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M Du

Publications and source records attributed to M Du.

At least 91 records · Page 5Linked to original sources

[Effect of monaural cochlear ablation on cell areas of ventral cochlear nucleus neurons in neonatal and adult guinea pigs].

The changes of the cross-sectional areas of anteroventral cochlear nucleus (AVCN) and posteroventral cochlear nucleus (PVCN) were studied in neonatal and adult guinea pigs after monaural cochlear ablation with computer imaging analysis system. The cross-sectional areas of neurons in AVCN and PVCN were not significantly changed after 24 h of monaural cochlear ablation in neonatal guinea pigs. But the cell areas of AVCN neurons of ablated side were respectively reduced by 20.93%, 25.70% and 28.72% compared to non-ablated side in 4 d, 7 d, 60 d after cochlear ablation, the cell areas of PVCN neurons were reduced by 17.58%, 20.30% and 38.55% respectively. The area reduction of AVCN and PVCN neurons of ablated side in 60 d group with monaural cochlear ablation were 51.00% and 32.75% relative to normal control group. Our results showed that cochlear ablation could results in rapid cell area reduction of VCN neurons in guinea pigs. Our investigation implied that it is important to stimulate the auditory nerve early in the patients with hearing loss.

Animals↗

[Simultaneous determination of tyrosine and tryptophan in amino acid injection, animal and plant extracts by polarization spectrofluorimetry].

A new method for the simultaneous determination of tyrosine and tryptophan by polarization spectrofluorimetry has been developed. The interference of phenylalanine and light scattering of solvent were eliminated by using vertically crossed polarizers. The overlapping of fluorescence spectra of the two amino acids was solved with filters. The linear ranges of determination were 0.02-12.0 mg.L-1(tyrosine) and 0.01-2.50 mg.L-1(tryptophan). The mean recoveries of tyrosine and tryptophan in samples were 95.4% and 101.7% (in amino acid injection). 99.2% and 100.0% (in wild jujube kernel), 95.3% and 97.2% (in shrimp shell) respectively. The proposed method has been used to determine tyrosine and tryptophan in amino acid injection, extracts of wild jujube kernel and shrimp shells with satisfactory results.

Amino Acids↗

Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue.

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD62L expression reflected the differentiation of the B cell. Plasma cells were alpha 4 beta 7+, CD62L-, whereas a subset of memory B cells were alpha 4 beta 7-, CD62L+. Homing receptor expression in MALT lymphoma B cells was heterogeneous, however, in line with their memory B-cell phenotype in the majority of cases, the neoplastic B cells were alpha 4 beta 7-, CD62L+. Neoplastic plasma cells were always alpha 4 beta 7+, CD62L-. The venules in normal gastric mucosa expressed mucosal addressin cell adhesion molecule-1 but not peripheral lymph node addressin. In normal MALT, H. pylori-associated follicular gastritis and MALT lymphomas high endothelial venules coexpressed mucosal addressin cell adhesion molecule-1 and peripheral lymph node addressin. These findings suggest expression of lymphocyte homing receptors by B cells and vascular addressins by mucosal venules are similar in normal MALT and MALT lymphomas, and factors controlling normal mucosal B-cell traffic are also operational in MALT lymphomas.

Antigens, Surface↗

[A pathological study of in situ thrombosis of small pulmonary arteries and arterioles in autopsy cases of chronic cor pulmonale].

OBJECTIVE: To study the incidence of thrombosis of small pulmonary arteries and arterioles during the exacerbation stage of chronic cor pulmonale. METHODS: 49 autopsy cases died from the exacerbation of chronic cor pulmonale were chosen as the study group, while other 103 autopsy cases without chronic cor pulmonale and disseminated intravascular coagulation (DIC) as control group. Morphologic and morphometric studies were taken on lung tissues and other organs with focus on the thrombi in small pulmonary arteries and arterioles. RESULTS: 44 cases of the study group had multiple thrombi in small pulmonary arteries and arterioles, the incidence is 89.8%, and in 9 of them, thrombi in proximal pulmonary arteries co-existed, the incidence is 18.4%, 80% of the thrombi existed in pulmonary arteriole. In control group, only 3 cases had thrombi in small pulmonary arteries and arteriole, the incidence is 2.9%. All thrombi adhered to endangium, implying that they were in situ thrombi. No intravascular thrombosis were found in other organs. chi(2) test showed that the incidence of thrombosis and the number of thrombi in small pulmonary arteries and arteriole in cases with chronic cor pulmonale were significantly higher than that of the control group (P < 0.01). CONCLUSIONS: Multiple in situ thrombosis in small pulmonary arteries and arterioles is a prominent and common pathological change during the exacerbation stage of chronic cor pulmonale. The study suggests a new diagnostic and therapeutic concept and provides a morphological and theoretical basis for the clinical application of anticoagulants or even the thrombolytic agents for the cases of chronic cor pulmonale in the exacerbation stage.

Aged↗

Minimum dose of fludarabine for the maximal modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during therapy.

1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP). To determine the lowest dose of fludarabine needed for modulation of ara-C metabolism, the present study administered fludarabine at a test dose (15 mg/m2 over 30 min) followed by 2 g/m2 ara-C infused over 4 h. The next day, the fludarabine/ara-C couplet was repeated but with a standard dose (30 mg/m2) of fludarabine. There was a dose-dependent accumulation of F-ara-ATP in circulating leukemia blasts; the median peak concentrations were 33 and 41 microM with 15 and 30 mg/m2 of fludarabine, respectively. These intracellular levels of F-ara-ATP effectively increased ara-CTP accumulation to similar levels. To further titrate the dose of fludarabine, the next cohort of patients (n = 4) initially received fludarabine test doses of 7.5 or 5 mg/m2, followed by the 30 mg/m2 dose of fludarabine on the next day; each dose was infused 4 h prior to 2 g/m2 of ara-C. The peak levels of F-ara-ATP at 7.5 and 5 mg/m2 fludarabine were between 3 and 39 microM. The AML blasts that achieved >/=10 microM intracellular F-ara-ATP accumulated ara-CTP similar to the levels achieved after 30 mg/m2 of fludarabine. However, <10 microM intracellular F-ara-ATP resulted in less ara-CTP accumulation compared to that observed after the conventional dose of fludarabine. These data suggest that the modulation of the ara-CTP accumulation by fludarabine is dependent on the cellular concentration of F-ara-ATP, and that 15 mg/m2 fludarabine infused over 30 min consistently produces cellular F-ara-ATP levels that maximize ara-CTP accumulation in AML blasts. These findings point to the feasibility of intensifying the fludarabine-ara-C regimen by using fludarabine as a 15 mg/m2/dose twice daily with intermediate-dose ara-C.

Acute Disease↗

Recognition of beta-D-Gal p-(1-->3)-beta-D-Glc pNAc-OR acceptor analogues by the Lewis alpha-(1-->3/4)-fucosyltransferase from human milk.

The Lewis alpha-(1-->3/4)-fucosyltransferase (E.C. 2.4.1.65) transfers L-fucose from GDP-fucose to OH-4 of the Glc pNAc residue in the disaccharide beta-D-Galp-(1-->3)-beta-D-Glc pNAc-OR [R = (CH2)8COOMe] (1) to give the Lewis-A blood group determinant beta-D-Gal p-(1-->3)-[alpha-L-Fuc p-(1-->4)]-beta-D-Glc pNAc-OR. Five deoxy analogous of 1, as well as its N-propionyl derivative, were chemically synthesized and kinetically evaluated as both substrates and inhibitors for the enzyme from human milk. The unmodified acceptor 1 had Km = 640 microM with Vmax set arbitrarily to 100. The 6-deoxy (Km = 400 microM, V(max) = 90) and N-propionyl compounds (Km = 330 microM, V(max) = 170) remained excellent substrates while the 4-deoxy compound was a very weak competitive inhibitor with Ki = 9 mM. Deoxygenation of OH-2' and OH-4'(of the Gal residue) in 1 had little effect on the activity. The OH-6 group of the Gal residue proved to be critical for recognition by the enzyme since substitution of this group with hydrogen led to an inactive compound.

Animals↗

Positive correlation between apoptotic and proliferative indices in gastrointestinal lymphomas of mucosa-associated lymphoid tissue (MALT).

To understand the role of deregulation of apoptosis in the pathogenesis of gastrointestinal MALT lymphoma, apoptosis has been quantitatively studied in paraffin sections from 40 cases (19 low grade, 21 high grade). The extent of apoptosis was correlated with histological grade, proliferative activity as measured by immunostaining of Ki67 proliferation antigen, and the expression of bcl-2 and p53 oncoproteins, which are known to participate in the regulation of apoptosis. Both apoptotic and proliferative indices were significantly (P < 0.00001) higher in high-grade than in low-grade tumours. Overall, apoptotic indices were negatively correlated with bcl-2 expression, particularly in low-grade tumours in which both strong bcl-2 expression and low levels of apoptosis were observed. Thus, the slow expansion of low-grade MALT lymphoma may partly result from a prolonged life-span of tumour cells, due to bcl-2-mediated blockage of apoptosis. No difference in apoptotic indices was found between p53-positive and p53-negative cases. Furthermore, correlation analysis revealed a significantly positive association between apoptotic and proliferative indices. This supports the current belief that the mechanisms controlling apoptosis and proliferation are both activated during the cell cycle and whether a cell enters the proliferation cycle or the apoptotic process depends on survival factors.

Apoptosis↗

Replication error phenotype and p53 gene mutation in lymphomas of mucosa-associated lymphoid tissue.

Low grade mucosa-associated lymphoid tissue (MALT) lymphomas commonly arise from a background of chronic inflammatory lesions and can transform into high grade tumors at a late stage. Because chronic inflammation is closely associated with genetic instability, which is one of the mechanisms leading to activation of oncogenes and inactivation of tumor suppressor genes, it is possible that genetic instability plays an important role in MALT lymphomagenesis. In this study, we have examined the frequency of replication error (RER+) phenotype, a newly defined manifestation of genetic instability, and its relationship to p53 mutations in 40 MALT lymphomas (16 high grade and 24 low grade). RER+ phenotype was detected in 21/40 (52.5%) MALT lymphomas (12/24, 50% in low grade; 9/16, 56.2% in high grade). Five of seven reactive lymphoid infiltrates adjacent to tumors also showed one microsatellite alteration, four of which were identified in the corresponding lymphoma lesions in the same patient. In five RER+ high grade lymphomas with low grade lesions, homogeneous and heterogeneous microsatellite alterations were observed between the two components. The same 40 cases were investigated for p53 gene mutations at exons 5 to 8 by PCR-SSCP and direct sequencing. p53 point mutations were found in 11 (27.5%) of the 40 cases. These mutations were statistically related to RER+ phenotype (P < 0.05). Our results demonstrate that the RER+ phenotype is a common genetic feature of MALT lymphomas. Genetic instability occurs throughout the spectrum of the lymphoma development and may be related to the accumulation of genetic aberrations such as p53 mutations. The observation of identical microsatellite alterations between the adjacent lymphoid infiltrates and their corresponding lymphomas provides genetic evidence for evolutionary link of the two lesions. The homogeneous and heterogeneous microsatellite alterations observed between low and high grade components indicate their clonal lineage and genetic diversity.

Base Sequence↗

Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion.

Indirect antigenic stimulation by H. pylori-specific T cells is implicated in the development of low-grade gastric lymphoma of mucosa-associated lymphoid tissue (MALT), however, the role of direct antigen stimulation is unknown. To study the role of direct antigen stimulation in MALT lymphomagenesis and its relationship with the pathogenesis of distinct pathological lesions, which represent different stages of the tumour progression, we cloned and sequenced the rearranged immunoglobulin (Ig) heavy chain gene in three low-grade (two from the lung, one from the stomach) and one high-grade (from the stomach) cases. In the low-grade gastric case, we studied the Ig sequence in primary as well as its disseminated and recurrent tumours. In the high-grade gastric case, we analysed the Ig sequence in tumour cell populations microdissected from the residual diffuse low-grade lesions, diffuse high-grade areas from follicles colonized by high-grade blasts. Compared with the published germline sequences, the heavy chain variable (VH) genes of three MALT lymphomas, in which the putative germline was identified, contained frequent somatic mutations, showing a much higher ratio of replacement/silent mutations in the complementarity determining regions (CDRs) than the framework regions (FRs). Ongoing mutation as indicated by intraclonal variation of the Ig sequence clearly existed in low-grade tumour including its dissemination and recurrence, but was not evident in high-grade tumour cell populations including those microdissected from independent colonized follicles. In addition, the germlines of VH genes used by the three MALT lymphomas are frequently found in autoreactive antibodies. Our results suggest that MALT lymphoma derives from postgerminal centre memory B cells, possibly autoreactive B cell clones, and that direct antigen stimulation may play an important role in the clonal expansion of low-grade MALT lymphoma.

Animals↗

[Location of the surface protein antigen I/II on Mutans Streptococci with immunogold electron microscope].

Mutans Streptococci possess a number of surface protein antigens. The surface protein antigen I/II with a molecular mass of 190,000 is considered to play an important role in the initial attachment to tooth surface. The antigen is highly immunogenic and has been successfully used as a vaccine against dental caries. The object of this study is to locate the surface protein antigen I/II of Mutans Streptococci with immunogold electron microscope. The results suggest that (1) antigen I/II locate on the cell wall surface of serotype c, e, f; (2) antigen I/II locate on the "fuzz coat" of the cell wall of serotype d, g; (3) some antigen I/II locate at the surface of cell wall of serotype a; (4) antigen I/II are absent on the cell wall surface of serotype b strain.

Antigens, Surface↗

The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma.

The genetic mechanisms underlying the genesis of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas and their transformation into high-grade lymphoma are poorly understood. p53 inactivation, commonly caused by mutation and allele loss, has been shown to play an important role in the early development and/or the late disease progression of many human tumors including lymphoid malignancies and, thus, may also be important in MALT lymphomagenesis. We examined 75 cases (48 low grade and 27 high grade) of MALT lymphoma for p53 allele loss and mutation as well as protein accumulation. DNA samples prepared from microdissected cell populations were used for the detection of p53 gene abnormalities. Loss of heterozygosity (LOH) of the gene was detected by polymerase chain reaction-based analysis of p53 CA repeat polymorphism, whereas p53 mutation was studied by single-strand conformation polymorphism analysis and direct sequencing. p53 expression was assessed by immunostaining with CM1 polyclonal antibody. p53 allele loss and mutation, which resulted in the alteration in the amino acid sequence, were found in both low-grade (LOH, 3 of 44 [6.8%]; mutation, 9 of 48 [18.8%]) and high-grade (LOH, 6 of 21 [28.6%]; mutation, 9 of 27 [33.3%]) MALT lymphomas, particularly in the latter group. p53 staining was not observed in any low-grade tumors but in 6 high-grade cases that harbored missense mutations. There were also differences in the extent of p53 abnormalities, between low- and high-grade tumors. Of the 11 low-grade tumors showing p53 abnormalities, only 1 tumor showed the concomitance of p53 mutation and allele loss, whereas in high-grade tumors, 6 of 9 affected cases displayed both p53 mutation and allele loss. Our results suggest that p53 partial inactivation may play an important role in the development of low-grade MALT lymphomas, whereas complete inactivation may be associated with high-grade transformation.

Alleles↗

Dosimetric evaluation of the conformation of the multileaf collimator to irregularly shaped fields.

PURPOSE: The goal of this study was to evaluate the dosimetric characteristics of geometric MLC prescription strategies and compare them to those of conventional shielding block. METHODS AND MATERIALS: Circular fields, square fields, and 12 irregular fields for patients with cancer of the head and neck, lung, and pelvis were included in this study. All fields were shaped using the MLC and conventional blocks. A geometric criterion was defined as the amount of area discrepancy between the MLC and the prescription outline. The "least area discrepancy" (LAD) of the MLC conformation was searched by selecting the collimator angle, meanwhile keeping a preselected position along the width of the leaf into the prescribed field. Five LAD conventions were studied. These included the LAD-0, LAD-1/3, LAD-1/2, and LAD-2/3 that inserted the leaves at the 0, 1/3, 1/2, and 2/3 of the leaf end into the prescription field, respectively. In addition, the LAD optimization was applied to the transecting (TRN) approach for leaf conformation that prescribed an equal area of overblocking and underblocking under each leaf. Film dosimetry was performed in a 20 cm polystyrene phantom at 10 cm depth 100 cm from source to axis distance (SAD) for both 6 and 18 MV photons with each of the above MLC conformations and conventional blocks. The field penumbra width, defined as the mean of the separation between the 20% and 80% isodose lines along the normal of the prescription field edge, was calculated using both the MLC and conventional block film dosimetry and compared. In a similar way, the d20 is defined as the mean separation between the 20% isodose line and the prescription field edge, and the d80 is defined as the mean separation between the 80% isodose line and the prescription field edge. RESULTS: The field penumbra width for all MLC conventions was approximately 2 mm larger than that of the conventional block. However, there was a larger variation of the separation distribution in the penumbra region of the irregular fields for the MLC, which had a standard deviation of 1 mm (a factor of 5 larger than the conventional block). The dosimetry for the circular fields showed that the LAD-TRN, LAD-1/2, and LAD-1/3 approximated the conventional blocking well in terms of d20 and d80; however, no single convention produced the best conformation for both measures. The dosimetric result of the patient treatment fields was similar for all sites. The LAD-1/3, LAD-1/2, and LAD-TRN strategies conformed to within 1 to 1.5 mm of the d80 of the conventional block for both 6 MV and 18 MV, respectively. The LAD-1/2 and LAD-TRN conformations were virtually identical, although it is proven analytically that the LAD-1/2 convention has the least overall area discrepancy of all conventions. CONCLUSIONS: The five MLC conformation conventions resulted in similar dosimetric penumbrae for all field shapes studied. The LAD-1/3, LAD-TRN, and LAD-1/2 produced the more favorable approximation to conventional block. The field penumbra width, although useful for evaluating irregular field shapes, could not describe the large local variations in the penumbra along the field edge for the MLC. These local variations could be of clinical concern when they appear near vital organs. However, the variation in a local region can potentially be reduced by minimizing the jaggedness of the leaf steps in that local region. The dosimetric results were useful as guidelines for the clinicians in the evaluation and adjustment of MLC leaf positions.

Head and Neck Neoplasms↗

Effects of treatment setup variation on beam's eye view dosimetry for radiation therapy using the multileaf collimator vs. the cerrobend block.

PURPOSE: The purpose of this study is to quantify and compare retrospectively the effects of treatment setup variation on beam's eye view (BEV) dosimetry for radiation therapy using a multileaf collimator (MLC) vs. cerrobend block. METHODS AND MATERIALS: A study was performed on a group of 18 patients with cancer of the head and neck, lung, and pelvis who were treated with irregularly shaped fields. The BEV dosimetry of the fields shaped with cerrobend blocks and the MLC was measured with films at the depth of dose prescription in a solid water phantom. A "one-half-leaf" insertion convention was used to shape the MLC. In addition, an average of 15 sequential daily port films was taken per patient during the course of radiotherapy. The port films were aligned with the prescription film for each patient. Systematic error and random error of treatment setup for each patient were calculated. The effects of setup variation were incorporated by convolving the patient portal imaging data with the corresponding BEV film dosimetry. Two parameters were used to quantify the BEV dosimetry. First, the field penumbra width was calculated, which represented the average of the normal separations between 20 and 80% isodose lines along the prescription outline. Second, the ratio of areas covered by the 90 and 20% isodose lines, A90/20, was determined. The BEV dosimetry was then characterized with and without the effects of treatment setup variation. In addition, the difference in BEV dosimetry between the cerrobend block and the MLC was used to estimate the corresponding changes in tumor control probability (TCP). These changes were also compared to the changes in TCP for the treatment with or without the effects of random setup variation. RESULTS: With or without daily setup variation, the use of cerrobend block was more favorable than the MLC in terms of the field penumbra width and A90/20 for all treatment sites. In the absence of daily variation, the MLC field penumbra width was on average 1.3 mm larger than that of the cerrobend block, and 0.9 mm larger in the presence of daily setup variation. Similarly, the ratio A90/20 of the cerrobend block was on average 0.03 larger than that of MLC without daily setup variation, and 0.02 with daily setup variation. The difference in field penumbra width and A90/20 between the MLC and the cerrobend block was slightly reduced due to the effects of daily setup variation. For both the cerrobend block and the MLC, daily setup variation produced a significant increase in the field penumbra width, 2.3 mm for the cerrobend block and 1.9 mm for the MLC, and a decrease in the A90/20, 0.06 for the former and 0.05 for the latter. The change due to the daily setup variation was about a factor of 2 larger than the changes due to replacing the cerrobend block with the MLC. Using the TCP model, the change in TCP due to the daily setup variation was more than a factor of 3 larger than the change in TCP due to replacing the cerrobend block with the MLC. It was noted that the average changes in the penumbra, the A90/20 and the TCP calculated for the patient population did not adequately describe the changes for the individual patient. CONCLUSION: Our results do not show significant dosimetric differences between the MLC and the cerrobend block in conventional radiation treatment, whether or not daily setup variation was taken into consideration. The effects of daily setup variation alone produced a larger dosimetric change. The same results were obtained when the data were applied to calculate changes in TCP. For optimal radiation therapy, efforts should be concentrated on reducing daily setup variation. Our results also demonstrate the importance of frequent evaluation of MLC treatment using electronic portal imaging devices.

Equipment Design↗

Effectiveness of Norplant implants through seven years: a large-scale study in China.

The effectiveness of Norplant implants over a seven year period of continuous use was studied in a multicenter trial. Pregnancy rates were 0.4 per 100 in both year six and year seven. More than 3,600 women completed 6 years and more than 2,400 women completed 7 years. Pregnancy rates increased with weight (p < .05) and decreased with age, but in years 6 and 7 combined, the pregnancy rate neither reached nor exceeded 1 per 100 woman years in any 5 year age group or in any 10 kg weight group.

Adult↗

High-resolution SSCP analysis using polyacrylamide agarose composite gel and a background-free silver staining method.

We describe here an improved methodology for single-strand conformation polymorphism (SSCP) analysis of PCR products. The method utilizes a polyacrylamide agarose composite gel and background-free silver staining. In comparison with conventional pure polyacrylamide gel for PCR-SSCP analysis, the composite gels have a much greater mechanical strength and improved resolution. The background staining commonly seen in many silver staining protocols has been eliminated by incorporation of thiosulfate, which can prevent nonspecific deposits of silver salts. As shown in our titration tests, the composite gel and background-free silver staining together have allowed clear identification of point mutations in samples containing as little as 5% of the target sequences, the same sensitivity achieved by radioactive labeling methods.

DNA↗

Modulation of the cellular metabolism of cytarabine and fludarabine by granulocyte-colony-stimulating factor during therapy of acute myelogenous leukemia.

Previous in vitro investigations demonstrated that human leukemia cells, when incubated with hematopoietic growth factors such as granulocyte-colony-stimulating factor (G-CSF), augment the accumulation of the triphosphate 1-beta-D-arabinofuranosylcytosine (ara-C cytarabine). To test whether G-CSF infusion prior to ara-C infusion would biologically modulate the accumulation of ara-9-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP) and other ara nucleotides in the leukemia blasts during therapy, protocols were designed to infuse G-CSF prior to fludarabine (9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate) and ara-C to increase the accumulation of the active triphosphates [9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-triphosphate (F-ara-ATP) and ara-CTP] in acute myelogenous leukemia (AML) blasts during therapy. To complement these in vivo studies, ex vivo accumulation of ara-CTP was also investigated before and after G-CSF infusion. Patients (n = 5) treated on the fludarabine/ara-C/G-CSF regimen received a 30 mg/m2 dose of fludarabine followed by a 2 g/m2 dose of ara-C infused i.v. for 4 h. Beginning at 24 h, and every day, patients received a 6-h infusion of 400 microgram/m2 G-CSF. At 48 h, the fludarabine and ara-C couplet was repeated. Comparison of F-ara-ATP pharmacokinetics in circulating AML cells of patients on the fludarabine/ara- C/G-CSF regimen demonstrated that the area under concentration time curve (AUC) of F-ara-ATP increased significantly (median, 1.4-fold; range, 0.9-1.5; P = 0.045) after G-CSF infusion. This was due to an increased rate of F-ara-ATP accumulation by AML cells. The AUC of ara-CTP, on the other hand, was not affected (median, 1.0-fold; range, 1.0-1.2; P = 0.571) after G-CSF infusion. Because fludarabine potentiates the accumulation of ara-CTP, the effect of G-CSF on ara-CTP metabolism may not be evident in the AML blasts of patients on the fludarabine/ara-C/G-CSF regimen. To determine the effect of G-CSF when ara-C was infused alone, four additional patients were treated on a pilot protocol in which ara-C (2 g/m2) was infused on days 1 and 3 and G-CSF on day 2. The AUC of ara-CTP accumulation in these patients decreased by a median of 48% after G-CSF infusion. Consistent with these in vivo investigations, ex vivo ara-CTP accumulation was decreased in the AML blasts after G-CSF infusion. Based on these data it could be concluded that (a) infusion of G-CSF before fludarabine augmented the rate of F-ara-ATP synthesis in circulating AML blasts during therapy, suggesting that G-CSF may benefit fludarabine therapy by biological modulation; (b) G-CSF did not increase ara-CTP accumulation, rather it may have caused it to decrease; and (c) these data imply that when G-CSF and ara-C are used in combination, administration of fludarabine prior to ara-C may maintain the ara-CTP AUC.

Antineoplastic Combined Chemotherapy Protocols↗

A five-year evaluation of NORPLANT II implants in China.

A five-year study of NORPLANT II rod implants was undertaken in four large cities and metropolitan areas in eastern China. Designed to test the safety, efficacy and acceptability of these implants, the study involved 1,208 women and was conducted concurrently with a similar study of NORPLANT capsule implants. At the end of five years, the gross pregnancy rate was 0.65 per 100, and the continuation rate was 65.3 per 100. Both these values were similar to and not statistically different from the rates of the capsule implant users. In 4,828 woman-years of use, there were few severe adverse events reported. Users and providers found the method to be an acceptable long-term contraceptive method of great reliability.

Adult↗

Effect of granulocyte-macrophage colony-stimulating factor on the metabolism of arabinosylcytosine triphosphate in blasts during therapy of patients with chronic myelogenous leukemia.

Because in vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates arabinosylcytosine (ara-C) metabolism in leukemia blasts, we analyzed the pharmacokinetics of ara-C triphosphate (ara-CTP) in the blasts of patients with chronic myelogenous leukemia who were undergoing therapy with GM-CSF and ara-C. Patients received a 2-h infusion of 1.0 g/m2 ara-C followed by daily infusions of GM-CSF (125 micrograms/m2/day i.v. over 6 h) for 2-4 days. After the last GM-CSF infusion, a second, identical dose of ara-C was administered. The cellular pharmacokinetics of ara-CTP in circulating blasts were determined during and after each ara-C dose, and the area under the accumulation and elimination curve (AUC) measured over 12 h was compared before and after GM-CSF. Ara-CTP accumulation peaked within 1 h after the end of each ara-C infusion. Comparison of the AUC of ara-CTP before and after GM-CSF administration suggested that in the blasts of three of four patients, GM-CSF treatment decreased the ara-CTP AUC; the AUC values were altered only slightly in a fourth patient. Studies of these patients' blasts incubated in vitro with ara-C before and after clinical infusion of GM-CSF revealed similar ara-CTP accumulation patterns. Together, these studies suggest that 2-4 days of GM-CSF administration does not increase the accumulation of ara-CTP in the circulating blasts from patients in the blastic phase of chronic myelogenous leukemia.

Arabinofuranosylcytosine Triphosphate↗