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PubMed1985

Low-dose cytosine arabinoside treatment for acute nonlymphocytic leukemia in elderly patients.

Thirty patients older than 65 years of age with acute nonlymphocytic leukemia were treated with low-dose cytosine arabinoside (10 mg/m2 subcutaneously every 12 hours for 15 to 21 days). Fifteen achieved complete remission and five had partial remission. Treatment was more effective when initial bone marrow cellularity was low (P = 0.007). Four of six patients with secondary leukemia entered complete or partial remission. Therapy was well tolerated with reduced myelosuppression and few number of early deaths. Sixteen patients followed the whole treatment as outpatients. Six of 12 patients who achieved complete remission showed no evidence of post-therapeutic bone marrow aplasia. These data are consistent with the view that low-dose cytosine arabinoside acts on leukemic cells as a differentiating agent.

Acute Disease↗

PubMed1985

Low-dose cytosine arabinoside in the myelodysplastic syndromes and acute myelogenous leukemia.

Seven patients with a myelodysplastic syndrome or "smoldering" acute myelogenous leukemia were treated with cytosine arabinoside in low dosage. Four patients experienced transient, partial responses characterized by improved peripheral blood counts, cessation of transfusion requirements, and a decreased incidence of infection. Treatment was associated with significant, transient hematologic toxicity. The appropriate clinical role of low-dose cytosine arabinoside remains uncertain.

Adult↗

PubMed1985

High-dose cytosine arabinoside in previously treated patients with poor-prognosis non-Hodgkin's lymphoma.

Fourteen previously treated patients with relapsed or refractory poor-prognosis non-Hodgkin's lymphoma were given chemotherapy regimens containing high doses of cytosine arabinoside alone (seven patients) or with an anthracycline or amsacrine (seven patients). Five patients achieved a complete remission and two patients had a partial remission. The durations of remission, however, were short (median, 3 months; range, 2-6 months). Toxicities included conjunctivitis, photophobia, stomatitis, dermatitis, cerebellar dysfunction, diarrhea, nausea, vomiting, liver dysfunction, and severe myelosuppression. Recovery of an absolute granulocyte count greater than 500/microliter and an untransfused platelet count greater than 20,000/microliter required a median of 31 (range, 28-35) and 30 (range, 27-43) days, respectively. Six patients died with recurrent or residual disease before bone marrow recovery. Younger age, good performance status, and a previous complete remission were predictive of a good response. High-dose cytosine arabinoside has major myelotoxicity but significant activity in some patients with poor-prognosis non-Hodgkin's lymphoma.

Adolescent↗

PubMed1988

Treatment of the blastic phase of chronic myelogenous leukemia with mitoxantrone and high-dose cytosine arabinoside.

Twenty-seven patients in the blastic phase of chronic myelogenous leukemia received combination chemotherapy with mitoxantrone 5 mg/m2 intravenously daily for 5 days, and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. The patients' median age was 42 years (range, 19-61 years), and 26 of them had Philadelphia chromosome-positive disease. Overall, seven patients (26%) achieved complete remission, and one (4%) had a partial remission for an overall response rate of 30%. Eight patients died during remission induction, and 11 had resistant disease. The median survival was 14 weeks for the total population, and 24 weeks for patients achieving a complete remission. The nonmyelosuppressive toxicity of the combination was acceptable; serious neurologic and pulmonary toxicities were uncommon. Significant marrow hypoplasia was observed resulting in a high incidence of febrile episodes (85% of patients). The combination of mitoxantrone and high-dose cytosine arabinoside did not significantly improve overall prognosis. Since chemotherapy continues to produce disappointing results, other innovative approaches need to be explored.

Adult↗

PubMed1990

Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia.

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.

Adolescent↗

PubMed1990

Intermediate-dose cytosine arabinoside and amsacrine. An effective regimen with low toxicity in refractory acute nonlymphocytic leukemia.

Results of remission induction therapy in refractory acute nonlymphocytic leukemia (ANLL) has been improved since the introduction of high-dose cytosine arabinoside. However, the toxicity of these regimens attributes to an early death rate of about 20% to 30%. The authors treated 37 poor-risk patients with ANLL with intermediate-dose cytosine arabinoside and amsacrine for remission induction. One consolidation course and no maintenance therapy was given. Eleven of 19 patients with a first relapse entered complete remission (58%); ten of 15 patients in this group older than 50 years were complete responders (67%). Median duration of second remission was 8.2 months (range, 2-14). Three of 13 patients with primarily resistant disease had a complete remission (23%), but there was no response in five patients with a myeloid blastic phase of chronic myelogenous leukemia. Side effects of this remission induction regimen were mild; no cardiac, pulmonary, or central nervous system toxicity was observed. Five patients (14%) died during the remission induction phase, three from complications during aplasia and two from refractory leukemia.

Adult↗

PubMed1994

Pulmonary insufficiency complicating therapy with high dose cytosine arabinoside in five pediatric patients with relapsed acute myelogenous leukemia.

BACKGROUND: The occurrence of fatal or nearly fatal pulmonary insufficiency in 5 of 22 pediatric patients with relapsed acute myelogenous leukemia (AML) treated with high dose cytosine arabinoside (Ara-C) at St. Jude Children's Research Hospital, Memphis, Tennessee, and institutions affiliated with the Pediatric Oncology Group (POG) is reported. METHODS: Cytosine arabinoside (1.0-1.5 g/m2/day) was given as a 5-day continuous infusion to all patients. Four patients with persistent leukemia received a second 3- or 5-day course. The POG protocol included the administration of granulocyte colony stimulating factor for the priming of myeloblasts. Diagnostic criteria for pulmonary insufficiency included noncardiogenic pulmonary edema with exclusion of underlying cardiorespiratory, infectious, or metabolic conditions. Autopsy material also was reviewed. RESULTS: Of the 22 patients 5 died (23%), including 2 who received a second course of Ara-C as a result of pulmonary insufficiency that developed at a median of 8 days (range, 3-38 days) after the first course. Three patients died despite intubation and pressor support. Two patients were managed successfully with colloids, diuresis, and oxygen by face mask; remission was achieved in both. The postmortem examination of one patient disclosed airless lungs, profound pulmonary edema, and subpleural nodules, but no evidence of leukemia. CONCLUSION: Pulmonary insufficiency from high dose Ara-C varies in severity and may be fatal. It may occur during or after treatment. Awareness of this potential complication, careful attention to fluid status, and aggressive supportive care may optimize outcome.

Acute Disease↗

PubMed1983

Cerebellar degeneration caused by high-dose cytosine arabinoside: a clinicopathological study.

Twenty-four patients with leukemia or lymphoma refractory to conventional chemotherapy were given a course of systemic, high-dose cytosine arabinoside (3 gm/m2 every 12 hours for twelve doses). Four patients developed cerebellar degeneration during treatment. Ataxia of gait and limb movements, dysarthria, and nystagmus appeared five to seven days after the first dose, worsened over the next two to three days, and then remained stable for two to six days. Incomplete improvement occurred over the following one to two weeks. Postmortem examination disclosed loss of Purkinje cells in the depths of cortical sulci with relative preservation of those at the crests of folia and those in the most posterior inferior portions of the cerebellum. Other patients developed a mild, reversible cerebellar syndrome over the same time course as that of the irreversible disorder. Manifestations ranged from nystagmus alone to dysarthria and unsteadiness of gait without limb ataxia. We conclude that cytosine arabinoside at this dosage causes a cerebellar degeneration with characteristic clinical and pathological features. Among the present patients with refractory hematological malignancies, such degeneration occurred with an incidence of 16.7%, more than twice that reported in previous series.

Acute Disease↗

PubMedDate not supplied

Triple combination of retinoic acid + low concentration of cytosine arabinoside + hexamethylene bisacetamide induces differentiation of human AML blasts in primary culture.

Differentiation induction therapy provides an alternative therapeutic approach for patients with acute myeloid leukemia (AML) who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy. The effect of a triple combination of retinoic acid (RA) + low concentration of cytosine arabinoside (Ara-C) + hexamethylene bisacetamide (HMBA) on differentiation of blasts from 24 AML patients was studied. Non-adherent mononuclear cells were seeded at a concentration of 5 x 10(5) cells per ml in 24-well tissue culture plates containing RPMI 1640 culture medium with 20 per cent fetal calf serum and 10 per cent 5637-conditioned medium and incubated with 10(-6) M retinoic acid, 10(-6) M cytosine arabinoside and/or 2 mM hexamethylene bisacetamide for six days at 37 degrees C in a humidified incubator under 5 per cent CO2. Morphological, cytochemical and functional differentiation into mature cells were induced in blasts from 22 out of the 24 AML patients following exposure to the triple combination of 10(-6) M RA + 10(-6)M Ara-C + 2 mM HMBA in primary culture. These effective results justify a clinical trial of such triple combination for AML patients who are either unsuitable for or unresponsive to conventional cytotoxic chemotherapy.

Acetamides↗

PubMed1983

Mouse teratocarcinoma cells resistant to aphidicolin and arabinofuranosyl cytosine: isolation and initial characterization.

With the long-range goals of elucidating the biochemical genetics and the phenotypic expression, both in vitro and in vivo, of mutator strains of mammalian cells, we have isolated and partially characterized a series of drug-resistant mutants from a subline a feeder-dependent parental mouse teratocarcinoma line (PSA-1) known to be capable of chimerizing host blastocysts via the injection of inner cell mass. Two series of stable mutants were isolated--one (Aphr) selected on the basis of resistance to aphidicolin (Aph), a specific inhibitor of DNA polymerase-alpha, and the other (AraCr) selected by resistance to arabinofuranosyl cytosine, an analogue of cytosine. Irrespective of the method of selection, most of the 32 mutants isolated were resistant to both agents, although to different degrees, and with variations in growth characteristics, deoxynucleoside sensitivities, and sensitivities to mutagens (5-bromodeoxyuridine, N-methyl-N'-nitro-N-nitrosoguanidine and ultraviolet light). A protocol of multi-step selection provided stable mutants highly resistant to aphidicolin and only mildly resistant to AraC, even in the absence of prior mutagenesis, and is thus recommended as an approach to the isolation of candidate mutator strains of multipotent teratocarcinomas.

Animals↗

PubMed1989

Substituent effects on degradation rates and pathways of cytosine nucleosides.

A previous report on the influence of a 6-methyl substituent on cytosine nucleoside degradation proposed that N-glycosyl hydrolysis predominated over the deamination pathway which was characteristic of the unsubstituted parent compounds. The UV absorption data which led to this hypothesis were not conclusive. Evidence for N-glycosyl hydrolysis was indirect and the product concentration was not quantitated. In the present study, specific HPLC methods were employed to assay four cytosine nucleosides and their corresponding bases, thus allowing comparison of the N-glycosyl hydrolysis rate to the overall rate of loss for each nucleoside. These data indicated that the 6-methyl nucleosides underwent partial or complete hydrolysis to yield their corresponding sugars and 6-methylcytosine, which then deaminated to 6-methyluracil. An increase in the reactivity and a change in the reaction products of the 6-methyl nucleosides were attributed to an alteration in conformation. In addition, the 6-methyl arabinosyl nucleoside reacted much faster than the 6-methyl ribosyl nucleoside, presumably due to 2'-OH participation. Degradation of 5-methyl deoxycytidine was also re-examined since its degradation was previously attributed solely to N-glycosyl hydrolysis. In the present study, simultaneous deamination and hydrolysis were measured, although N-glycosyl hydrolysis was found to predominate.

Biotransformation↗

PubMed1979

A comparative trial of daunorubicin, cytosine arabinoside, and thioguanine, and a combination of the three agents for the treatment of acute myelocytic leukemia.

In this study 523 previously untreated patients with acute myelocytic leukemia were randomly allocated to induction therapy with daunorubicin 60 mg/M2 daily X 3, cytosine arabinoside and thioguanine 100 mg/M2 each every 12 hours until marrow hypoplasia was achieved, or a 5-day course of the three drugs with daunorubicin 100 mg/M2 given on dav 1 and cytosine arabinoside plus thioguanine each given at a dose of 100 mg/M2 every 12 hours for five days. All patients received cyclophosphamide 600 mg/M2 followed in 24 hours by hydroxyurea 500 mg/M2 every six hours for four doses monthly for maintenance therapy. Patients were randomized to receive one of three antimetabolite treatments beginning 24 hours after the last dose of hydroxyurea each month for seven days. One such treatment consisted of 6-mercaptopurine 100 mg/M2 daily, another group received 6-thioguanine at the same dose daily, and the third group received 50 mg/M2 of both antimetabolites daily. There were no significant differences in complete response rate, remission duration, or survival among the various treatment groups.

Adult↗

PubMed1982

The effects of exposure to cytosine arabinoside upon the proliferation of leukemia colony forming units in vitro.

The sensitivity of leukemic colony forming units to exposure to cytosine arabinoside in vitro was measured for both acute myelocytic leukemia cells and for chronic myelocytic leukemia cells. There was significant variability in the sensitivity of the leukemic cells of different patients. By simultaneous measurement of the sensitivity of leukemic clonogenic cells to 3H-TdR one can distinguish between metabolic and cell cycle kinetic resistance to cytosine arabinoside.

Bone Marrow↗

PubMed1983

Cytosine arabinoside induced liver damage: histopathologic demonstration.

Two patients with acute leukemia developed abnormal liver function tests after the administration of cytosine arabinoside. Other possible causes for such abnormalities were not likely. In both patients a close chronologic relationship between the administration of the drug and the appearance of the laboratory abnormalities was noted. The liver damage was also documented by biopsy. To our knowledge this is the first time that the hepatotoxic effects of cytosine arabinoside are histologically demonstrated.

Adult↗

PubMed1989

Remission induction in children with acute non-lymphocytic leukemia using cytosine arabinoside and doxorubicin or daunorubicin: a report from the Childrens Cancer Study Group.

Four hundred ninety evaluable patients were treated on an induction regimen consisting of two to four courses of cytosine arabinoside plus an anthracycline. Overall, 78% of patients went into remission, 10% died during induction, and 12% were induction failures. For the first 152 patients, courses consisted of 7 days continuous infusion with cytosine arabinoside (Ara-C, 100 mg/m2) and 3 days of doxorubicin (30 mg/m2). Because of unacceptable toxicity, particularly for children less than 3 years of age, the anthracycline was changed to daunorubicin, and the doses of both induction drugs for children under 3 was reduced. For children aged 3 years and older the change in anthracycline was associated with a significant increase in induction failures (7% to 16%, P = .04) and a decrease in deaths (15% to 8%, P = .09). For younger children, for whom doses were also changed, the effect was greater; Mortality decreased from 29% to 1% (P less than .0001), and the remission induction rate increased from 66% to 88% (P = .005). The therapy modifications also influenced survival following remission induction: Daunorubicin-treated patients, aged 3 years and over, did significantly better than those given doxorubicin (P = .03), but the opposite was seen in younger children (P = .06). Gastrointestinal and skin toxicities and septicemia were significantly more common when doxorubicin was being used, but the extent of myelosuppression was similar for the two anthracyclines.

Age Factors↗

PubMed1991

Bulbar and pseudobulbar palsy complicating therapy with high-dose cytosine arabinoside in children with leukemia.

Three of 38 children given high-dose cytosine arabinoside therapy developed a previously undescribed complication. Neurological problems are a frequent occurrence in patients given this therapy, particularly cerebellar ataxia, but the development of bulbar and pseudobulbar palsy has not been reported. In two of these cases, it was sufficiently marked for the course of treatment to be curtailed and occurred at a relatively low cumulative dose of the drug. Neurotoxicity can occur at any time using high-dose cytosine therapy.

Adolescent↗

PubMed1977

Effects of cytosine arabinoside, 6-aminonicotinamide, and 6-mercaptopurine riboside on ectoderm and mesoderm of mouse limb buds.

The effects of cytosine arabinoside, 6-aminonicotinamide, and 6-mercaptopurine riboside on the incorporation of [14C] glucose moieties and [32P] phosphate into acid-soluble material and lipids, RNA, DNA, and protein were measured in the dissected mesoderm and ectoderm of mouse limb buds at the 42-45 (day 11) somite stage. Due to the different proliferative capacities of the two tissues the incorporation of the precursors into mesodermal cells was considerably higher the than into ectodermal ones. Cytosine arabinoside inhibited the incorporation of the precursor moieties only into DNA, but very early after its application. This effect was more obvious in mesoderm than ectoderm. 6-Aminonicotinamide interfered only with glucose metabolism, whereas the incorporation of phosphate was not affected. 14C radioactivity in the various cell components was similarly reduced in mesoderm and ectoderm. 6-mercaptopurine riboside caused an increased incorporation of precursor material in all fractions studied in the mesoderm as well as in the ectoderm during the first 12 hours. This was succeeded by a dramatic decrease of incorporated 14C and 32P radioactivity. Differences of response in the tissues could not be detected with this drug. It is suggested that the malformations of the extrmities caused by these antimetabolites may be predominantly attributed to changes in the cell function rather than to gross effects on cell metabolism.

6-Aminonicotinamide↗

PubMed1977

Cytosine arabinoside-induce transplacental dysgenetic hydrocephalus in mice.

Pregnant mice were injected with 30 mg of cytosine arabino side/kg body weight on 13-1/3 and 14 days of gestation. Within six hours after the first injection, pyknotic nuclei and nuclear debris were found at the matrix layer surrounding the lateral ventricles of the embryonic brain. Autoradiographic studies using tritiated thymidine revealed that most of the matrix cells exposed to cytosine arabinoside during DNA synthesis were killed by this dose of the drug. Twenty-four hours after the second injection, most of the matrix cells had disappeared. When experimental animals were examined after birth, they showed marked dilation of the lateral ventricles. The dilatation of the lateral ventricles was more pronounced in the parieto-occipital region. The young showed rapid enlargement of the cranial vault and subsequently died by 35 days of age.

Abnormalities, Drug-Induced↗