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PubMed1981

Treatment of refractory adult acute lymphocytic leukaemia and acute undifferentiated leukaemia with an anthracycline antibiotic and cytosine arabinoside.

Ten patients with acute lymphocytic leukaemia (ALL) and four patients with acute undifferentiated leukaemia (AUL) in relapse or refractory to conventional therapy were treated with remission induction therapy consisting of an anthracycline antibiotic and cytosine arabinoside. Twelve patients had previously demonstrated resistance to vincristine-prednisone and nine patients had prior anthracycline therapy. Nine patients achieved complete remission after one course of therapy with a median time to remission of 30 d. Of five nonresponders, three died of sepsis with marrow hypocellularity and no evidence of residual leukaemia. Only two patients had unequivocal evidence for resistance to an anthracycline-cytosine arabinoside regimen. Myelosuppression and infection were the most significant complications of therapy. The data presented indicate that marrow ablative chemotherapy with an anthracycline antibiotic and cytosine arabinoside is an effective regimen for remission induction in adults with ALL and AUL refractory to vincristine-prednisone. The use of these agents in remission consolidation therapy may offer the possibility of providing a reduction in residual resistant cells that are present after successful remission induction therapy with conventional agents.

Adolescent↗
PubMed1984

A requirement for DNA synthesis in foetal hepatocyte differentiation. Effect of cytosine arabinoside on the appearance of the liver isoenzyme of pyruvate kinase.

In hepatocyte cultures derived from 15-day-old foetal rats, the appearance of the liver (L) form of pyruvate kinase is blocked when cytosine arabinoside is added on the 2nd day of culture. When added on the 3rd day of culture, the inhibitor of DNA synthesis does not prevent the appearance of the enzyme. If cytosine arabinoside is added on the 2nd day of culture and removed on the 4th day, the enzyme is detected by the 6th day of culture. The specificity of the action of cytosine arabinoside for the L form of pyruvate kinase is in contrast with the lack of effect observed on total protein synthesis and the activity of the embryonic (M2) form of the enzyme.

Animals↗
PubMed1988

Results of induction and consolidation treatment with intermediate and high-dose cytosine arabinoside and m-Amsa of patients with poor-risk acute myelogenous leukaemia.

50 patients (aged 18-58 years) with acute myelogenous leukaemia after a preleukaemic phase (n = 14), acute myelogenous leukaemia that previously failed to respond to conventional chemotherapy (n = 9) or relapsed disease (n = 27) were given remission induction therapy consisting of cytosine arabinoside (1 g/m2 q 12 h x 12) and m-Amsa (115 mg/m2 for 1 or 3 days). Overall, 27 patients (54%) achieved complete remission. The complete remission rate for patients with acute myelogenous leukaemia after a preleukaemic phase (7/14) and those with primary refractory or relapsed leukaemia (20/36) seems superior to that obtained with conventional remission-induction therapy. 12 patients received 1-3 courses of consolidation chemotherapy with cytosine arabinoside (3 g/m2 q 12 h x 8) and m-Amsa (115 mg/m2 for 1 d). 3 of them subsequently underwent autologous bone marrow transplantation. The median duration of remission for the remaining 9 patients was 8 months. 11 patients did not receive consolidation therapy; their median duration of remission was 3 months. The difference between the two groups was not significant. 4 patients underwent allogeneic bone marrow transplantation after achievement of complete remission. The impact of high-dose cytosine arabinoside consolidation chemotherapy on poor-risk acute myelogenous leukaemia remains unclear.

Adult↗
PubMed1977

A phospholipid derivative of cytosine arabinoside and its conversion to phosphatidylinositol by animal tissue.

We have synthesized an analog (ara-CDP-DL-dipalmitin) of cytidine diphosphate diglyceride (CDP-diglyceride) in which the antitumor drug, cytosine arabinoside, is substituted for the cytidine moiety. Enzymes in rat and human liver convert this analog to phosphatidylinositol, thereby releasing cytosine arabinoside-5'-monophosphate, an obligatory intermediate in the activation of cytosine arabinoside. Unlike cytidine diphosphate diglyceride, however, ara-CDP-DL-diapalmitin is not an efficient substrate for phosphatidylglycerophosphate synthesis in liver or phosphatidylserine in Escherichia coli. The antitumor activity of ara-CDP-DL-dipalmitin in mice bearing L5178Y leukemia is described.

Animals↗
PubMed1976

Effect of cytosine arabinoside and 5-iodo-2'-deoxyuridine on a cytomegalovirus infection in newborn mice.

Murine cytomegalovirus was inhibited by 0.6 to 1.2 mug of cytosine arabinoside per ml and by 0.3 to 0.6 mug of 5-iodo-2'-deoxyuridine in mouse embryo fibroblast cells. Human cytomegalovirus was inhibited by similar concentrations of the two drugs in WI-38 cells. Intraperitoneal inoculation of suckling mice with 10(4.5) plaque-forming units of murine cytomegalovirus provides a model for disseminated human cytomegalovirus infection in human newborn infants and is characterized by a widespread infection involving the liver, spleen, lung, kidney, and brain with a 70 to 90% mortality in 7 to 9 days. Treatment with 12.5 mg of cytosine arabinoside per kg or 25 mg of 5-iodo-2'-deoxyuridine per kg twice daily for 8 days had no effect on final mortality or the pathogenesis of the infection with the exception of reduced viral titers in the spleen of 5-iodo-2'-deoxyuridine-treated animals. These data indicate that neither cytosine arabinoside nor 5-iodo-2'-deoxyuridine are effective in the treatment of murine cytomegalovirus infections in suckling mice and suggest that they may be of limited value in the treatment of severe cytomegalovirus infections in human neonates.

Animals↗
PubMed1970

Combination chemotherapy using L-asparaginase, daunorubicin, and cytosine arabinoside in adults with acute myelogenous leukaemia.

Cytosine arabinoside and daunorubicin used in an intensive intermittent regimen have been shown to be an effective combination for the induction of complete remissions in 14 out of 23 adult patients with acute myelogenous leukaemia. This gives an overall complete remission rate of 60%. A further patient had a good partial remission. The addition of L-asparaginase to the regimen has not increased the incidence of remission and there were more side effects in the L-asparaginasetreated group. Of the 10 patients treated with L-asparaginase in addition to cytosine arabinoside and daunorubicin, five achieved a complete remission. Of the 13 patients treated with cytosine arabinoside and daunorubicin without L-asparaginase, nine achieved a complete remission and one a good partial remission.

Adolescent↗
PubMed1987

High-dose cytosine arabinoside, daunomycin and 6-thioguanine in relapsed or refractory acute nonlymphocytic leukemia.

Fifteen patients with relapsed (10) or primarily refractory (5) acute nonlymphocytic leukemia were treated with a combination of cytosine arabinoside (3 g/m2 i.v. every 12 h, 12 doses, days 1-6), 6-thioguanine (100 mg/m2 orally every 12 h, 12 doses, days 1-6) and daunomycin (60 mg/m2 i.v. on days 5 and 6 only). Complete remission was achieved in 11 patients. Eight of 10 relapsed patients and 3 of 5 primarily refractory patients entered remission. Median remission duration was 7.5 months (2-36+ months). Ten of the 11 remissions resulted from a single induction course. The time to hematologic recovery was comparable to that seen with 'standard'-dose cytosine arabinoside regimens. Nonhematologic toxicity, although considerable, was not greater than that seen with high-dose cytosine arabinoside alone. The most significant problem was gastrointestinal toxicity with diarrhea occurring in the majority of patients. Mild neurologic toxicity (reversible cerebellar dysfunction) occurred in 2 patients.

Acute Disease↗
PubMed2002

Treatment of blastic phase chronic myeloid leukemia with mitoxantrone, cytosine arabinoside and high dose methylprednisolone.

Fourteen patients with blastic phase chronic myelogenous leukemia received combination chemotherapy with mitoxantrone 5 mg/m2 intravenously daily for 3 days, cytosine arabinoside 100 mg/m2 intravenously over 2 hours bid for 7 days and high dose methylprednisolone 1000 mg/day intravenously for 5 days. The patients' mean age was 52 +/- 10 (range 34-64) and Philadelphia chromosome was positive in all. Five patients (35%) achieved complete remission and four patients (28%) had a partial remission. Overall remission rate was 64%. The mean survival was 11.1 +/- 8.6 months (median 13) for all patients, 19.4 +/- 4.0 months (median 19) for those achieving a complete remission, 12.50 +/- 5.7 months (median 14) for patients with partial remission and 1.8 +/- 1.8 months (median 2) for the unresponsive patients. Two of 5 unresponsive patients died early after the second course of remission induction. The treatment regimen was generally well tolerated. Marrow hypoplasia was observed in 9 (64%) patients and 7 (50%) had febrile episodes. Non-myelosupressive toxicity of the regimen was acceptable. Nausea and vomiting were observed in 8 (57%) patients and 3 (21%) patients developed flushing due to cytosine arabinoside. These results suggest that the regimen with mitoxantrone, cytosine arabinoside and high dose methylprednisolone in remission-induction of blastic phase chronic myelogenous leukemia may be a valid option that may also improve overall prognosis.

Adult↗
PubMedDate not supplied

Combined carboplatin and cytosine arabinoside in metastatic melanoma refractory to dacarbazine.

This is a preliminary report on the efficacy and toxicity of the combination chemotherapy regimen with carboplatin and cytosine arabinoside in dacarbazine-resistant metastatic melanoma. Patients were considered eligible in the presence of measurable disease sites, an ECOG performance status of 2 or less, a life expectancy of at least 2 months, and prior dacarbazine treatment. The planned schedule consisted of cytosine arabinoside (150 mg/m2 intravenously plus 50 mg subcutaneously), followed by a rapid infusion of carboplatin (350 mg/m2 on day 1). Courses were administered every 3 weeks according to hematologic recovery. Twenty-one consecutive patients were evaluable for activity and toxicity, the response rate was 19% (95% confidence interval, 5-42%). There was no complete remission. Toxicity was tolerable being myelosuppression the main side effect. In conclusion, the combination of carboplatin and cytosine arabinoside has limited activity as a salvage treatment in melanoma patients failing on dacarbazine chemotherapy. Moreover, the regimen is well tolerated and easy to administer in an outpatient setting.

Adult↗
PubMed1996

Modulation of cisplatin antitumor activity by short infusional high-dose cytosine arabinoside in advanced pretreated head and neck carcinoma: a phase II study.

The aim of the present study, which included 24 pretreated patients (both with radiotherapy and/or cisplatin-containing chemotherapy) with histological grade I/II head and neck cancer, was to investigate whether the enhancing action of cytosine arabinoside on cisplatin antitumor activity might be evidenced without excessive hematological toxicity with the administration of short infusional high-dose cytosine arabinoside, applied before cisplatin. Cytosine arabinoside was administered on day 1 of the treatment cycle at 0h and 12h at the dosage of 500 mg/m2 (1 hour infusion), and cisplatin at 6h and 18h of the same day with a dose of 20 mg/m2. On days 2, 3 and 4, only cisplatin 30 mg/m2/24h was administered. 19 patients were evaluable for activity including 14 patients pretreated with cisplatin-containing chemotherapy. 2/19 achieved complete response (CR), 2/19 a partial response (PR), 8/19 had stable disease and 7/19 progressive disease. Objective responses (2 CR and 1 PR) were evidenced in 3/14 patients previously resistant to cisplatin at the same dosage as in the present regimen. WHO grade IV toxicity for granulocytes was recorded in only one patient.

Adult↗
PubMed1985

Intraperitoneal chemotherapy with high-dose cisplatin and cytosine arabinoside for refractory ovarian carcinoma and other malignancies principally involving the peritoneal cavity.

Sixty-two patients with refractory ovarian carcinoma or other malignancies principally confined to the peritoneal cavity were treated with an intraperitoneal combination chemotherapy regimen consisting of cisplatin (100 mg/m2 or 200 mg/m2) and cytosine arabinoside (4 X 10(-3) mol/L or 10(-2) mol/L). Sodium thiosulfate was simultaneously administered intravenously (IV) to protect against cisplatin-induced nephrotoxicity. Sixteen of 52 evaluable patients demonstrated evidence of a clinical response including 14 (36%) of 39 with refractory ovarian carcinoma. Systemic toxicity was not severe except for cisplatin-induced emesis and a single episode of major renal insufficiency. Dose-limiting toxicity was bone marrow suppression with cytosine arabinoside administered at 10(-2) mol/L. We conclude that combination intraperitoneal therapy with high-dose cisplatin and cytosine arbinoside can be safely administered with objective tumor responses observed in patients with ovarian carcinoma refractory to front-line chemotherapy and in occassional individuals with other malignancies principally confined to the peritoneal cavity.

Adult↗
PubMed2002

Synergism between cytosine-guanine oligodeoxynucleotides and monoclonal antibody in the treatment of lymphoma.

Synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine dinucleotides (CpG ODN) are potent immunostimulatory agents that can activate various immune cell subsets. We have found that CpG ODN show a variety of effects that could be useful in enhancing the efficacy of antibody therapy of lymphoma. In a mouse model, CpG ODN alone had no effect on survival of animals inoculated with lymphoma. In contrast, CpG ODN plus monoclonal antibody (MAb) was more effective at inhibiting tumor growth than MAb alone or MAb plus control ODN. Cytosine-guanine ODN plus MAb cured mice with a large tumor burden that could not be cured with MAb therapy alone. We also evaluated the effects of CpG ODN on the phenotype of human malignant B cells. Cytosine-guanine ODN upregulated the expression of a number of antigens, including CD20. The upregulation of CD20 was most extensive in cells that had low baseline expression of this antigen. We conclude that CpG ODN enhances the efficacy of MAb in a murine lymphoma model, most likely by activating effector cells, and upregulates expression of CD20 on primary human malignant B cells. Given the effects of CpG ODN on both target antigen expression and effector-cell function, further evaluation of the combination of CpG ODN plus rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) and CpG ODN plus other MAbs is warranted.

Adjuvants, Immunologic↗
PubMedDate not supplied

Comparative studies of cyclocytidine (NSC-145668) and cytosine arabinoside (NSC-63878) in mice.

The distribution of cyclocytidine and cytosine arabinoside has been studied in normal BDF mice and in mice bearing 6-day solid L1210 lymphocytic leukemia by whole-body radioautography, bioassay, and radiochemical techniques. Radioactivity was widely distributed throughout the tissues between 15 minutes and 12 hours after a single intravenous dose of either cyclocytidine-2-14C or cytosine arabinoside-2-14C. Whole-body radioautograms demonstrated that for most tissues, cytosine arabinoside-derived 14C was uniformly excreted by 48 hours; cyclocytidine-derived 14C, however, was localized in certain tissues as early as 15 minutes after drug administration and was retained in these sites for 48 hours. Depot loci of 14C included salivary and adrenal glands, fat, cardiac muscle, gastrointestinal tract, and L1210 tumor. The distribution and persistence of cyclocytidine-derived radioactivity is consistent with other reports of toxicity induced by the drug in these tissues. Radiochromatography and bioassay data from BDF mice dosed intraperitoneally with cyclocytidine demonstrated that 65%-95% of the 14C-radioactivity in a number of tissues was the parent compound itself. Thus, cyclocytidine contributed in large measur to the generation of the radioautograms. This study demonstrates that the retention of cyclocytidine in body tissues may serve to effect the sustained release of the deaminase-resistant chemotherapeutic drug from these depot sites and thus prolong cytotoxic levels of drug in tumor tissue.

Adipose Tissue↗
PubMed2001

Treatment of Tumor in Mice by Oral Administration of Cytosine Deaminase Gene Carried in Live Attenuated Salmonella.

To study the possibility of oral gene therapy using live attenuated Salmonella, eukaryotic expression vectors EGFPN1, pLCDSN were introduced into a live attenuated AraA(-) auxotrophic mutant of Salmonella typhimurium (SL3261) and were administered orally to BALB/c and C57BL/6 mice. After six weeks, these mice were challenged with 4T(1) and Lewis cancer cells. Until the tumors reached to about 10 mm in diameter, 5-fluorocytosine was given through intraperitoneal injection. Flow cytometry, confocal microscopy and PCR methods were used to detect the integration and expression of the genes. The inhibition of the tumor and the survival time of the mice were also investigated. Results showed that cytosine deaminase gene integration could be detected in almost all kinds of mice tissue. And the GFP expression was much stronger in spleen and tumor than in other tissues. Cytosine deaminase/5-fluorocytosine system had significant antitumoractivities in vivo. The anti-tumor activities of cytosine deaminase/5-fluorocytosine at 500 mg/kg on 4T(1) and Lewis carcinoma in BALB/c and C57BL/6 mice were more potent than the efficiency of 5-fluorouracil 10 mg/kg(P 0.05). Therefor, this experiment demonstrates the potential value of live attenuated Salmonella as carrier for oral gene therapy.

Journal Article↗
PubMed1990

Jaundice and hepatorenal syndrome associated with cytosine arabinoside.

A young man receiving high dose cytosine arabinoside (3g/m2 every 12 hours) for promyelocytic leukemia developed rapidly increasing hyperbilirubinemia and hepatorenal syndrome. The patient had been treated previously with courses of standard dose cytosine arabinoside without hepatic or renal complications. His condition rapidly deteriorated, and he required hemodialysis. The total bilirubin increased to 45.4 mg/dL, but alkaline phosphatase remained normal. Twelve days after starting chemotherapy, the patient died of hepatorenal failure. Liver necropsy revealed mild bile stasis and microvesicular steatosis. We suspect high dose cytosine arabinoside played a major role in causing impairment of bilirubin transport within the hepatocyte in this patient.

Acute Kidney Injury↗
PubMed1990

[Treatment of myelodysplastic syndrome using continual subcutaneous infusion of low doses of cytosine arabinoside].

The authors summarize their experience with the administration of small doses of cytosine arabinoside continuously by subcutaneous infusion in 13 patients with myelodysplastic syndrome. Alcysten Spofa was administered in doses of 20 mg/sq.m per day for 5-17 days in one cycle. A total of 26 therapeutic cycles were administered. Favourable responses were obtained in four patients, partial results were achieved in two patients; in seven instances treatment produced no response. The authors compare also the results obtained in this group with a previous group of 11 patients treated with small doses of cytosine arabinoside, which was administered intermittently, i.e. twice a day by the subcutaneous route. Continuous administration did not produce more favourable therapeutic results, it caused however a larger number of infections and haemorrhagic complications as compared with intermittent administration. The authors recommend administration of small doses of cytosine arabinoside in patients with prognostically adverse types of myelodysplastic syndrome - intermittently 10 mg subcutaneously twice a day for 14-21 days.

Aged↗
PubMed1978

[Selective treatment of leukemia L1210 with combination of deoxycytidine and lethal doses of cytosine arabinoside].

Oral administration of deoxycytidine simultaneously with intraperitoneal injections of toxic doses of cytosine arabinosidetomice with advanced L1210 leukemia diminished the toxic effects preventing drug death of these mice. They developed a marked antitumor effect. The mean survival time of these mice was considerably extended as compared to that of untreated animals or those given one of these drugs alone. At the optimum schedule of treatment about 23% of the mice survived over 60 days. Deoxycytidine protection reduced the antileukemic effect of cytosine arabinoside administered in nontoxic doses. The deoxycytidine plus cytosine arabinose combination was ineffective in the treatment of transplantable myeloid leukemia in mice.

Administration, Oral↗
PubMed1980

Mechanism of 5-azacytidine-induced transfer RNA cytosine-5-methyltransferase deficiency.

The administration of 5-azacytidine to mice leads to a specific, rapid, time-dependent, and dose-dependent decrease of transfer RNA (tRNA) cytosine-5-methyltransferase activity of mouse liver and the synthesis of tRNA specifically lacking 5-methylcytidine. The mechanism of this enzyme deficiency was investigated. The pretreatment of mice with RNA synthesis inhibitors such as actinomycin D and D-galactosamine prevented the enzyme deficiency induced by 5-azacytidine administration. These results suggested that RNA synthesis was a prerequisite for the induction by 5-azacytidine of the enzyme inhibition in vivo. Indeed, a slowly sedimenting RNA (4 to 7S) from the livers of mice treated with 5-azacytidine, when present in an in vitro tRNA methyltransferase assay, decreased specifically the activity of tRNA cytosine-5-methyltransferase. The pretreatment of mice with actinomycin D or D-galactosamine prior to the administration of 5-azacytidine effectively prevented the formation of such inhibitory RNA in vivo as determined by an in vitro tRNA methyltransferase assay. These results indicate that the administration of 5-azacytidine to mice leads to the rapid synthesis of a low-molecular-weight RNA fraction which is capable of specifically inactivating tRNA cytosine-5-methyltransferase activity in vivo and in vitro.

Animals↗