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Biomedical subjects

G Juliusson

Publications and source records attributed to G Juliusson.

At least 73 records · Page 4Linked to original sources
PubMed1994

Retreatment of chronic lymphocytic leukemia with 2-chlorodeoxyadenosine (CdA) at relapse following CdA-induced remission: no acquired resistance.

B-cell chronic lymphocytic leukemia (CLL) initially responds well to treatment with alkylating agents, but subsequently resistance may develop. We recently showed that the nucleoside analogue 2-chlorodeoxyadenosine (CdA) produce a high remission rate in previously treated patients with symptomatic CLL. We report here the results of retreatment with CdA given to 6 previously CdA-treated patients who had progression off therapy. Two initially had a complete remission and 4 a partial remission. The median time from the start of initial CdA-treatment to retreatment was 19 months (range 8-28 mos). The tumor cell response to CdA was assessed by calculating the elimination rate of circulating leukemia cells. The lymphocyte half-life varied in the different patients, but was similar in all six patients when comparing the first CdA-course with CdA-treatment at relapse, with a correlation coefficient of r2 = 0.89. However, the toxicity towards thrombopoiesis was greater at relapse than during the initial treatment in four of the six patients. CLL cells do not seem to acquire resistance to CdA, but retreatment with CdA at relapse following CdA-induced remission is hampered by more severe drug-related cytopenia. Thus, the quality of subsequent reduced, despite continuing sensitivity of the leukemia cells to CdA.

2-Chloroadenosine↗
PubMed1994

2-Chloro-2'-deoxyadenosine--clinical, biochemical and pharmacokinetic considerations.

2-Chloro-2'-deoxyadenosine (CdA) is a new antimetabolite with very promising effect in the treatment of chronic lymphoproliferative diseases. It has also been shown to have good activity in acute myelogenous leukemia in children. CdA induces DNA single strand breaks and poly(ADP)-ribosylation, apoptosis and is cytotoxic to non-proliferating as well as proliferating cells. Earlier, CdA has only been given as continuous infusion. Recently, however, pharmacokinetic studies have shown that the bioavailability of oral CdA is 50% and of s.c. injection 100%. Furthermore, studies of the intracellular pharmacokinetics shows that there is a prolonged retention of its nucleotide metabolites supporting intermittent dosing.

Antimetabolites, Antineoplastic↗
PubMed1994

Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin's lymphomas: a randomized trial from the Lymphoma Group of Central Sweden.

Two hundred fifty-nine previously untreated patients with low-grade non-Hodgkin's lymphomas (NHLs), Ann Arbor stages III and IV, entered a randomized multicenter trial comparing the therapeutic effect of chlorambucil/prednisone (ChP) vs. CHOP. All patients had symptomatic disease. The therapeutic aim was to achieve an asymptomatic state in the ChP group (n = 132), while in CHOP-treated patients (n = 127) the intention was to reach a complete remission (CR). The response rate (CR+PR at 8 months) was 36% in the ChP and 60% in the CHOP group (p < 0.01). Three and 5-year survival rates were 59% and 41% in the ChP group and 64% and 44% in the CHOP group. The corresponding median survival times were 46 and 52 months. After correction for intercurrent deaths, the overall 5-year survival was 49% for ChP and 54% for CHOP-treated patients. The differences were statistically not significant. The time from diagnosis to randomization (time with asymptomatic disease) was longer than one year in half of the patients. The median survival time from diagnosis was 68 months, with no differences between the treatment groups. In all histological subgroups (CLL, IC, CC, and CB-CC), a higher remission rate was seen with the CHOP regimen but with no statistically significant influence on survival. Comparing patients below and above 65 years of age, no significant difference in survival was noted between the two treatment groups. The results do not support the use of intensive chemotherapy as first-line therapy in symptomatic low-grade NHL.

Actuarial Analysis↗
PubMed1993

Chronic lymphocytic leukemia cells with allelic deletions at 13q14 commonly have one intact RB1 gene: evidence for a role of an adjacent locus.

We have previously shown that 30% of patients with B-cell chronic lymphocytic leukemia (B-CLL) have hemizygous deletions of the retinoblastoma (RB1) gene at 13q14. RB1 gene deletions may thus participate in malignant transformation of B-CLL, but it is also possible that a neighboring gene on 13q is the relevant one. To answer this question the remaining RB1 allele of eight clones with hemizygous deletions was studied by reverse transcription-polymerase chain reaction (RT-PCR), single-strand conformation polymorphism (SSCP) analysis, and immunofluorescense techniques. Cells from 10 patients without RB1 gene deletions were also studied by these methods. Lack of RB1 mRNA and RB protein expression was seen in leukemia cells from one of the patients. All other cases were found to be normal with regard to immunofluorescense, RT-PCR, and SSCP analysis, indicating at least one functional RB1 allele and supporting the importance of another gene in the 13q14 deletions. We then performed extended Southern blot analyses of the 13q region, using probes for 10 different loci. In 14 of 31 CLL clones (45%), deletions of a region telomeric to the RB1 gene (D13S25) were observed. In 4 of the cases the deletions were homozygous. Hemizygous deletions of the RB1 gene were observed in 11 of these patients and in none of the patients without D13S25 deletions. These data thus indicate that a gene(s) telomeric to RB1 is involved in the malignant transformation of CLL clones and that deletions of this region are a common event in this disease.

Base Sequence↗
PubMed1993

On the bioavailability of 2-chloro-2'-deoxyadenosine (CdA). The influence of food and omeprazole.

The pharmacokinetics of oral CdA (0.24 mg/kg) was studied in 4 patients (1 with hairy cell leukaemia and 3 with B-cell chronic lymphocytic leukaemia) to determine any effect of food and fasting with and without omeprazole. Food intake did not significantly influence the bioavailability of CdA (42% after food intake vs 46% while fasting) but it did reduce the maximum plasma concentration (Cmax) by 40%; 83 compared to 116 nM while fasting. The time to reach maximum concentration (tmax) was delayed about 0.8 h after food intake. Pretreatment with omeprazole did not significantly influence the bioavailability of CdA (51% vs 46% without), or the interindividual variability in bioavailability in the fasting state (C. V. 0.26 with and C. V. 0.27 without). In conclusion, there was a small, though not statistically significant reduction in the bioavailability of CdA after food intake. Omeprazole did not significantly improve the bioavailability of CdA.

Adult↗
PubMed1993

Cytogenetics in CLL and related disorders.

Chromosome analysis of more than 1200 patients with chronic lymphocytic leukaemia reported to the International Working Party on Chromosomes in CLL and in the literature is analysed. Clonal chromosomal abnormalities are found in about half of the patients, and one third of those with clonal aberrations have trisomy 12, with or without additional changes. The most common structural abnormalities involve the long arm of chromosome 13, usually as deletions involving 13q14, the site of the retinoblastoma gene. Other recurrent abnormalities are deletions of the long arms of chromosome 11 and 6. 14q+ markers are frequent in patients at advanced stage, but are almost always within complex abnormalities. The number of clonal abnormalities in the CLL cells has a strong prognostic impact. Trisomy 12 as a single abnormality is an adverse prognostic sign, whereas patients with 13q abnormalities generally do comparatively well. Lymphoid leukaemia with monoclonal immunoglobulin secretion frequently involves clonal chromosomal abnormalities, and the type of change is similar to that seen in true CLL. In B cell prolymphocytic leukaemia, t(11;14) is a common finding, together with trisomy 12. T cell prolymphocytic leukaemia is characterized by an inversion of the long arm of chromosome 14, with breaks at q11 and q32, and trisomy of 8q, whereas large granular lymphocytic leukaemia has shown no consistent abnormality. Hairy cell leukaemia seems to involve a specific set of non-random chromosome abnormalities, such as inv(5)9.

Chromosome Aberrations↗
PubMed1993

Etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) as outpatient salvage therapy for refractory multiple myeloma.

Fifty-six patients with refractory multiple myeloma were treated with intermittent courses of etoposide, doxorubicin, cyclophosphamide and high-dose betamethasone (EACB) every 4th week. The overall response rate was 30%. Durable remissions exceeding 1 year were obtained in 12 of the 17 responding patients. A significant prolongation of the survival time was found for responding patients (median 13 months) compared to those patients who did not respond (median 9 months) to EACB therapy (p = 0.01). A low frequency of neutropenic fever episodes was noted compared to other salvage treatment regimens. The EACB regimen was usually well tolerated and could be administered safely on an out-patient basis. This regimen might be an alternative especially for elderly patients unresponsive to initial therapy.

Actuarial Analysis↗
PubMed1993

High complete remission rate from 2-chloro-2'-deoxyadenosine in previously treated patients with B-cell chronic lymphocytic leukemia: response predicted by rapid decrease of blood lymphocyte count.

PURPOSE: This study attempted to characterize the response of previously treated patients with B-cell chronic lymphocytic leukemia (CLL) to the purine analog 2-chloro-2'-deoxyadenosine (CdA) and to assess factors that predict response. PATIENTS AND METHODS: We treated 18 CLL patients with about-monthly courses of five daily 2-hour intravenous infusions of 0.12 mg CdA/kg. RESULTS: Complete remissions (CRs) were achieved in seven patients (39%), with a total response rate of 67%. CR patients received a median of 4.5 courses. One patient with CR relapsed and died 14 months from start of CdA treatment, whereas the other six patients with CR remain in remission following a mean observation period of 14 months. The median duration of partial remissions (PRs) was 9 months, with a median treatment-free interval of 15 months. Thrombocytopenia was the most common dose-limiting toxicity. Non-responding patients had a median survival of 3.5 months, and systemic fungal infections were the most common cause of death. Immunoglobulin (Ig) levels improved significantly in hypogammaglobulinemic patients during CdA treatment. Responses were predicted by a rapid decrease of blood lymphocyte counts following the first treatment course. CONCLUSION: A high CR rate was achieved with limited toxicity. A treatment strategy to enable high-quality response and limitation of treatment-related toxicity is provided.

Adult↗
PubMed1992

Response to 2-chlorodeoxyadenosine in patients with B-cell chronic lymphocytic leukemia resistant to fludarabine.

BACKGROUND: Patients with untreated B-cell chronic lymphocytic leukemia have a high rate of complete remission when given the halogenated nucleoside analogue fludarabine. However, patients in whom the disease has proved refractory to primary treatment have a reduced life expectancy and a dismal outcome. METHODS: We treated four consecutive patients who had unsatisfactory responses to second-line or subsequent treatment with fludarabine with another halogenated nucleoside analogue, 2-chlorodeoxyadenosine. RESULTS: One patient with progressing lymphocytosis, anemia, and thrombocytopenia despite 10 courses of fludarabine entered a complete remission when treated with 2-chlorodeoxyadenosine. Two patients who had less-than-partial remissions after six courses of fludarabine had good partial remissions when treated with 2-chlorodeoxyadenosine. One patient with Coombs-positive hemolytic anemia who had no response to three courses of fludarabine had a partial remission, with resolution of hypogammaglobulinemia, when treated with 2-chlorodeoxyadenosine. CONCLUSIONS: There was no evidence of cross-resistance between fludarabine and 2-chlorodeoxyadenosine despite their similar structures. 2-Chlorodeoxyadenosine may induce a complete remission in chronic lymphocytic leukemia that is highly resistant to chemotherapy, and it deserves wider clinical evaluation in patients with this condition.

2-Chloroadenosine↗
PubMed1992

Transcription of unrearranged Ig H chain genes in human B cell malignancies. Biased expression of genes encoded within the first duplication unit of the Ig H chain locus.

Analysis of the H chain class switch recombination events on the productive and nonproductive alleles of several human B cell lines has demonstrated that, in the majority of cases, the two loci had rearranged different CH genes. The absence of a strict correlation between the two rearrangement events has been interpreted in favor of a stochastic switching mechanism in human B cells. Based on the accessibility model for the H chain class switch, we have considered an alternative explanation, namely, that transcriptional activation of more than one CH gene could render more than one isotype accessible for recombination. In order to test this possibility, we have stimulated a number of IgM-bearing B cell tumors and analyzed the transcriptional response of their unrearranged C gamma and C alpha H chain genes at the Ig class level by Northern hybridization and at the subclass level by RNA-RNA solution hybridization. Our data show that human clonal B cell populations can simultaneously express germ-line transcripts of both gamma and alpha genes. Our data also demonstrate a bias in the expression of the different isotypes in the B cell chronic lymphocytic leukemias analyzed, with the genes present with the first duplication unit of the H chain locus (gamma 3, gamma 1, and alpha 1) being expressed almost exclusively. These findings indicate that transcriptional activation of large chromosomal regions containing more than one CH gene could render all the genes available for recombination and, therefore, provide an explanation for the asymmetry in the rearrangement events that have previously been described in human B cell tumors. The possible relevance of our findings to the molecular mechanism of the H chain class switch is discussed.

B-Lymphocytes↗
PubMed1992

Rapid recovery from cytopenia in hairy cell leukemia after treatment with 2-chloro-2'-deoxyadenosine (CdA): relation to opportunistic infections.

Sixteen patients with symptomatic hairy cell leukemia were treated with a single course of 2-chloro-2'-deoxyadenosine (CdA), 0.7 mg/kg total dose. Twelve patients achieved complete remission (CR). One patient with a CD19+/CD5+/CD25- phenotype and one with a pentostatin-treated CD19+/CD25- variant form had minor responses. Two patients with advanced disease and poor performance status died early from invasive mycosis. Three patients recovered from infections caused by cytomegalovirus and by candida. No patient had infections caused by bacteria or by unknown organisms. The median time to full recovery from anemia and thrombocytopenia was 6 and 2 weeks from start of therapy, respectively. Patients with infections, however, recovered at 13 and 5 weeks, respectively. Neutrophil, monocyte, and lymphocyte counts returned to normal at a median of 5, 5, and 10 weeks, respectively. Infections developed more frequently in pancytopenic patients than in those with one or more blood cell count within the normal range (P less than .01). All patients with one or no previous therapy had a CR, whereas those with more than one previous regimen had a lower CR rate (P less than .01). Thus, 1 week of CdA therapy frequently induced CR also in patients resistant to interferon. Toxicity was limited, and recovery from cytopenia was faster than what is reported during interferon therapy.

2-Chloroadenosine↗
PubMed1992

Retinoblastoma gene deletions in B-cell chronic lymphocytic leukemia.

Approximately 10% of B-cell chronic lymphocyte leukemia (B-CLL) cases have structural chromosomal aberrations involving band 13q14. To evaluate a possible role of RBl gene deletions in B-CLL we investigated the malignant cells of 27 patients by molecular genetic and cytogenetic techniques. Four of the cases had chromosomal aberrations that involved 13q14 (including one case with a 13q14 deletion that was observed in a single metaphase cell), and 11 had other chromosomal abnormalities, whereas the malignant cells of 12 patients were either cytogenetically normal or failed to divided in vitro. Eight patients (30%) were found to have hemizygous deletions of the RBl gene. These cases included all four patients with chromosomal changes at 13q14, but also three patients without chromosome abnormalities and one case with a chromosomal aberration not involving 13q. The deletions were interstitial in all cases but one, as defined by probes located centromeric and telomeric of the RBl locus. Inactivation of RBl may thus be a significant event in the development of some B-CLL clones.

Autoradiography↗
PubMed1992

On the bioavailability of oral and subcutaneous 2-chloro-2'-deoxyadenosine in humans: alternative routes of administration.

PURPOSE: The antimetabolite 2-chloro-2'-deoxyadenosine (CdA) is a promising alternative to alkylating agents for the treatment of lymphoproliferative disorders. Its use, however, is hampered by the need for intravenous (IV) administration. The aim of the present study was to determine the bioavailability of subcutaneously (SC) and orally administered CdA, and to establish an oral dose of CdA that could supersede IV administration. PATIENTS AND METHODS: A previously developed high-performance liquid chromatography method was used for the determination of plasma CdA concentrations in 13 patients. Ten patients were treated on alternate days with 0.14 mg/kg/d CdA as a 2-hour IV infusion or by a SC injection. Three of these patients were also given 0.14 mg/kg CdA orally in enteric-coated capsules. Ten patients were administered CdA orally that was dissolved in phosphate-buffered saline (PBS) after treatment with 20 mg omeprazole 1 and 6 hours before the administration of CdA. RESULTS: The bioavailability of SC CdA was 102% +/- 28% (mean +/- SD), and the bioavailability of CdA administered in enteric-coated capsules was 19%, 24%, and 60%. In the three patients who were given 0.14 mg/kg orally dissolved in PBS, the bioavailability was 48% +/- 8%, whereas in the seven patients who received 0.28 mg/kg, the bioavailability was 55% +/- 17%. In the 10 patients who were treated with the CdA solution orally, the coefficients of variation of the areas under the curve (AUCs) after oral and IV administration were similar. Thus, oral administration did not add to the interindividual variability. CONCLUSIONS: We conclude that orally administered CdA can supersede IV infusion if the dose is doubled. SC administration gives a high peak concentration of short duration with an AUC identical to that of IV infusion. Thus, SC injection can also be used as an alternative to IV infusion.

Administration, Oral↗
PubMed1991

On the pharmacokinetics of 2-chloro-2'-deoxyadenosine in humans.

The antitumoral effect of 2-chloro-2'-deoxyadenosine (CdA) in the treatment of lymphoproliferative diseases in general and of hairy cell leukemia in particular has recently been demonstrated. Detailed information on the pharmacokinetics of CdA, however, is lacking. The pharmacokinetics of CdA after 2- and 24-h infusions of 0.14 mg/kg was described in 12 patients with lymphoproliferative diseases using a newly developed high-performance liquid chromatography method. The plasma concentration data from individual patients were fitted to a two-compartment model with alpha- and beta-half-lives of 35 +/- 12 (mean +/- SD) min and 6.7 +/- 2.5 h, respectively. The volume of distribution was 9.2 +/- 5.4 liters/kg. The steady-state concentration of CdA during the 24-h infusion was 22.5 +/- 11.1 nM. The areas under the time versus concentration curves were 552 +/- 258 and 588 +/- 185 nM x h, respectively, for the 24- and 2-h infusions. The interindividual variability of the determinants of the plasma pharmacokinetics of CdA was small (the coefficients of variation were between 0.22 and 0.58). At 6.3 +/- 1.5 h after the start of the 2-h infusion, the concentration of CdA was the same as the steady-state concentration during the 24-h infusion. When the mean plasma concentrations of the 12 patients were fitted to a 3-compartment model, the half-lives of the alpha-, beta-, and tau-phases were 8 min, 1 h 6 min, and 6.3 h, respectively. The long terminal half-life of CdA after 2-h infusion supports the use of intermittent infusions.

2-Chloroadenosine↗