopoeia, 30th ed, p907)Vincristine: An antitumor alkaloid isolated from VINCA ROSEA. (Merck, 11th ed.)Deoxyuridine: 2'-Deoxyuridine. An antimetabolite that is converted to deoxyuridine triphosphate during DNA synthesis. Laboratory suppression of deoxyuridine is used to diagnose megaloblastic anemias due to vitamin B12 and folate deficiencies.Precursor Cell Lymphoblastic Leukemia-Lymphoma: A neoplasm characterized by abnormalities of the lymphoid cell precursors leading to excessive lymphoblasts in the marrow and other organs. It is the most common cancer in children and accounts for the vast majority of all childhood leukemias.Drug Administration Schedule: Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience.6-Mercaptopurine: An antimetabolite antineoplastic agent with immunosuppressant properties. It interferes with nucleic acid synthesis by inhibiting purine metabolism and is used, usually in combination with other drugs, in the treatment of or in remission maintenance programs for leukemia.Dermatologic Agents: Drugs used to treat or prevent skin disorders or for the routine care of skin.Pregnancy, Ectopic: A potentially life-threatening condition in which EMBRYO IMPLANTATION occurs outside the cavity of the UTERUS. Most ectopic pregnancies (>96%) occur in the FALLOPIAN TUBES, known as TUBAL PREGNANCY. They can be in other locations, such as UTERINE CERVIX; OVARY; and abdominal cavity (PREGNANCY, ABDOMINAL).Fluorouracil: A pyrimidine analog that is an antineoplastic antimetabolite. It interferes with DNA synthesis by blocking the THYMIDYLATE SYNTHETASE conversion of deoxyuridylic acid to thymidylic acid.Formyltetrahydrofolates: Tetrahydrofolates which are substituted by a formyl group at either the nitrogen atom in the 5 position or the nitrogen atom in the 10 position. N(5)-Formyltetrahydrofolate is leukovorin (citrovorum factor) while N(10)-formyltetrahydrofolate is an active coenzyme which functions as a carrier of the formyl group in a number of enzymatic reactions.Folate Receptors, GPI-Anchored: Cell surface receptors that bind to and transport FOLIC ACID, 5-methyltetrahydrofolate, and a variety of folic acid derivatives. The receptors are essential for normal NEURAL TUBE development and transport folic acid via receptor-mediated endocytosis.Doxorubicin: Antineoplastic antibiotic obtained from Streptomyces peucetius. It is a hydroxy derivative of DAUNORUBICIN.Phosphoribosylaminoimidazolecarboxamide Formyltransferase: An enzyme that catalyzes the conversion of aminoimidazole-4-carboxamide ribonucleotide to 5-formyl-aminoimidazole-4-carboxamide ribonucleotide in the purine de novo synthesis pathway. It requires the cofactor N(10)-FORMYLTETRAHYDROFOLATE as the formyl donor.Osteosarcoma: A sarcoma originating in bone-forming cells, affecting the ends of long bones. It is the most common and most malignant of sarcomas of the bones, and occurs chiefly among 10- to 25-year-old youths. (From Stedman, 25th ed)Injections, Spinal: Introduction of therapeutic agents into the spinal region using a needle and syringe.Prednisone: A synthetic anti-inflammatory glucocorticoid derived from CORTISONE. It is biologically inert and converted to PREDNISOLONE in the liver.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Cytarabine: A pyrimidine nucleoside analog that is used mainly in the treatment of leukemia, especially acute non-lymphoblastic leukemia. Cytarabine is an antimetabolite antineoplastic agent that inhibits the synthesis of DNA. Its actions are specific for the S phase of the cell cycle. It also has antiviral and immunosuppressant properties. (From Martindale, The Extra Pharmacopoeia, 30th ed, p472)Thymidylate Synthase: An enzyme of the transferase class that catalyzes the reaction 5,10-methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 22.214.171.124.Leukemia, Lymphoid: Leukemia associated with HYPERPLASIA of the lymphoid tissues and increased numbers of circulating malignant LYMPHOCYTES and lymphoblasts.Hydroxychloroquine: A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p970)Central Nervous System Neoplasms: Benign and malignant neoplastic processes that arise from or secondarily involve the brain, spinal cord, or meninges.Pregnancy, Tubal: The most common (>96%) type of ectopic pregnancy in which the extrauterine EMBRYO IMPLANTATION occurs in the FALLOPIAN TUBE, usually in the ampullary region where FERTILIZATION takes place.Sarcoma 180Pteroylpolyglutamic Acids: Derivatives of folic acid (pteroylglutamic acid). In gamma-glutamyl linkage they are found in many tissues. They are converted to folic acid by the action of pteroylpolyglutamate hydrolase or synthesized from folic acid by the action of folate polyglutamate synthetase. Synthetic pteroylpolyglutamic acids, which are in alpha-glutamyl linkage, are active in bacterial growth assays.Isoxazoles: Azoles with an OXYGEN and a NITROGEN next to each other at the 1,2 positions, in contrast to OXAZOLES that have nitrogens at the 1,3 positions.Psoriasis: A common genetically determined, chronic, inflammatory skin disease characterized by rounded erythematous, dry, scaling patches. The lesions have a predilection for nails, scalp, genitalia, extensor surfaces, and the lumbosacral region. Accelerated epidermopoiesis is considered to be the fundamental pathologic feature in psoriasis.Asparaginase: A hydrolase enzyme that converts L-asparagine and water to L-aspartate and NH3. EC 126.96.36.199.Gestational Trophoblastic Disease: A group of diseases arising from pregnancy that are commonly associated with hyperplasia of trophoblasts (TROPHOBLAST) and markedly elevated human CHORIONIC GONADOTROPIN. They include HYDATIDIFORM MOLE, invasive mole (HYDATIDIFORM MOLE, INVASIVE), placental-site trophoblastic tumor (TROPHOBLASTIC TUMOR, PLACENTAL SITE), and CHORIOCARCINOMA. These neoplasms have varying propensities for invasion and spread.Remission Induction: Therapeutic act or process that initiates a response to a complete or partial remission level.Biological Transport: The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.Hydroxymethyl and Formyl Transferases: Enzymes that catalyze the transfer of hydroxymethyl or formyl groups. EC 2.1.2.Probenecid: The prototypical uricosuric agent. It inhibits the renal excretion of organic anions and reduces tubular reabsorption of urate. Probenecid has also been used to treat patients with renal impairment, and, because it reduces the renal tubular excretion of other drugs, has been used as an adjunct to antibacterial therapy.Mucositis: An INFLAMMATION of the MUCOSA with burning or tingling sensation. It is characterized by atrophy of the squamous EPITHELIUM, vascular damage, inflammatory infiltration, and ulceration. It usually occurs at the mucous lining of the MOUTH, the GASTROINTESTINAL TRACT or the airway due to chemical irritations, CHEMOTHERAPY, or radiation therapy (RADIOTHERAPY).Nucleotide Deaminases: Catalyze the hydrolysis of nucleotides with the elimination of ammonia.Carcinoma, Ehrlich Tumor: A transplantable, poorly differentiated malignant tumor which appeared originally as a spontaneous breast carcinoma in a mouse. It grows in both solid and ascitic forms.Double-Blind Method: A method of studying a drug or procedure in which both the subjects and investigators are kept unaware of who is actually getting which specific treatment.Vinblastine: Antitumor alkaloid isolated from Vinca rosea. (Merck, 11th ed.)Antibodies, Monoclonal: Antibodies produced by a single clone of cells.Arthritis, Juvenile: Arthritis of children, with onset before 16 years of age. The terms juvenile rheumatoid arthritis (JRA) and juvenile idiopathic arthritis (JIA) refer to classification systems for chronic arthritis in children. Only one subtype of juvenile arthritis (polyarticular-onset, rheumatoid factor-positive) clinically resembles adult rheumatoid arthritis and is considered its childhood equivalent.Combined Modality Therapy: The treatment of a disease or condition by several different means simultaneously or sequentially. Chemoimmunotherapy, RADIOIMMUNOTHERAPY, chemoradiotherapy, cryochemotherapy, and SALVAGE THERAPY are seen most frequently, but their combinations with each other and surgery are also used.Arthritis, Psoriatic: A type of inflammatory arthritis associated with PSORIASIS, often involving the axial joints and the peripheral terminal interphalangeal joints. It is characterized by the presence of HLA-B27-associated SPONDYLARTHROPATHY, and the absence of rheumatoid factor.Trophoblastic Neoplasms: Trophoblastic growth, which may be gestational or nongestational in origin. Trophoblastic neoplasia resulting from pregnancy is often described as gestational trophoblastic disease to distinguish it from germ cell tumors which frequently show trophoblastic elements, and from the trophoblastic differentiation which sometimes occurs in a wide variety of epithelial cancers. Gestational trophoblastic growth has several forms, including HYDATIDIFORM MOLE and CHORIOCARCINOMA. (From Holland et al., Cancer Medicine, 3d ed, p1691)Time Factors: Elements of limited time intervals, contributing to particular results or situations.Administration, Oral: The giving of drugs, chemicals, or other substances by mouth.Leukemia L5178: An experimental lymphocytic leukemia of mice.Cisplatin: An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle.Hypoxanthines: Purine bases related to hypoxanthine, an intermediate product of uric acid synthesis and a breakdown product of adenine catabolism.
Methotrexate-induced papular eruption: Methotrexate-induced papular eruption appears in patients being treated with methotrexate, such as those with rheumatic disease, presenting with erythematous indurated papules, usually located on the proximal extremities.James, William; Berger, Timothy; Elston, Dirk (2005).Alamanda PolymersAnakinraDihydrofolate reductase inhibitor: A dihydrofolate reductase inhibitor (DHFR inhibitor) is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.Dihydrofolate reductaseACR score for rheumatoid arthritis: ACR score is a scale to measure change in rheumatoid arthritis symptoms. It is named after the American College of Rheumatology.AminopterinNutrition and cognition: Food is conventionally regarded as a means to provide energy and building material within the body. Recently, the ability of food to prevent and protect against diseases has started to become recognized, mainly in relation to the effects of nutrients on molecular processes within the body.Glucarpidase: HNOS (monomer)Combination therapy: Combination therapy or polytherapy is therapy that uses more than one medication or modality (versus monotherapy, which is any therapy taken alone). Typically, these terms refer to using multiple therapies to treat a single disease, and often all the therapies are pharmaceutical (although it can also involve non-medical therapy, such as the combination of medications and talk therapy to treat depression).Folinic acidTetrahydromethanopterinLow-dose chemotherapy: Low-dose chemotherapy is being studied/used in the treatment of cancer to avoid the side effects of conventional chemotherapy. Historically, oncologists have used the highest possible dose that the body can tolerate in order to kill as many cancer cells as possible.Immunosuppressive drug: Immunosuppressive drugs or immunosuppressive agents or antirejection medications are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:SulfasalazineDeoxyuridineMercaptopurineOvarian pregnancyFolate receptor: Folate receptors bind folate and reduced folic acid derivatives and mediates delivery of tetrahydrofolate to the interior of cells. It is then converted from monoglutamate to polyglutamate forms - such as 5- methyltetrahydrofolate - as only monoglutamate forms can be transported across cell membranes.DoxorubicinDihydrofolic acidOsteosarcomaConcentration effect: In the study of inhaled anesthetics, the concentration effect is the increase in the rate that the Fa(alveolar concentration)/Fi(inspired concentration) ratio rises as the alveolar concentration of that gas is increased. In simple terms, the higher the concentration of gas administered, the faster the alveolar concentration of that gas approaches the inspired concentration.CytarabineThymidylate synthase inhibitor: Thymidylate synthase inhibitors are chemical agents which inhibit the enzyme thymidylate synthase and have potential as an anticancer chemotherapy. Five agents were in clinical trials in 2002: raltitrexed, pemetrexed, nolatrexed, ZD9331, and GS7904L.HydroxychloroquineInterstitial pregnancyIsoxazolePsoriasis: (psora + -iasis)AsparaginaseGestational trophoblastic disease: Gestational trophoblastic disease (GTD) is a term used for a group of pregnancy-related tumours. These tumours are rare, and they appear when cells in the womb start to proliferate uncontrollably.Mediated transportUDP-4-amino-4-deoxy-L-arabinose formyltransferase: UDP-4-amino-4-deoxy-L-arabinose formyltransferase (, UDP-L-Ara4N formyltransferase, ArnAFT) is an enzyme with system name 10-formyltetrahydrofolate:UDP-4-amino-4-deoxy-beta-L-arabinose N-formyltransferase. This enzyme catalyses the following chemical reactionProbenecid and colchicine: Probenecid with colchicine is a combination medication used to treat gout. Brand names include ColBenemid, Col-Probenecid, and Proben-C.Peri-implant mucositis: Peri-implant mucositis defines the presence of inflammation in the soft tissue surrounding a dental implant without signs of any loss of supporting bone.Zitzmann, NU; Berglundh, T.AminohydrolaseSimon–Ehrlich wager: Julian L. Simon and Paul Ehrlich entered in a widely followed scientific wager in 1980, betting on a mutually agreed-upon measure of resource scarcity over the decade leading up to 1990.Placebo-controlled study: Placebo-controlled studies are a way of testing a medical therapy in which, in addition to a group of subjects that receives the treatment to be evaluated, a separate control group receives a sham "placebo" treatment which is specifically designed to have no real effect. Placebos are most commonly used in blinded trials, where subjects do not know whether they are receiving real or placebo treatment.VinorelbineMonoclonal antibody therapyChildhood arthritisAbscopal effect: The abscopal effect is a phenomenon in the treatment of metastatic cancer where localized treatment of a tumor causes not only a shrinking of the treated tumor but also a shrinking of tumors in different compartments from the treated tumor. Initially associated with single-tumor, localized radiation therapy, the term has also come to encompass other types of localized treatments such as electroporation and intra-tumoral injection of therapeutics.Dactylitis: Dactylitis or sausage digit is inflammation of an entire digit (a finger or toe), and can be painful.STARD7: StAR-related lipid transfer domain protein 7 (STARD7) or gestational trophoblastic tumor gene-1 (GTT1) is a lipid transporter that specifically binds and transports phosphatidylcholine between membranes.Temporal analysis of products: Temporal Analysis of Products (TAP), (TAP-2), (TAP-3) is an experimental technique for studyingOsmotic controlled-release oral delivery system: OROS (Osmotic [Controlled] Release Oral [Delivery] System) is a controlled release oral drug delivery system in the form of a tablet. The tablet has a rigid water-permeable jacket with one or more laser drilled small holes.Lipoplatin: Lipoplatin (Liposomal cisplatin) is a nanoparticle of 110 nm average diameter composed of lipids and cisplatin. This new drug has successfully finished Phase I, Phase II and Phase III human clinical trials (2,3).
(1/4604) Electronic volume analysis of L1210 chemotherapy.
The rapid analysis of in vivo chemotherapy on the L1210 ascites tumor grown in C57BL/6 X DBA/2F1 mice has been shown by means of an electronic volume analysis. The drugs were injected on the 4th day of tumor growth, and the cells in the peritoneal cavity were studied at 24-hr intervals on the 5th through 7th day. Using the electronic cell volume distributions, combined with labeling indices, cell morphology, and cell counts, it was found that the alkylating agents. 1,3-bis(2-chloroethyl)-1-nitrosourea and cyclophosphamide, at the dosages used, were more effective than the S-phase-specific drugs, palmitoyl ester of 1-beta-D-arabinofuranosylcytosine, vincristine, and methotrexate. (+info)
(2/4604) Tissue pharmacokinetics, inhibition of DNA synthesis and tumor cell kill after high-dose methotrexate in murine tumor models.
In Sarcoma 180 and L1210 ascites tumor models, the initial rate of methotrexate accumulation in tumor cells in the peritoneal cavity and in small intestine (intracellularly) after s.c. doses up to 800 mg/kg, showed saturation kinetics. These results and the fact that initial uptake in these tissues within this dosage range was inhibited to the expected relative extent by the simultaneous administration of leucovorin suggest that carrier mediation and not passive diffusion is the major route of drug entry at these extremely high doses. Maximum accumulation of intracellular drug occurred within 2 hr and reached much higher levels in small intestine than in tumor cells at the higher dosages. At a 3-mg/kg dose of methotrexate s.c., intracellular exchangeable drug levels persisted more than four times longer in L1210 cells than in small intestine, but differences in persistence (L1210 cell versus gut) diminished markedly with increasing dosage. At 96 mg/kg, the difference in persistence was less than 2-fold. In small intestine and L1210 cells, theduration of inhibition of DNA synthesis at different dosages correlated with the extent to which exchangeable drug was retained. Toxic deaths occurred when inhibition in small intestine lasted longer than 25 to 30 hr. Recovery of synthesis in small intestine and L1210 cells occurred synchronously and only below dosages of 400 mg/kg. Within 24 hr after dosages of greater than 24 mg/kg, the rate of tumor cell loss increased to a point characterized by a single exponential (t1/2=8.5 hr). The total cell loss, but not the rate of cell loss, was dose dependent. (+info)
(3/4604) Modulation of the cytotoxicity of 3'-azido-3'-deoxythymidine and methotrexate after transduction of folate receptor cDNA into human cervical carcinoma: identification of a correlation between folate receptor expression and thymidine kinase activity.
Cervical carcinoma is an AIDS-defining illness. The expression of folate receptors (FRs) in cervical carcinoma (HeLa-IU1) cells was modulated by stable transduction of FR cDNA encapsidated in recombinant adeno-associated virus-2 in the sense and antisense orientation (sense and antisense cells, respectively). Although sense cells proliferated slower than antisense or untransduced cells in vivo and in vitro in 2% (but not 10%) FCS, [methyl-3H]thymidine incorporation into DNA was significantly increased in sense cells in 10% serum; therefore, the basis for this discrepancy was investigated. The activity of thymidine kinase (TK) was subsequently directly correlated with the extent of FR expression in single cell-derived clones of transduced cells. This elevated TK activity was not a result of recruitment of the salvage pathway based on the presence of adequate dTTP pools, normal thymidylate synthase (TS) activity, persistence of increased thymidine incorporation despite the exogenous provision of excess 5,10-methylene-tetrahydrofolate, and documentation of adequate folates in sense cells. The increase in TK activity conferred significant biological properties to sense cells (but not antisense or untransduced cells) as demonstrated by augmented phosphorylation of 3'-azido-3'-deoxythymidine (AZT) and concomitantly greater sensitivity to the cytotoxic effects of AZT. Conversely, sense cells were highly resistant to methotrexate, but this was reversed by the addition of AZT. The direct correlation of FR expression and TK activity indicates a previously unrecognized consequence of FR overexpression. (+info)
(4/4604) Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation.
Methotrexate (MTX) is one of the most active and widely used agents for the treatment of acute lymphoblastic leukemia (ALL). To elucidate the mechanism for higher accumulation of MTX polyglutamates (MTX-PG) in hyperdiploid ALL and lower accumulation in T-lineage ALL, expression of the reduced folate carrier (RFC) was assessed by reverse transcription-polymerase chain reaction in ALL blasts isolated from newly diagnosed patients. RFC expression exhibited a 60-fold range among 29 children, with significantly higher expression in hyperdiploid B-lineage ALL (median, 11.3) compared with nonhyperdiploid ALL (median, 2.1; P <.0006), but no significant difference between nonhyperdiploid B-lineage and T-lineage ALL. Furthermore, mRNA levels of RFC (mapped by FISH to chromosome 21) were significantly related to chromosome 21 copy number (P =.0013), with the highest expression in hyperdiploid ALL blasts with 4 copies of chromosome 21. To assess the functional significance of gene copy number, MTX-PG accumulation was compared in ALL blasts isolated from 121 patients treated with either low-dose MTX (LDMTX; n = 60) or high-dose MTX (HDMTX; n = 61). After LDMTX, MTX-PG accumulation was highest in hyperdiploid B-lineage ALL with 4 copies of chromosome 21 (P =.011), but MTX-PG accumulation was not significantly related to chromosome 21 copy number after HDMTX (P =.24). These data show higher RFC expression as a mechanism for greater MTX accumulation in hyperdiploid B-lineage ALL and indicate that lineage differences in MTX-PG accumulation are not due to lower RFC expression in T-lineage ALL. (+info)
(5/4604) Role of folylpolyglutamate synthetase and folylpolyglutamate hydrolase in methotrexate accumulation and polyglutamylation in childhood leukemia.
Inefficient polyglutamylation is a mechanism of resistance to methotrexate (MTX) in childhood T-lineage acute lymphoblastic leukemia (T-ALL) and in acute myeloid leukemia (AML) in comparison with childhood c/preB-ALL. We analyzed the profile of MTX polyglutamylation in childhood c/preB-ALL, T-ALL, and AML (n = 45, 15, and 14, respectively), the activity of the MTX-polyglutamate synthesizing enzyme folylpolyglutamate synthetase (FPGS) (n = 39, 11, and 19, respectively) and of the MTX-polyglutamate breakdown enzyme folylpolyglutamate hydrolase (FPGH) (n = 98, 25, and 34, respectively). MTX-Glu4-6 accumulation after 24 hours exposure to 1 micromol/L [3H]-MTX in vitro was lower in T-ALL (threefold) and AML (fourfold) compared with c/preB-ALL (P =.001). The FPGS activity was twofold lower in T-ALL and AML than in c/preB-ALL samples (P <. 01). FPGH activity was not different between c/preB-ALL and T-ALL, but threefold higher in AML (P <.001). FPGS, FPGH, and the ratio FPGS/FPGH were correlated with MTX-Glu4-6 accumulation (r =.49, r = -.34 and r =.61, respectively). Multivariate analysis showed that FPGS, but not FPGH, was an independent contributor for MTX-Glu1-6 accumulation, but not for MTX-Glu4-6 accumulation. In conclusion, low FPGS activity is associated with low accumulation of MTX-Glu4-6 in T-ALL and AML. For the group of AML as compared with the group of ALL, a high FPGH activity can play an additional role. (+info)
(6/4604) Multimodality therapy for locally advanced and limited stage IV breast cancer: the impact of effective non-cross-resistance late-consolidation chemotherapy.
To determine the effectiveness of non-cross-resistant late-consolidation chemotherapy in locally advanced breast cancer (LABC) and stage IV breast cancer, we review our experience with two regimens. Between 1985 and 1991, we enrolled 56 patients with LABC, who were treated with a doxorubicin-based adjuvant regimen, followed by a late-consolidation non-cross-resistant regimen containing methotrexate, 5-fluorouracil, cisplatin, and cyclophosphamide. Between 1985 and 1996, a total of 45 patients with limited stage IV breast cancer underwent surgical excision of all evaluable disease, making them metastatic (stage IV) with no evaluable disease. Surgery was followed by a doxorubicin-containing regimen and then a late-consolidation non-cross-resistant regimen, which was either methotrexate, 5-fluorouracil, cisplatinum, and cyclophosphamide or 5-fluorouracil, mitomycin, etoposide, and cisplatin. Twenty-four patients with limited bone metastases that were unresectable were treated with a doxorubicin-containing regimen, radiation therapy to all sites of disease, and then one of the two late non-cross-resistant regimens. With a median follow-up of 84 months, 78% of patients with LABC are alive, and 68% are free of disease. After a median follow-up of 44 months, 53% of patients with stage IV with no evaluable disease are alive and free of disease. The use of non-cross-resistant late-consolidation chemotherapy is an effective strategy in the treatment of patients with LABC and selected patients with limited stage IV breast cancer. (+info)
(7/4604) High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission.
We explored the combination of busulfan/cyclophosphamide/etoposide as conditioning regimen prior to bone marrow transplantation in 31 patients with acute myeloid leukemia (AML) in first complete remission. The preparative regimen consisted of 16 mg/kg busulfan, 30-60 mg/kg VP-16, and 120 mg/kg cyclophosphamide. With a median follow-up of 30.5 months (range, 5-60 months), 25 patients are alive in continuous complete remission. Estimated disease-free survival at 5 years is 80.5%. Death was due to transplant-related toxicity (graft-versus-host disease and cytomegalovirus infection, graft-versus-host disease and pneumonia, sepsis and mucositis, respectively). None of the patients have relapsed. As demonstrated by the results of this analysis, the conditioning regimen busulfan/cyclophosphamide/etoposide is effective and well tolerated in patients with AML in first complete remission. Main nonhematological toxicities were mucositis and hepatotoxicity. The low mortality and relapse rate appears to justify allogeneic bone marrow transplantation for patients with AML in first complete remission who have an HLA-identical donor. Whether this regimen offers a substantial improvement in disease-free and overall survival over presently used regimens warrants further investigation. (+info)
(8/4604) The effectiveness of non-surgical management of early interstitial pregnancy: a report of ten cases and review of the literature.
OBJECTIVE: To assess the effectiveness of non-surgical management of interstitial pregnancy. DESIGN: A prospective interventional study. SUBJECTS: Eleven women with the ultrasound diagnosis of interstitial ectopic pregnancy. METHODS: Women with suspected early pregnancy complications were examined by transvaginal ultrasound. Those with the diagnosis of interstitial pregnancy were offered non-surgical treatment with methotrexate, which was administered systemically or by local injection. Follow-up with regular measurements of beta-human chorionic gonadotropin and ultrasound scans continued until the pregnancy had resolved completely. RESULTS: Ten women were managed non-surgically, and one woman opted for surgery. Five women received systemic and five local methotrexate. Local therapy was successful in all five cases (100%), whereas four out of five (80%) women receiving systemic methotrexate were cured. Significant side-effects were noted in two women following systemic therapy. In comparison, there were no side-effects in the group of women who received local therapy. There were no significant differences between the two treatment groups in the length of time taken for the pregnancy to resolve. CONCLUSIONS: Non-surgical treatment of interstitial pregnancy with methotrexate appears to be safe and effective. Local administration appears to be more successful and better tolerated by patients and may be used as the first-line therapy. (+info)