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PubMed1992

Granulocyte-macrophage colony-stimulating factor and interleukin-3 enhance the incorporation of cytosine arabinoside into the DNA of leukemic blasts and the cytotoxic effect on clonogenic cells from patients with acute myeloid leukemia.

In the present study the effects of the 48-hour administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) (100 U/mL) or interleukin-3 (IL-3) (100 U/mL) on the proliferative activity of leukemic cells and on the intracellular metabolism and cytotoxic efficacy of a subsequent 12-hour application of cytosine arabinoside (ara-C) at doses of 0.1, 1.0, 10.0, and 100.0 mumol/L were evaluated on bone marrow cells from 17 patients with acute myeloid leukemia. After GM-CSF or IL-3, a 1.2- to 2.4-fold increase in S-phase cells was observed in nine of 14 GM-CSF and seven of 11 IL-3 cases. 3H-Cytosine arabinoside incorporation into the DNA was enhanced 1.33- to 18.3-fold over respective controls in 14 of 17 patients. While in control specimens are ara-C dose-dependent increase in 3H-ara-C uptake was accompanied by a corresponding rise in intracellular ara-C-5' triphosphate (ara-CTP) levels, ara-CTP concentrations were not increased after GM-CSF or IL-3 exposure, resulting in a higher ara-C to ara-CTP ratio over controls. This finding may be explained by a stimulatory effect of GM-CSF and IL-3 on ara-C phosphorylating enzymes and a more rapid incorporation of ara-CTP into the DNA of leukemic blasts. These effects translated into a 2.2- to 229.0-fold increase in the cytotoxic activity of ara-C against clonogenic leukemic cells after GM-CSF or IL-3 pretreatment. Hence, GM-CSF and IL-3 enhance the intracellular metabolism of ara-C and its incorporation into the DNA of leukemic cells leading to a higher antileukemic activity of ara-C on clonogenic leukemic cells (CFU-L).

Acute Disease↗
PubMed1992

[Mitoxantrone and conventional-dose cytosine arabinoside for relapsed and refractory acute leukemia].

Fourteen patients with relapsed or refractory acute leukemia received combination chemotherapy of mitoxantrone 6 mg/m2/day intravenously for three to six days and cytosine arabinoside 60 mg/m2/day intravenously over 24 hours continuously for five to ten days. Complete remission was attained in six patients (42.9%) and partial response in two patients (14.3%). Six patients (42.9%) had resistant disease, and four patients (28.6%) died during the myelosuppressive phase. Of the patients achieving complete remission, four relapsed and other two continued complete remission up to 27.3 months. Median remission duration was approximately 10.6 months. No significant difference was found with regard to the efficacy of our regimen between AML and ALL. Hematological toxicity was no more severe than the prior cumulative chemotherapy. Major non-hematologic side effects were nausea and vomiting (71.4%), stomatitis (64.3%) and liver dysfunction (57.1%), which were moderate and manageable, while no cardiotoxicity was observed in any patient. In conclusion, the combination chemotherapy of mitoxantrone and conventional dose cytosine arabinoside is an effective salvage therapy in relapsed or refractory acute leukemia, and our regimen has possible utility as first-line chemotherapy in de novo acute leukemia also.

Acute Disease↗
PubMed2006

Cross-resistance to cytosine arabinoside in human acute myeloid leukemia cells selected for resistance to vincristine.

AIM: The goals of the study were to reveal the involvement of P-glycoprotein (P-gp), the product of multidrug resistance 1 gene (MDR1) in cellular resistance to vincristine (VCR) and investigate cross-resistance against cytosine arabinoside (Ara-C) in HL60 and HL60/VCR cell lines. METHODS: HL60 cells (human acute myeloid leukemia cell line) were cultured on medium with 1-50 nM of VCR for 4-6 weeks, and VCR resistant cells (HL60/VCR) were selected. The viability of cells was assessed by MTT assay and the expression of MDR1 gene was detected by RT-PCR. RESULTS: No expression of MDR1 gene was revealed in HL60 cells, but MDR1 started to be expressed after incubation of cells with 2 nM of VCR and its expression level elevates with increase of agent concentration. MTT test has shown that HL-60/VCR cells were 75-fold more resistant to VCR and 42-fold higher resistant to cytosine arabinoside (Ara-C) compared to sensitive HL60 cells. CONCLUSION: Aquired resistance to VCR and cross-resistance to Ara-C correlates with MDR1 gene expression in vitro.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

[Comparative study of high doses vs conventional doses of cytosine arabinoside combined with cisplatin and dexamethasone in patients with refractory lymphoma].

Forty-three patients with advanced malignant lymphoma resistant to previous chemotherapy were randomized in two groups: one received a high dose versus a low-dose cytosine arabinoside, in combination with dexamethasone and cisplatinum. Ten of 24 patients (41%) in the low-dose regimen achieved response: six complete remission (CR) and four partial remission (PR), compared with 5 of 19 (30%) (three CR and two PR). Survival was better in the low dose regimen: 39 versus 23 weeks. Toxicity was most frequent and severe in the high dose schedule. These results suggests that the use of cytosine arabinoside and cisplatinum is useful in the treatment of refractory lymphoma, and that the low-dose would be a better alternative than a high dose.

Adult↗
PubMed1989

Cytosine arabinoside kills postmitotic neurons: evidence that deoxycytidine may have a role in neuronal survival that is independent of DNA synthesis.

Cytosine arabinoside (ARA C), a competitive inhibitor of the incorporation of 2'-deoxycytidine into DNA in other cell types, caused a concentration-dependent inhibition of KCl- and insulin-stimulated survival of postmitotic ciliary parasympathetic ganglion neurons, and the nerve growth factor (NGF)-stimulated survival of postmitotic dorsal root ganglion (DRG) sensory neurons in vitro. The IC50 for survival was 2 x 10(-8) M for both types of neurons after 4 d under the culture conditions used. The inhibition of DRG survival by ARA C in the presence of varying concentrations of NGF indicated that ARA C acted as an apparent noncompetitive antagonist of NGF. This cytotoxic effect of ARA C was blocked by 2'-deoxycytidine, but not by cytosine, 2'-deoxyadenosine, 2'-deoxyguanosine, or 2'-deoxythymine, indicating that ARA C was interfering with a deoxycytidine-specific survival process. Cytidine could block ARA C toxicity, but it was 40 times less potent than 2'-deoxycytidine. The blockade of the cytotoxic effect of ARA C by 2'-deoxycytidine indicated that 2'-deoxycytidine was an apparent competitive antagonist of ARA C toxicity. 2'-Deoxycytidine, by itself, was not survival-promoting. Other antimitotic agents, such as adenine arabinoside, thymine arabinoside, 5-fluorodeoxyuridine, 5-bromodeoxycytidine, 5-azadeoxycytidine, and aphidicolin had no effect on neuronal survival at a concentration 5000 times the EC50 of ARA C, indicating that inhibition of DNA synthesis or repair was probably not the mechanism by which ARA C inhibited neuronal survival and that other 2'-deoxynucleosides were not involved in the survival-promoting process. Nitrobenzylthioinosine, an inhibitor of 2'-deoxycytidine and ARA C membrane transport in other cell types, inhibited the cytotoxic effect of ARA C in neurons, suggesting that ARA C entered the neurons through a similar transport mechanism and that ARA C needed to gain access to the inside of the neuron to be effective. These results indicate that ARA C, in addition to being an antimitotic agent for dividing cells, is also cytotoxic for postmitotic neurons. This inhibition of neuronal survival by ARA C is hypothesized to be due to inhibition of a 2'-deoxycytidine-dependent process that is independent of DNA synthesis or repair. Thus, 2'-deoxycytidine may have an important and previously unrecognized role in cellular function that in the case of neurons is critical for survival.

Animals↗
PubMedDate not supplied

The effects of cytosine arabinoside and GM-CSF in leukemic cells in vitro.

An in vitro pilot study was conducted of the possible utility of combining low doses of cytosine arabinoside (araC) and GM-CSF to stimulate leukemic cell differentiation. Cytosine arabinoside induced macrophage differentiation in some cultures but only when the drug produced substantial cytostatic effects. GM-CSF, when present alone, failed to induce leukemic cell differentiation. When GM-CSF and araC were simultaneously present the level of both araC associated cytotoxicity and araC associated differentiation were reduced in 3 studies. In only a single study was there evidence suggesting that GM-CSF increased araC-associated differentiation.

Cell Differentiation↗
PubMed1989

Liquid-chromatographic monitoring of cytosine arabinoside and its metabolite, uracil arabinoside, in serum.

This is a "high-performance" liquid-chromatographic method for quantifying the antileukemic drug cytosine arabinoside (cytarabine; 1-beta-D-arabinofuranosylcytosine; Ara-C), with a structural analog, 5-methylcytidine, as the internal standard. We used a C18 reversed-phase column and ammonium acetate (0.5 mol/L, pH 6.5) as the mobile phase, monitoring the column effluent at 280 nm. Tetrahydrouridine was present in the sample-collection tubes to inhibit conversion of cytosine arabinoside to uracil arabinoside. The standard curve is linear to 100 mg/L. Analytical recovery is 98%. Coefficients of variation for within-run and between-run imprecision were 2.0% and 4.3% at 20 mg/L and 2.7% and 2.7% at 80 mg/L, respectively. Assay sensitivity was limited by the amount of endogenous material in each patient's serum, making assay of a pre-infusion sample necessary for accurate calculations. In a trial patient population, the assay was shown to have potential for the detection of toxic concentrations in patients receiving high doses of Ara-C.

Aged↗
PubMed1988

[High dosage and intermediate dosage cytosine arabinoside in the treatment of secondary leukemias].

Patients with secondary acute myeloid leukaemia (AML) following treatment with alkylating agents and/or radiation show a poor response to standard induction therapy. Between 1983-1987 8 consecutive patients were treated with high-dose cytosine arabinoside (HD-ARA C; 3 g/sqm twice daily for 6 days) or intermediate-dose cytosine arabinoside (ID-ARA C; 0.5 g/sqm twice daily for 6 days). Complete remission was achieved in 3 patients (HD-ARA C: 2/3l; ID-ARA C: 1/5) and partial remission in 3 patients (ID-ARA C: 3/5). One patient (HD-ARA C) died during prolonged aplasia, one patient (ID-ARA C) proved refractory to treatment. The respective duration of remission in the 3 responsive patients was 3, 7 and 8 months. The probability of survival of the whole group was 50% after 12 months and 25% after 24 months. Our results confirm the efficacy of monotherapy with ARA C in the treatment of secondary AML. Consolidation therapy with ID-ARA C for 4 days seems to prolong remission.

Adult↗
PubMed1988

High-dose cytosine arabinoside and fractionated total-body irradiation: an improved preparative regimen for bone marrow transplantation of children with acute lymphoblastic leukemia in remission.

Twenty children with acute lymphoblastic leukemia in second (18 patients) or third (two patients) complete remission after bone marrow relapse received allogeneic bone marrow transplants from histocompatible sibling donors. The preparative regimen for marrow transplantation consisted of 12 doses of 3,000 mg/m2 cytosine arabinoside twice daily for six days followed by 1,200 cGy total-body irradiation (six doses of 200 cGy twice daily for three days). The preparative regimen was well tolerated, and all patients showed marrow engraftment promptly. Twelve patients are alive in complete remission 12+ to 79+ months posttransplant; eight patients are over 48 months posttransplant. Six patients died 1 to 9 months posttransplant of nonleukemic causes: (two each of graft-v-host disease, interstitial pneumonitis, and infection). Two patients developed recurrent leukemia at 15 and 30 months posttransplant. Both have died at 19 and 36 months posttransplant. Life table analysis reveals an actuarial survival and event-free survival rate of 58% and a marrow relapse rate of 17%. These results suggest that high-dose cytosine arabinoside and fractionated total-body irradiation is a relatively nontoxic and highly effective preparative regimen for allogeneic bone marrow transplantation for acute lymphoblastic leukemia that deserves further evaluation.

Adolescent↗
PubMed1978

Simultaneous assay by six methods of the effect on haemopoietic precursor cells of adriamycin, methyl CCNU, 60Co gamma-rays, vinblastine, and cytosine arabinoside.

The spleen colony assay, three agar colony assays and two repopulating assays have been employed to measure the effect of single doses of adriamycin, methyl CCNU, 60CO gamma-rays, vinblastine and repeated injection of cytosine arabinoside on early haemopoietic precursors. The results show that there is no consistent correlation between the effect of these agents on the six assays, and the differences in proliferation rate of the cells contributing to the various assays could not be demonstrated by the phase specific agents vinblastine and cytosine arabinoside. The relatively high survival of granulocyte repopulating ability after adriamycin and methyl CCNU indicates that the capacity for differentiation and maturation can be influenced by cytotoxic agents so that colony assays while estimating the number of progenitor cells surviving do not necessarily provide a reliable guide to the capacity of the cells for restoring haemopoiesis. Comparison of colony formation by normal bone marrow cells with the three agar colony assays showed that the agar diffusion chamber method gave three times as many colonies and a much smaller variation between experiments compared to the in vitro agar assay with endotoxin mouse serum as colony stimulating factor. The thin layer feeder cell method gave an intermediate number of colonies.

Animals↗
PubMed1986

[A case of complete remission from acute myelogenous leukemia in second relapse achieved using an intermediate-dose cytosine arabinoside (ID Ara-C) regimen].

A 57-year-old-male patient with acute myelogenous leukemia in second relapse who was refractory to BHAC . AMP [behenoyl arabinosyl cytosine (BHAC), aclacinomycin, 6-mercaptopurine and prednisolone (PSL)] and BHAC . DVP [BHAC, daunomycin, vincristine and PSL] was treated with an intermediate-dose cytosine arabinoside (ID Ara-C) regimen. This schedule consisted of a 1-h infusion of Ara-C at a dose of 500 mg/m2 every 12 h for 6 d (days 3-8), in combination with doxorubicin 50 mg/m2 on day 1 and vincristine 1 mg/m2 on day 2. The patient achieved a complete remission 23 days after completion of Ara-C and was treated with ID Ara-C (Ara-C days 3-6) as a consolidation. Remission duration was only 2.5 months. Plasma Ara-C concentrations were assayed by HPLC and the peak level was 6.7 micrograms/ml. Side effects were mild nausea, vomiting, alopecia and moderate skin rash.

Cytarabine↗
PubMed1978

Treatment of adult acute lymphoblastic leukemia with cytosine arabinoside, vincristine, and prednisone.

Thirteen adults with acute lymphoblastic leukemia were entered into a protocol in which cytosine arabinoside infusion was added to vincristine and prednisone as remission induction and periodic intensification therapy. Central nervous system prophylaxis consisting of cranial irradiation and intrathecal methotrexate was given, and all patients received continuous oral 6-mercaptopurine and methotrexate as maintenance treatment. Myelotoxicity was severe during induction, with prolonged granulocyte and platelet count nadirs noted. Nine of 13 patients (69%) obtained a complete remission and one (8%) obtained a partial remission. The median duration of complete remission was 38.1 weeks. It was concluded that cytosine arabinoside in combination with vincristine and prednisone is an effective but toxic antileukemic regimen which did not produce a major improvement in remission duration.

Adult↗
PubMed1987

Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia.

The cytotoxic effect of cytosine arabinoside (ara-C) is presumably mediated by cytosine arabinoside 5'-triphosphate (ara-CTP). We tested for a correlation between intracellular ara-CTP pharmacokinetics and clinical response among 51 patients who received high dose ara-C (3 g/m2 at 12-hr intervals) as therapy for refractory acute leukemia. After accounting for pretreatment clinical variables that correlated with response, measurement of ara-CTP pharmacokinetics added significant prognostic information. This provides a rationale for manipulation of schedules of high dose ara-C administration in those patients whose pharmacokinetic characteristics are inconsistent with response to an every 12-hr schedule.

Acute Disease↗
PubMed1985

[Sequential combination of high-dose cytosine arabinoside and L-asparaginase in the treatment of refractory acute leukemia and malignant lymphoma].

Clinical effects of sequential administration of high-dose cytosine arabinoside with L-asparaginase were studied in 5 cases of refractory acute leukemia and 2 cases of non-Hodgkin's lymphoma. A total 12 courses were carried out on these 7 patients and complete remission was obtained in 2 courses and partial remission in 3 courses. Two cases of lymphoma with pleural effusion or CNS invasion achieved partial and complete remission, respectively. The side effects associated with this sequential therapy were nausea, vomiting, diarrhea, fever and conjunctivitis, although these were tolerable. These observations suggest that high-dose cytosine arabinoside combined with L-asparaginase is a useful regimen for refractory leukemia and lymphoma.

Adult↗
PubMed1979

Effects of cytosine arabinoside on the incorporation of pyrimidine nucleosides into hamster cells transformed by herpes simplex type 1 and type 2 viruses and by human cytomegalovirus.

The incorporation of 3H-thymidine and 3H-deoxycytidine into acidoprecipitable fraction of hamster cells transformed by herpes simplex viruses type 1 and type 2 and of 3H-thymidine into hamster cells transformed by human cytomegalovirus was found to be resistant to the action of cytosine arabinoside. More 3H-thymidine was incorporated into these cells in the presence than in the absence of the drug. Similar stimulaton of 3H-thymidine uptake could be achieved by using unlabelled deoxycytidine instead of cytosine arabinoside. Incorporation of both nucleosides into spontaneously and SV40 transformed cells was efficiently inhibited by the drug.

Animals↗
PubMed1979

Differential cell-cycle-dependent inhibition of DNA synthesis by hydroxyurea and cytosine arabinoside in cultured L5178Y mouse lymphoma cells.

The effect of various concentrations of hydroxyurea and cytosine arabinoside on DNA synthesis, measured as 3H-thymidine incorporation, in exponentially growing and synchronized L5178Y cells in culture was investigated. The experiments revealed that each compound causes differential inhibition of DNA synthesis at various times of the S-phase. Maximum sensitivity to hydroxyurea occurred in cells in the late S, and maximum sensitivity to cytosine arabinoside in the early S-phase. When they were given simultaneously in low concentrations an additive effect was observed.

Animals↗
PubMed1984

[Combination chemotherapy of mitomycin C and cytosine arabinoside in the intravesical treatment for superficial bladder tumors: report 2. Evaluation of prophylactic intravesical infusion therapy].

Combined chemotherapy of Mitomycin C (20 mg to 30 mg) and Cytosine Arabinoside (200 mg) was given by intravesical infusion to 25 patients with superficial bladder tumor who underwent transurethral treatment for prevention of postoperative recurrence. The prophylactic effect of this therapy was evaluated as follows. 1) The postoperative recurrence rates by the actuarial method were 4.0% in six months, 8.1% in one year, 22.2% in two years, 37.4% in three years and 37.4% in five years. 2) The prophylactic effect on recurrence tended to be marked on primary tumors, solitary tumors, low grade tumors and relatively large tumors. 3) The correlation of doses and the recurrence rate was significantly observed: prophylactic effect tended to increase in proportion to increase of doses of both Mitomycin C and Cytosine Arabinoside.

Adult↗
PubMed1983

[Reduced dosage of cytosine arabinoside in the treatment of acute myelocytic leukemia. Apropos of 3 cases].

Two out of three patients with acute myeloid leukemia responded to treatment with small subcutaneous doses of cytosine-arabinoside alone. Although marked cytopenia may transiently occur this treatment has no other side effects and is simple to administer. It may therefore be useful for elderly patients. Morphological studies and indirect evidence suggest that this schedule, dosage and route of administration for cytosine-arabinoside may promote differentiation within the malignant clone rather than acting as a cytotoxic agent.

Aged↗