Severe persistent cerebellar dysfunction complicating cytosine arabinoside therapy

A case of persistent cerebellar dysfunction following high-dose cytosine arabinoside (Ara-C) treatment of acute myelogenous leukemia is reported. The symptoms developed after a cumulative dose of 24 g/m2, and 6 months after the start of symptoms, the signs of cerebellar damage were unchanged. The symptoms aggravated during a subsequent low-dose therapy with Ara-C, 15 mg twice daily. This supports the presumption that this adverse effect is caused by the cumulative dose rather than by high plasma concentrations.     

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.     

Low-dose cytosine arabinoside therapy in a patient with myelofibrosis during transformation to acute non-lymphocytic leukemia

A patient with myelofibrosis transforming into acute non-lymphocytic leukaemia (ANLL) was treated with low doses of cytosine arabinoside (ARA-C). Complete remission was obtained twice without serious toxicity. It is suggested that low-dose ARA-C may be an effective and rather non-toxic therapy in patients with myeloproliferative disorders transforming to ANLL.     

Selective therapy of leukemia L1210 by a combination of deoxycytidine and lethal doses of cytosine arabinoside

Peroral administration of deoxycytidine (dC) to mice with leukemia L1210 simultaneously with intraperitoneal injections of toxic doses of cytosine arabinoside (araC) reduces the severity of toxicosis and prevents the death of the animals by poisoning. A marked antitumor effect is observed in these animals. The mean life span of such mice is much longer than that of untreated mice and also of mice receiving dC or araC alone. With the optimal scheme of treatment about 23% of mice live longer than 60 days. Protection with dC weakens the antileukemic effect of araC when the latter is given in nontoxic doses. This combination is not effective against transplantable myeloid leukemia of mice.Oncologic Scientific Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Blokhin.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 85, No. 3, pp. 340–343, March, 1978.     

Developmental defects in mice and rats treated postnatally with cytosine arabinoside

ICR Swiss albino mice and Sprague-Dawley rats were given cytosine arabinoside parenterally beginning at 1, 5, or 10 days of age. Animals were treated for 5 consecutive days at dosages ranging from 3.125 to 50 mg/kg/day. Numerous deaths and retardation of growth occurred in both species treated at higher dosages beginning at 1 day of age. Animals were examined histologically at 20 days of age. Cerebellar hypoplasia was especially marked in mice and rats treated beginning at 1 day of age. There was reduction in size of the cerebellum, with poorly delineated molecular, Purkinje cell, and internal granular layers. Retinal lesions were observed in both species, but were considerably more extensive in rats treated with cytosine arabinoside than in mice. Numerous rosettes were observed in the peripheral retina, with relative sparing of the central regions. Focal renal cortical dysplasia was also observed in animals treated beginning at 1 day of age. Autoradiographic studies indicated that significant cellular division occurs in the retina and renal cortex postnatally in both species. The significance of these studies with regard to the use of cytosine arabinoside in viral chemotherapy in newborn infants are yet to be determined.     

Micellar electrokinetic capillary chromatography quantification of cytosine arabinoside and its metabolite, uracil arabinoside, in human serum

Cytosine arabinoside (Ara-C) is widely used to induce remission in adult granulocytic leukemia. High doses can be infused in refractory leukemia or in relapse. After injection, Ara-C is quickly metabolized to uracil arabinoside (Ara-U), the main inactive metabolite. We here described a micellar electrokinetic capillary chromatography (MECC) method to simultaneously determine Ara-C/Ara-U in human serum using 6-O-methylguanine as an internal standard. The assay was linear from 6.25 to 200 microg/ml with a quantification limit between 3 and 6 microg/ml. The analytical precision was satisfactory between 2 and 4.3% (within-run) and 3.7 and 7.3% (between-runs). This assay was applied to the analysis of serum from acute granulocytic leukemia patient treated by high doses cytarabine (3 g/m2 body surface).     

Effect of azathioprine and cytosine arabinoside on humoral and cellular immunity in vitro

The influence of azathioprine and cytosine arabinoside on humoral and cell-mediated immunity was investigated. In these studies, two tissue culture systems which allow the generation either of a thymus-independent humoral immune response against DNP or of a thymus-dependent cell-mediated cytotoxic response against alloantigen were used. Whereas azathioprine inhibited the in vitro induction of cytotoxic lymphocytes in concentrations 300-fold lower (50% inhibition concentration: 0·3 μg/ml) than that necessary to block the humoral anti-DNP response, cytosine arabinoside had no such selective effect. For cytosine arabinoside the 50% inhibitory concentrations were 0·35 μg/ml and 0·25 μg/ml for the thymus-independent humoral immune response and the thymus-dependent cell-mediated immune response respectively. Neither drug had any effect on the effector phase of either antibody-forming cells or of cytotoxic lymphocytes.     

Effect of actinomycin D and cytosine arabinoside on rabies and VSV multiplication.

VSV and rabies virus are only poorly sensitive to cytosine arabinoside at doses as high as 250 μg/ml which completely inhibit host DNA syntheses. Rabies virus is more sensitive than VSV to doses of actinomycin D higher than 0.01 gm/ml but this is probably due to the duration of the viral cycle.     

Mitoxantrone and cytosine arabinoside in previously untreated adult patients with acute non-lymphocytic leukemia

Twenty-five adult patients with previously untreated acute non-lymphocytic leukemia (ANLL) were treated with mitoxantrone (Mto) 12 mg/m2 daily by 30 minutes intravenous (IV) infusion for 3 days and cytosine arabinoside (Ara-C) 200 mg/m2 daily by continuous infusion for 7 days, as an induction therapy. After complete remission (CR) was observed, they were given two more courses of consolidation therapy which was as Mto 12 mg/m2 daily by 30 minutes IV infusion for one day, and Ara-C 200 mg/m2 daily by 30 minutes IV infusion for 5 days. CR was obtained in 18 of 25 patients (72%). Median remission duration was 294 days and length of survival was 366 days. 11 patients (44%) are still in remission. Myelosupression developed in all patients following induction therapy, but it was not observed after consolidation therapies. Non-hematological side-effects consisted of nausea, vomiting, alopecia, stomatitis, and transient elevation in liver enzymes. Our therapeutic responses are similar to those obtained by others.     

Experimental necrosis and arrest of proliferation of Schwann cells by cytosine arabinoside.

In developing rat cervical sympathetic trunks, Schwann cells proliferate intensely during the first week after birth but axonal populations do not increase. Thus, experimental inhibition of DNA synthesis should affect Schwann cells and spare axons whose cell bodies are not dividing. The present investigation was aimed at determining the effects of an inhibitor of DNA synthesis-cytosine arabinoside (ara-C)--on axons and Schwann cells in developing nerves. Ara-C (60 mg kg(-1) body weight) was injected subcutaneously to newborn rats every six hours for 36 hours. At intervals from 2--4 days of age, animals were given tritiated thymidine (4 muCi per gram body weight) to label Schwann cells in synthesis phase. One hour later rats were killed by systemic perfusion of phosphate buffered glutaraldehyde. Cervical sympathetic trunks (CST's) and sciatic nerves were removed and processed for radioautography and electron microscopy (EM). Labelled and unlabelled Schwann cell nuclei were counted to determine the labelling index (LI%) for each nerve. By the end of ara-C treatment there was almost complete absence of labelling but LI's rose sharply 24 hours after discontinuing ara-C. By EM axons appeared normal; Schwann cells, however, showed prominent nuclear and cytoplasmic changes consisting of nuclear degeneration, dilatation of rough endoplasmic reticulum and increased cytoplasmic density. Ara-C, by suppressing proliferation and causing necrosis of Schwann cells but sparing axons, results in a developmental alteration of axon-Schwann cell relationships. It is suggested that the pathogenetic mechanism involves an inbalance in DNA/RNA synthesis metabolism.     

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.     

Complement receptor type 1 gene regulation: retinoic acid and cytosine arabinoside increase CR1 expression

Complement receptor type 1 (CR1) is expressed principally on erythrocytes, monocytes, neutrophils and B cells, where it acts as a negative regulator of the complement cascade and as a clearance mechanism for immune complexes. As CR1 expression occurs in a number of lineages, its regulation may parallel other steps in haematopoiesis. Several leucocyte-cell lines (including K-562, THP-1, U-937 and HL-60) and B-cell lines, as well as peripheral blood cells (PBCs), were tested for the ability of various compounds to up-regulate their CR1 expression. While most of the compounds tested had minimal effects on CR1 message level, retinoic acid induced increases in mRNA levels in nearly all cell lines studied. Furthermore, in K-562 cells, the cytosine analogue Ara-C, an inducer of erythroid differentiation, caused the highest increases in CR1 mRNA levels as compared to untreated cells. Ara-C also induced significant increases in CR1 message in PBCs. These data suggest that induction of specific CR1 expression could be an integral part of blood cell differentiation and that the identified cell induction systems may be useful as models to study the regulation of CR1 gene expression.     

The origin of micronuclei induced by cytosine arabinoside and its synergistic interaction with hydroxyurea in human lymphocytes

Using human lymphocytes and the cytokinesis-block micronucleus(CBMN) assay we have recently shown that excision-repairableDNA lesions induced by methylnitrosourea (MNU) and ultraviolet(UV) light (254 nm) can be converted to micronuclei (MNi) withinone cell cycle if cytosine arabinoside (ARA-C) is added duringthe G₁ phase of the cell cycle after mitogen stimulation. Wehave proposed that this conversion resulted from the inhibitionby ARA-C of the gap-filling step during excision repair whichresults in the formation of single-stranded breaks at repairsites; these breaks are then converted to chromatid or chromosomebreaks and subsequently to MNi on completion of nuclear division.To confirm this hypothesis we have examined the origin of MNiinduced by ARA-C by using anti-kinetochore antibodies and foundthat between 77 and 86% of these MNi are kinetochore-negativewhich supports the idea that they originate mainly from acentricchromosome fragments. We have also demonstrated that combiningARA-C treatment with hydroxyurea (HU) during G¹ provides a synergisticimprovement in the conversion of spontaneous (4-fold increment)or MNU-induced (2-fold increment) excision-repairable DNA lesionsto MNi when compared to the effects with ARA-C alone. HU treatmenton its own did not influence micronucleus expression in untreatedcells and cells treated with MNU. ³To whom correspondence should be addressed     

Increased accumulation of cytosine arabinoside in human leukemic cells and enhancement of its cell-killing activity by uridine

The effects of uridine(UR) on the cell-killing activity of cytosine arabinoside(ara-C) against human leukemic cells, MOLT-4, and on ara-C accumulation in cells were studied. The 50% lethal dose(LD50) of ara-C as determined by clonogenic assay was decreased to 5.0 x 10(-8) mol from 9.0 x 10(-7) mol after 3 days exposure to 10(-3) mol of UR. The accumulation of 3H-ara-C at 24 and 48 h was significantly increased in culture medium containing 10(-8) mol of 3H-ara-C and 10(-3) mol of UR (5,129 +/- 123.5 vs 2,554 +/- 115.5 cpm/10(5) cells at 24 h, p less than 0.01, and 5,772 +/- 123.2 vs 1,372 +/- 51.8 cpm/10(5) cells at 48 h, p less than 0.01). It is noteworthy that cell-killing activity of ara-C against human leukemic cells was enhanced by the combination with a nucleoside(UR), but not with antileukemic agents.     

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.     

Effect of cytosine arabinoside on the human immunosystem: metabolism and cytotoxicity studied with mitogen-stimulated normal blood lymphocytes in vitro

The toxicity, metabolic effects and metabolism of cytosine arabinoside (Ara-C) were studied with normal human peripheral blood PHA-stimulated mononuclear cells in vitro. Clinically relevant Ara-C concentrations were toxic against mitogen-stimulated blood lymphocytes. Dose-dependent effects included: (i) increased cell loss, (ii) decreased DNA synthesis assessed by 3H-thymidine incorporation, (iii) decreased blastic transformation, (iv) decreased protein synthesis assessed by 14C-leucine incorporation, (v) an inhibition of the production of new cells, (vi) a delay in the proceeding of the PHA-stimulated cells to the cell cycle, (vii) an arresting of the cells in the S-phase, and (viii), a dose-dependent decrease of the number of mitoses in Ara-C-treated cultures. The mode of cell death was of the delayed type. The toxicity of Ara-C was effectively reversed by an excess of deoxycytidine, but not by cytidine or other conventional nucleosides, which is highly suggestive that the molecular mechanism of Ara-C toxicity is based on its anti-metabolic role in the salvage pathway of biosynthesis of DNA deoxycytidine. In fact, we demonstrated that Ara-C is metabolized to Ara-CTP and to a lesser extent also incorporated into DNA in human PHA-stimulated lymphocytes. Ara-C significantly decreased its own uptake and DNA incorporation. On the other hand, uracil arabinoside, which was the major catabolic product of Ara-C, was not toxic to human PHA-stimulated T-cells. The antiproliferative effect of Ara-C against human T-cells resembled that previously demonstrated with various cancer cell types.(ABSTRACT TRUNCATED AT 250 WORDS)