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PubMed1982

The isolation of an antigen binding factor from cultured murine T-lymphocytes.

BALB/c mice were immunized with the random sequence polypeptide [Glu60 Ala40] (GA). 125I-lymphocyte suspensions were prepared from lymph nodes, radiolabelled with 125I and cultured for 18 hours. Supernatant fluids were collected and passed over an immunoabsorbant composed of [D-Glu60 D-Ala40] (D-GA) bound to Sepharose. The non-adherent fraction was then applied to GA Sepharose and the adherent material eluted with 2 M NaSCN. The eluate was relabelled with 125I, reabsorbed to GA Sepharose and eluted. This fraction bound well to GA-Sepharose (50-80%) but not to the enantiomorphic D-GA Sepharose (5-10%). This material did not react with goat antisera directed against murine IgG, IgM or IgA. It was capable of binding to rabbit antiidiotypic sera raised against BALB/c anti-GA, but not to those antibodies raised against BALB/c anti-GAT. It also showed some reaction with rabbit antiserum to a rat T cell factor (TCF). Polyacrylamide gel electrophoresis revealed a major component with an approximate molecular weight of 63,000 which was not affected by reduction and alkylation.

Alanine↗
PubMedDate not supplied

Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia.

White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBCON, mWBCOFF, mANCON, mANCOFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBCON, neither mWBCON, (median 3.5 x 10(9)/L), mANCON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmol/mmol Hb)2 (median value) had pEFS values of 0.84 and 0.70, respectively (P = .16). All 5 patients who relapsed during therapy had mE-MTX*6TGN < 828 (nmol/mmol Hb)2 (P = .03). mWBCOFF and the degree of myelosuppression (= mWBCSHIFT = mWBCOFF - mWBCON; median: 2.5 x 10(9)/L) were related to age (rs = -0.50, P = .001 and rs = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBCSHIFT < 2.5 x 10(9)/L (P = .02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in order children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.

Administration, Oral↗
PubMed1990

Accumulation, intracellular metabolism, and antitumor activity of high- and low-dose methotrexate in human osteosarcoma xenografts.

High doses of methotrexate with leucovorin rescue are routinely used in the treatment of patients with osteosarcoma; the rationale for this application is controversial. Using human osteosarcoma xenografts growing in mice as a clinically relevant model, we compared the accumulation, intracellular metabolism, and tumor response of methotrexate administered as either high-dose (2400 mg/kg) or low-dose (150 mg/kg) infusions. The high-dose regimen, which included i.v. hydration and leucovorin rescue, resulted in plasma methotrexate levels that approximated those in patients receiving the drug at 12 g/m2. The low-dose infusion produced essentially the same toxicity as the higher dose level, without use of leucovorin. The HxOs33 tumor line was moderately sensitive to the high-dose infusion (55-day delay in tumor volume doubling time), whereas the second line, HxOs2, did not respond. Neither xenograft had a measurable response to low-dose methotrexate. Methotrexate was present in both tumors for up to 72 hr post-infusion, regardless of the dosage regimen. Only shorter-chain polyglutamates (MTXglu2 and MTXglu3) were detected over this period in the high-dose trial, and levels of these derivatives were uniformly higher in the resistant HxOs2 xenograft. Low-dose infusions were associated with formation of longer-chain polyglutamate species, with more abundant production in the HxOs2 line. Methotrexate polyglutamates exceeded baseline [3H]MTX binding of dihydrofolate reductase, as measured in tumor homogenates, at all testing intervals through 72 hr in both tumor lines. Nonetheless, high-dose methotrexate-induced suppression of [14C]formate incorporation into DNA was greater in the drug-sensitive HxOs33 tumor than in HxOs2. These results suggest a therapeutic advantage for high-dose methotrexate regimens in the treatment of human osteosarcoma but show that formation of tumor MTX polyglutamates is not the sole determinant of response to this agent.

Animals↗
PubMed2004

CT-2103: a novel macromolecular taxane with potential advantages compared with conventional taxanes.

CT-2103 (Xyotax) is a polymer-drug conjugate designed to improve upon the therapeutic index and tolerability of conventional taxanes. Because standard chemotherapy drugs distribute randomly in the body, both tumor and normal tissues are exposed to the cytotoxic effects of these drugs. In contrast, conjugation of low molecular weight drugs, such as paclitaxel, to a polymer results in significant passive tumor targeting by the enhanced permeability and retention effect. Moreover, appropriately designed polymer-drug conjugates form polymeric prodrugs that are inert during transport. The release of the active drug is dependent on cleavage of the polymer backbone following endocytic uptake of the conjugate into tumor cells. Preclinical studies show that CT-2103 accumulates in the tumor tissue and that paclitaxel is slowly and progressively released from the polymer. Clinical pharmacokinetics data show that CT-2103 is stable in plasma; data are consistent with prolonged tumor exposure and reduced systemic exposure to active drug. Based on the promising results in phase I/II studies, 3 phase III trials of CT-2103 were initiated in advanced non-small-cell lung cancer (NSCLC). These Selective Targeting for Efficacy in Lung Cancer, Lower Adverse Reaction (STELLAR) trials represent the largest randomized phase III programs in patients with NSCLC and a poor performance status.

Antineoplastic Agents↗
PubMed1999

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.

Carrier Proteins↗
PubMedDate not supplied

Methotrexate polyglutamate levels in circulating erythrocytes and polymorphs correlate with clinical efficacy in rheumatoid arthritis.

OBJECTIVES: To measure MTX polyglutamates in circulating erythrocytes (E-MTX), mononuclear cells (MNC-MTX) and polymorphs (PMN-MTX) in rheumatoid arthritis (RA) patients and to see whether these correlated with clinical efficacy and side effects. METHODS: Sixty-five patients (40F, 25M; mean age 57 yrs.) with RA (ARA revised criteria) who had been on weekly pulse MTX (2.5-37.5 mg) for at least 2 months were entered into this study. The patients were classified as responders (R), partial responders (PR) or non-responders (NR) when blood was sampled for the MTX determination. Side effects since the initiation of MTX were also recorded. MTX-polyglutamates were measured (blinded to clinical details) using an enzymatic assay. RESULTS: E-MTX in responders and partial responders were significantly higher (p < 0.001) than in non-responders. Similarly, PMN-MTX were also higher, but the difference was only significant for the R group (p = 0.0019). The differences in concentrations could not be explained on the basis of the dose, which tended to be higher in NR than in R (p = 0.085). The concommitant prednisolone dose was significantly lower in R than in NR (p = 0.001), as were the ESR and CRP (p = 0.007, and p = 0.05 respectively), but the MCV was higher (p = 0.047). E-MTX tended to be higher in patients with side effects, but this difference did not reach statistical significance (p = 0.15). CONCLUSION: The results suggest that circulating intracellular levels of MTX polyglutamates in RBC and PMN correlate with clinical efficacy but not with toxicity in patients with RA.

Adult↗
PubMed1999

[A 90-day subchronic oral toxicity study of Bacillus subtilis gum in F344 rats].

A 90-day subchronic toxicity study of Bacillus subtilis gum was performed in both sexes of F344 rats by feeding of CRF-1 pellet diet containing 0%, 0.18%, 0.55%, 1.66% and 5%. Rats were randomly allocated to 5 groups, each consisting of 10 males and females. No animals died during the administration period and no differences in body weights and food intakes were found among groups of either sex. Kidney weight was significantly increased in both sexes in the groups given concentrations of 1.66% or more. However, the increases of kidney weight were slight in themselves and other data on serum biochemistry and histopathology did not show any apparent toxicological signs including renal toxicity. These findings indicate that the treatment of Bacillus subtilis gum in the diet for 90 days does not exert serious toxicity in rats even at the highest dose.

Animals↗
PubMed2000

Leucovorin rescue from raltitrexed (tomudex)-induced antiproliferative effects: in vitro cell line and in vivo mouse studies.

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor that is effective for the treatment of advanced colorectal cancer and other solid tumors. However, a small minority of patients receiving RTX monotherapy will experience grade III/IV gastrointestinal toxicity that can be life-threatening, particularly if copresenting with neutropenia. Lack of vigilance in recognition and treatment of symptoms of toxicity or violations of protocol have led to treatment-related deaths in some hospitals. The safety of RTX could be improved if an effective rescue agent was available. Leucovorin (LV) is a reduced folate cofactor that competes with RTX for transport and polyglutamation in both tumor and normal tissues and thus has potential as a rescue agent. In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV. The mechanisms involved are inhibition of further drug uptake and polyglutamation and a redistribution and/or reduction in the concentration of preformed raltitrexed polyglutamates. A more clinically relevant in vivo mouse model was used to test the hypothesis further. BALB/c mice treated with 100 mg/kg/day x 4 days of RTX were used as a model for gastrointestinal and bone marrow toxicity. LV (200 mg/kg), which was given after the onset of severe weight loss and diarrhea (twice daily, days 5-7), prevented further weight loss and induced earlier recovery. This was accompanied by improvement in the histological appearance of the intestine (day 7) and the concentration of neutrophils and platelets in the blood (day 9). BALB/c mice could not tolerate 100 mg/kg daily x 5 days unless LV (200 mg/kg twice daily) was given on days 6-8. Measurement of RTX (polyglutamates) by RIA after 100 mg/kg RTX daily (days 1-4) showed less drug in plasma (3-4-fold), liver (8-11-fold), kidney (3-4-fold), and small intestinal epithelium (3-4-fold) on day 7 in LV-treated mice (100 or 200 mg/kg twice daily) compared with controls. A single injection of 100 mg/kg RTX (day 1) gave plasma levels of 3-4 pmol/ml on day 4 that are more clinically relevant. Administration of LV (100 or 200 mg/kg; twice daily on days 4-6) reduced the RTX concentration in the liver 2-4-fold on days 7, 9, and 11 compared with controls. A model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the homeostatic regulation of RTX polyglutamates. These data support the use of LV rescue in the small minority of patients treated with RTX who present with a severe pattern of antiproliferative toxicities. The use of LV is not recommended routinely because the antitumor activity of RTX may similarly be reversed.

Animals↗
PubMed2000

Breast cancer susceptibility gene 1 (BRCAI) is a coactivator of the androgen receptor.

In the present study, the role of BRCA1 in ligand-dependent androgen receptor (AR) signaling was assessed. In transfected prostate and breast cancer cell lines, BRCA1 enhanced AR-dependent transactivation of a probasin-derived reporter gene. The effects of BRCA1 were mediated through the NH2-terminal activation function (AF-1) of the receptor. Cotransfection of p160 coactivators markedly potentiated BRCA1-mediated enhancement of AR signaling. In addition, BRCA1 was shown to interact physically with both the AR and the p160 coactivator, glucocorticoid receptor interacting protein 1. These findings suggest that BRCA1 may directly modulate AR signaling and, therefore, may have implications regarding the proliferation of normal and malignant androgen-regulated tissues.

BRCA1 Protein↗
PubMed2000

Inhibition of polymer-induced red blood cell aggregation by poloxamer 188.

Previous reports have suggested that non-ionic poloxamer surfactants of appropriate molecular mass and composition can reduce red blood cell (RBC) aggregation in whole blood and in RBC-plasma suspensions. We have thus evaluated this phenomenon for RBC aggregated by several water-soluble polymers, using poloxamer 188 (P188), a non-ionic, tri-block molecule (total molecular mass of 8.40 kDa, 80% polyoxyethylene). Human RBC were washed, then re-suspended in isotonic solutions of dextran 70 (70.3 kDa), dextran 500 (476 kDa), PVP (360 kDa) or P-L-GLU (61.2 kDa); density-separated RBC were also studied. RBC aggregation was quantitated via a computerized Myrenne Aggregometer (extent, strength) and by the Microscopic Aggregation Index (MAI) method. Over the range of 0.5 to 5 mg/ml, poloxamer 188 inhibited both the extent and strength of aggregation in a dose-dependent manner, with the magnitude of the decrease related to polymer type (e.g., at 5 mg/ml, 62% decrease for dextran 70 vs. 14% decrease for P-L-GLU); MAI results with dextran 70 also showed a dose-dependent decrease. Poloxamer 188 at 5 mg/ml was more effective with younger, less-dense cells. Based upon the depletion model for polymer-induced aggregation, these findings suggest that poloxamer 188 acts by penetrating the depletion layer near the glycocalyx, thereby reducing the osmotic gradient between the intercellular gap and the suspending medium. Regardless of the specific mechanism(s) of action, poloxamers appear to offer interesting approaches for future basic science and clinical studies, and thus the possibility for greater insight into RBC aggregation.

Cells, Cultured↗
PubMedDate not supplied

Mode of action of methotrexate-albumin in a human T-cell leukemia line and activity against an MTX-resistant clone.

Limitations of low mol. wt anticancer drugs are short tumor exposure times and toxicity to normal tissue. Methotrexate (MTX) covalently linked to human serum albumin (HSA) as a macromolecular carrier caused tumor regressions concomitant with a favorable toxicity profile in a clinical phase I trial (Hartung et aL, Clin. Cancer Res., 1999, 5, 753). We examined the uptake, intracellular degradation, metabolism and thymidylate synthase (TS) inhibition of MTX-HSA in the T-cell leukemia line CCRF-CEM and the MTX transport resistant clone CCRF-CEM/MTX. The number of MTX molecules per albumin molecule was determined by electrospray mass spectrometry. A loading ratio (LR) of approximately 1.4 mol MTX/albumin revealed intact complexes with one and two MTX molecules/albumin. In the complex with an LR of 5.7, albumin with up to 16 MTX molecules was seen. MTX-HSA was taken up by CCRF-CEM cells via endocytosis and cleaved by lysosomal enzymes. Liberated MTX was a poor substrate of folylpolyglutamate synthetase and was exported into the medium. TS was inhibited and cell survival was impaired by MTX-HSA in a time- and concentration-dependent manner. CCRF-CEM/MTX cells exhibited a growth inhibition of 30-40% after MTX-HSA treatment, but no TS inhibition. The alternative uptake route via endocytosis enables MTX-HSA to overcome transport resistance to MTX.

Antimetabolites, Antineoplastic↗
PubMed2002

Methotrexate intracellular disposition in acute lymphoblastic leukemia: a mathematical model of gamma-glutamyl hydrolase activity.

Methotrexate (MTX) is an antifolate that is widely used for the treatment of childhood acute lymphoblastic leukemia (ALL) and a number of other malignant and nonmalignant diseases. Within cells, MTX is metabolized to more active methotrexate polyglutamates (MTXPG), and these polyglutamates are subsequently cleaved in lysosomes by gamma-glutamyl hydrolase (GGH). GGH is reported to act as either an endopeptidase or an exopeptidase, exhibiting species differences in these functions. To better define the in vivo functions of GGH in human leukemia cells, we characterized GGH activity with different MTXPG substrates (MTX with three to five glutamates) in human T- and B-lineage leukemia cell lines, and in primary leukemia cells from newly diagnosed patients with ALL. Parameters estimated from fitting a series of hypothetical mathematical models to the data revealed that the experimental data were best fit by a model where GGH simultaneously cleaved multiple glutamyl residues, with highest activity at cleaving the outermost or two outermost residues from a polyglutamate chain. The model also revealed that GGH has a higher affinity for longer chain polyglutamates. Together, these findings provide new insights to the intracellular disposition of MTX in human ALL cells, and provides a mechanism-based model for characterizing differences among patients and genetic subtypes of ALL.

Antimetabolites, Antineoplastic↗
PubMed2002

[Primary study on establishment of namalwa 12/MTX resistant cell strain and its mechanism].

BACKGROUND & OBJECTIVE: Methotrexate has been used to treat malignant tumor for 50 years. Different mechanisms of methotrexate resistance has been known in various kinds of leukemias. Because of individualized chemotherapy according to different drug metabolism in different leukemia patients, the treatment became more reasonable and scientific and the treatment effect has been gradually improved. However, there was few report about its drug resistance mechanism in lymphoma. This study was designed to establish Burkitt's lymphoma methotrexate resistant cell strain--Namlwa 12/MTX and study its resistant mechanism. METHODS: Namlwa 12/MTX resistant cell strain was established by repeated impulsed exposure to methotrexate. The difference of the methotrexate effect on Namlwa 12/MTX and Namlwa cell strains were evaluated with MTT method. The level of dihydrofolate reductase (DHFR) mRNA expression was assayed with RT-PCR. The function of the reduced folate carrier (RFC) were tested with 3H-MTX labeling and counted with beta-liquid scintillation counter. The capacity to form the polyglutamate methotrexate (MTXPG) in these cell strains was assayed with 3H-MTX labeling and high pressure liquid chromatography (HPLC) separation. RESULTS: More than 20 times methotrexate resistance was found in Namalwa 12/MTX cell strain in comparison with the Namalwa cell strain. This resistance was not associated with the dysfunction of the RFC, but was closely associated with the amount of MTXPG formed. The amount of total MTXPG (MTXPG1-6) formed in these 2 cell strains was (1583 +/- 26) pmol/10(9) tumor cells and (4453 +/- 236) pmol/10(9) tumor cells, respectively (P < 0.05), while the amount of long chain MTXPG (MTXPG4-6) formed only accounted for 5.5% and 25.4% of the MTXPG1-6, respectively (P < 0.05). The level of DHFR mRNA expression was gradually increased with the formation of the drug resistance in Namalwa 12/MTX. CONCLUSION: Synthesizing difficulty of MTXPG and over-expression of DHFR mRNA level result in methotrexate resistance in Namalwa 12/MTX cell strain.

Antimetabolites, Antineoplastic↗
PubMed2002

[Study on adhesion of platelets to surface of copoly(benzyl glutamate-hydroxy ethyl glutamine)].

Copoly (benzyl glutamate-hydroxy ethyl glutamine) were prepared by partially aminolysis of poly benzyl glutamate with hydroxyl ethylamine at 60 degrees C for predeternined period. As aminolysis was proceeding, the content of hydroxy ethyl glutamine in copolymer increased and the yield of aminolysis decreased. When aminolysis time reached 16.5 hours, a copolymer with 0.357 mole fraction of hydroxy ethyl glutamine was obtained. After 16.5 hours a soluble yellow viscous product of reaction was obtained. The aminolysized specimens displayed more swelling degree in water, that is, more hydrophilits. The meassurement of solid-liquid contact angles showed that an increase in critical surface tention with content of hydroxy ethyl glutamine in copolymer was observed. Likewise a obvious increase in polar component and a slight decrease in dispersive of surface free energy, thus an increase in total surface free energy with content of hydroxy ethyl glutamine was found. The platelet adhesion and deformation test indicated that less platelets were adhered to surfaces of all aminolysized specimens than that of both poly benzyl glutamate and polydimethylsilicone. The least adhered platelets on surface of copolymer with 0.133 mole fraction of content of hydroxy ethyl glutamine were observed. The partiall aminolysis of poly benzyl glutamate films is an effective method to improve its hydrophility and antithrombogenicity.

Animals↗
PubMed1992

Effect of cytochrome C oxidase and polyanions on the alkaline transition of ferricytochrome C.

Application of heparin, polyadenylate, polyglutamate and polygalacturonate resulted in changes in the electron absorption spectrum of cytochrome c that resembled those after cytochrome c oxidase application at neutral pH. The formed complexes of cytochrome c with polyanions retain the bond of Met-80 with heme iron. Cytochrome c oxidase and the polyanions increased the apparent pKa of alkaline transition of cytochrome c by an order of magnitude.

Animals↗
PubMed1992

Intracellular metabolism of 5-formyl tetrahydrofolate in human breast and colon cell lines.

This report describes the intracellular metabolism of 5-formyltetrahydrofolate into the various one-carbon substituted folate and polyglutamate pools in a human breast (MCF-7) and colon (HCT 116) carcinoma cell line. Metabolism into the one-carbon substituted pools was found to be time and dose dependent over a concentration range up to 50 microM. A 3-fold increase in total intracellular folate was noted over a 50-fold concentration range (1-50 microM) of 5-formyltetrahydrofolate tested in the colon cell line, while in the breast line, a 6-fold increase was detected over a 500-fold concentration range (0.1-50 microM). The level of 5, 10-methylenetetrahydrofolate, which was detectable only in the breast cell line, was found to increase by a factor of 10 (1.8 pmol/mg to 17.9 pmol/mg) over the concentration range studied. The majority of metabolism was into the 10-formyltetrahydrofolate and tetrahydrofolate pools in the breast cells and into the 5-methyltetrahydrofolate pool in the colon cells. Polyglutamation was also time and dose dependent, with a significant proportion of the total pool represented by the higher polyglutamate forms (Glu3-Glu5) after 24 h of continuous exposure to 5-formyl tetrahydrofolate. Pentaglutamate was the highest level noted in both cell lines. The intracellular half-life of the polyglutamate forms was inversely related to the length of the polyglutamate tail with half-lives of 71, 131, 143, 441, and 1167 min for the mono- through pentaglutamate, respectively. Finally, up to a 20:1 ratio of the biologically inactive (6R) isomer to active (6S) isomer of 5-formyltetrahydrofolate resulted in no effect on metabolism into the one-carbon substituted folate pools and only minimal decreases in metabolism to the polyglutamate forms. These studies suggest that prolonged exposure to even relatively low doses of 5-formyltetrahydrofolate may be optimal for intracellular metabolism to the most biologically relevant forms for ternary complex formation with thymidylate synthase and fluorodeoxyuradylate, since longer exposures result in a greater accumulation of the higher polyglutamates.

Breast Neoplasms↗