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PubMed1986

Cisplatin plus cytosine arabinoside in the treatment of squamous cell carcinoma of the head and neck.

Twenty-seven patients with squamous cell carcinoma of the head and neck were treated with i.v. cisplatin 50-100 mg/m2 followed by a rapid infusion of cytosine arabinoside 500-4,000 mg/m2. All except four of the patients had received prior irradiation and six had had prior chemotherapy. There was one early death. Of 25 evaluable patients, one (4%) achieved a complete remission and 10 (40%) achieved partial remissions lasting 6-50 weeks (median, 16 weeks). Ten patients (40%) were classified as having stable disease, including five (20%) who experienced minor responses lasting 5-8 weeks. Four patients (16%) had progressive disease. Drug doses, patient performance status, and prior exposure to chemotherapy did not appear to alter the response rate. Gastrointestinal toxicity was severe in some patients. Myelosuppression tended to be unpredictable and variable within individual patients and was not clearly related to drug doses. Two patients had generalized seizures and one became confused while hypomagnesemic. Renal toxicity, ototoxicity, and paresthesias were seen only at a cisplatin dose of 100 mg/m2. One patient developed stomatitis and one had an allergic reaction to cisplatin. There was one possible drug-related death. This regimen is reasonably well tolerated and may be somewhat more active than cisplatin alone, although further studies are needed to confirm it. Further studies involving additional doses of high dose cytosine arabinoside following cisplatin could also be worthwhile.

Adult↗

PubMed1993

Cisplatin, cytosine arabinoside, and pentoxifylline in the treatment of squamous cell carcinoma of the head and neck.

Nine patients were entered on a Phase I-II study of cisplatin, cytosine arabinoside, and pentoxifylline in the treatment of advanced head and neck cancer. The treatment regimen consisted of cisplatin 100 mg/m2 intravenously on day 1 only, cytosine arabinoside 2,000 mg/m2 intravenously on days 1 and 2, and pentoxifylline 400 mg orally three times daily beginning 7 to 14 days before the chemotherapy. The pentoxifylline was continued between chemotherapy cycles. Chemotherapy courses were repeated at 3- to 4-week intervals. Partial remission were seen in two patients, two patients were stable, and five patients failed on treatment. Dose-limiting toxicity was granulocytopenia. Pentoxifylline itself caused some nausea and anorexia. Although the patient numbers were small, there was no indication that pentoxifylline increased the efficacy of this chemotherapy in head and neck cancer. It is possible that another dose schedule might have been more effective.

Adult↗

PubMed1989

Alpha-streptococcal septicemia in leukemic children treated with continuous or large dosage intermittent cytosine arabinoside.

During a 2-year period after the introduction of an intensive chemotherapeutic protocol, alpha-hemolytic streptococci accounted for 75% of all episodes of sepsis among children with acute nonlymphocytic leukemia at our institution. Only one case had occurred in the previous 8 years. Fourteen of 15 episodes of streptococcal sepsis occurred after therapy with either continuous or large dosage intermittent cytosine arabinoside. Eleven episodes occurred at two specific treatment points. Septic episodes were complicated by shock (2 of 15), encephalopathy (2 of 15), pneumonia (3 of 15) and death (1 of 15). Oral mucosal lesions may provide a portal of entry for alpha-hemolytic streptococci. These data suggest that children receiving continuous or large dosage intermittent cytosine arabinoside for treatment of acute nonlymphocytic leukemia may be at increased risk for alpha-hemolytic streptococcal sepsis. Empiric antimicrobial therapy in these children when febrile and neutropenic should include antibiotics effective against alpha-hemolytic streptococci.

Anti-Bacterial Agents↗

PubMed1978

Cytosine arabinoside for varicella zoster: a second look.

Herpes zoster and disseminated herpes zoster, or varicella (V-Z), continue to be dreaded complications of patients with immunosuppression. Currently, there is no available therapy for V-Z, except for general supportive measures. Seven cases of V-Z are presented, showing the results of cytosine arabinoside administration when given as an intermittent intravenous infusion. The results compare favorably with previously unsuccessful continuous intravenous infusion. It is suggested that further evaluation of the intermittent administration of cytosine arabinoside for V-Z would be worthwhile.

Adult↗

PubMed2001

High-dose cytosine-arabinoside and cisplatin regimens as salvage therapy for refractory or relapsed AIDS-related non-Hodgkin's lymphoma.

No effective salvage regimen has been defined for patients with AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) who do not respond to first-line chemotherapy that contains anthracycline. Combined dexamethasone, cytosine arabinoside, and cisplatin (DHAP) and etoposide, methylprednisolone, cytosine arabinoside, and cisplatin (ESHAP) have shown good response rates in HIV-negative patients with relapsed lymphomas. We retrospectively analyzed patients with refractory or relapsed AIDS-NHL who had been treated with either DHAP or ESHAP to evaluate the feasibility and efficacy of these regimens. Twenty-six patients with refractory or relapsed AIDS-NHL were treated between 1990 and 1999 either with DHAP ( n = 13) or with ESHAP ( n = 13). Only 1 patient from each group (8%) had achieved complete remission with any previous therapy, and most had progressive disease after the regimen immediately preceding DHAP or ESHAP. In the ESHAP group, 4 patients (31%) achieved complete remission (CR) and 3 patients (23%) attained partial remission (PR) for an overall response rate of 54%. The median survival was 7.1 months (range, 1-58.9+ months) from the time ESHAP was begun. Among the 3 patients with primary refractory lymphoma, there was 1 CR, 1 PR, and one patient with stable disease. In contrast, only 1 PR (7%) was observed with DHAP; the median survival was 3 months. Myelosuppression was the most significant toxicity with grade 4 neutropenia occurring in all who received ESHAP and in 54% of patients treated with DHAP. Neutropenic fever occurred in 8 (62%) ESHAP-treated and 6 (46%) DHAP-treated patients. Although hematologic toxicity is profound, ESHAP appears to be an active salvage regimen for patients with relapsed or refractory AIDS-NHL.

Adult↗

PubMed2006

Flushing out of cerebrospinal fluid as a therapy for acute cerebellar dysfunction caused by high dose of cytosine arabinoside: a case report.

High dose of cytosine arabinoside is usually used in treatment of acute myelogenous leukemia. Here we report 1 case of a child who developed neurologic toxicity and rapidly improved after flushing out of cerebral spinal fluid, suggesting it could be treatment in the acute phase of toxicity. Efficacy of this treatment could be explained by reducing cytosine arabinoside metabolites in central nervous system.

Adolescent↗

PubMed2005

Universal 1/f noise, crossovers of scaling exponents, and chromosome-specific patterns of guanine-cytosine content in DNA sequences of the human genome.

Spatial fluctuations of guanine and cytosine base content (GC%) are studied by spectral analysis for the complete set of human genomic DNA sequences. We find that (i) 1/ f(alpha) decay is universally observed in the power spectra of all 24 chromosomes, and (ii) the exponent alpha approximately 1 extends to about 10(7) bases, one order of magnitude longer than has previously been observed. We further find that (iii) almost all human chromosomes exhibit a crossover from alpha(1) approximately 1 (1/ f (alpha(1))) at lower frequency to alpha(2) <1 (1/ f (alpha(2))) at higher frequency, typically occurring at around 30,000-100,000 bases, while (iv) the crossover in this frequency range is virtually absent in human chromosome 22. In addition to the universal 1/ f(alpha) noise in power spectra, we find (v) several lines of evidence for chromosome-specific correlation structures, including a 500,000 base long oscillation in human chromosome 21. The universal 1/ f(alpha) spectrum in the human genome is further substantiated by a resistance to reduction in variance of guanine and cytosine content when the window size is increased.

Base Composition↗

PubMed1984

The use of intermediate dose cytosine arabinoside (ID Ara-C) in the treatment of acute non-lymphocytic leukaemia in relapse.

Cytosine arabinoside in a high dose of 3 g/m2 (HD Ara-C), alone or in combination with doxorubicin, has been advocated for the treatment of patients with acute non-lymphocytic leukaemia (ANLL) in relapse. Although a remission rate of 65% has been reported, the toxicity was severe and was possibly related to the high plasma concentrations of Ara-C (about 100 microM) reached during 1 h infusion. It has been postulated, however, that the intracellular enzymes which convert Ara-C into the active metabolite cytosine arabinoside triphosphate (Ara-CTP), are saturated at plasma concentrations of about 10 microM. We calculated that this level could be reached with an intermediate dose of 0.5 g/m2 Ara-C, given in a 1 h infusion (ID Ara-C). Subsequently 15 patients with ANLL (12 in relapse and three refractory to conventional therapy) were treated with ID Ara-C every 12 h for 6 d in combination with doxorubicin and vincristine. The overall remission rate was 80%. The median duration of bone marrow depression was 20 d (range 14-29 d) and side effects were comparable to conventional treatment. These preliminary data suggest that the therapeutic results of this ID Ara-C regimen are not inferior to comparable schedules with HD Ara-C as reported by others while toxicity is less severe.

Acute Disease↗

PubMed1984

Low dose cytosine arabinoside: partial remission of acute myeloid leukaemia without evidence of differentiation induction.

Thirteen patients with acute myeloid leukaemia aged from 19 to 81 were treated with low dose cytosine arabinoside (ARA-C) in a dose of 10-15 mg/m2 twice daily subcutaneously. Three complete remissions were obtained. Partial responses were observed in a further two patients. To analyse the action of low dose ARA-C freshly isolated leukaemic cells and cells from the cloned promyelocytic leukaemia cell line (HL60) were cultured in vitro in the presence of cytosine arabinoside. Minimal evidence of differentiation induction was observed when compared with the cytotoxic effects of the drug. These results suggest that ARA-C does not exert its anti-leukaemic effects by halting proliferation through differentiation induction. Rather, it appeared that the capacity of this agent to kill cells in S-phase produced a progressive depletion of the cycling leukaemic cells. This resulted in a corresponding steady decline in the total leukaemic cell population.

Adult↗

PubMed1984

Prediction of response of acute nonlymphocytic leukaemia to therapy with 'high dose' cytosine arabinoside.

The Leukemia Intergroup Study has treated 110 patients with acute nonlymphocytic leukaemia with 'high dose' cytosine arabinoside remission induction therapy and studied the factors which were related to the outcome of therapy. With respect to death during remission induction therapy, only patient age was of prognostic significance. Treatment failure due to resistant leukaemia was associated with a high pretherapy leukaemic cell mass, the presence of few cells in S phase, and insensitivity of DNA synthesis to cytosine arabinoside. If, after 6 d of therapy, more than 40% of the marrow cells were leukaemic, the patient almost invariably failed to enter complete remission because of persistent leukaemia. Simultaneous consideration of the pretherapy labelling index and the per cent abnormal cells in the day 6 marrow permitted a distinction to be made between almost all patients who would enter remission or fail therapy because of persistent leukaemia.

Age Factors↗

PubMed1979

Differential lethal effects of both cytosine arabinoside and hydroxyurea on jejunal crypt cells and testosterone-stimulated accessory sex glands.

DNA-synthesizing cells from mouse jejunal crypts and accessory sex glands respond differently to the DNA synthesis inhibitors cytosine arabinoside and hydroxyurea. A single injection of either agent brought about a rapid inhibition of thymidine labelling in both the tissues. Whilst both agents had a lethal effect upon the majority of S-phase cells in the crypts, only a minority of S-phase cells in the accessory sex glands showed evidence of necrosis. These differences are considered in the context of possible physiological differences between continually dividing cells and putative G0 cells. The accessory sex glands are normally quiescent proliferative tissues. They were stimulated to undergo DNA synthesis and later mitosis by testosterone propionate injections, commencing three days after castration. Cytosine arabinoside was the more effective cytocidal agent in the accessory sex glands, and when two injections were scheduled so as to affect a large number of DNA-synthesizing cells, a compensatory hyperplasia was evoked. In the coagulating gland, this compensatory response involved the proliferation of many cells which, in the absence of cytotoxic perturbation, would be non-proliferatie (Q cells).

Animals↗

PubMed1975

L-asparaginase and prednisolone pretreatment followed by rubidomycin and cytosine arabinoside for induction of remission in adult patients with acute myeloblastic leukaemia.

77 unselected adult patients with acute myeloblastic leukaemia (AML), including practically all AML patients from an area with 1.9 million inhabitants, were randomized for either (1) 5 days pretreatment with 1-asparaginase and prednisolone followed by a combination of rubidomycin and cytosine arabinoside (ARAP), or (2) treatment with a combination of rubidomycin, cytosine arabinoside and prednisolone without 1-asparaginase pretreatment (RAP). Complete remission was induced with ARAP in 12 patients (31%) and with RAP in 13 patients (34%). Thus pretreatment with 1-asparaginase did not improve the therapeutic response. The overall remission frequency was significantly higher below the age of 60; 50% compared to 13% above this age. Side-effects such as liver dysfunction, nausea and vomiting were more common in patients pretreated with 1-asparaginase. Sterilization of the gut did not improve the remission frequency with either regime.

Adolescent↗

PubMed1975

Selective eradication of rat bone marrow erythroid cells by administration of cytosine arabinoside. Observations on resumption phase of erythropoiesis.

The in vivo effect of a single i.p. injection of cytosine arabinoside (250 mg/kg body weight) on the rat bone marrow is reported. Cytosine arabinoside (ara-C), a potent inhibitor of DNA-synthesis, was seen to produce selective necrosis of fast cycling bone marrow erythroblasts. The depleted erythroid marrow is replenished by stem cells which are members of the lymphoid-transitional cells compartment. An indirect correlation between the degree of erythroid cell depletion and the extent of marrow lymphocytosis was noted 6-12 h after the administration of ara-C. At 24-48 h, however, the marrow returned to its normal activity. The rat bone marrow 6-12 h following a single injection of ara-C is suggested as an experimental model for providing stem cells committed to the erythroid line.

Animals↗

PubMed1986

Cerebellar dysfunction during high dose cytosine arabinoside therapy in a case of acute myelogenous leukaemia.

A case of persistent cerebellar toxicity following systemic high dose cytosine arabinoside (HDCA) treatment of acute myelogenous leukaemia is reported. The symptoms, which developed at a cumulative dose of 32 g/m2, subsided to some extent following discontinuation of the drug, but left signs of cerebellar dysfunction 10 months later. A review of previously published reports indicates that the cerebellar toxicity of HDCA, which has been ascribed to loss of Purkinje cells, usually occurs when the accumulated dose exceeds 36 g/m2. That it may occur at even lower doses is supported by the present case. In addition, available evidence of re-appearance or worsening of previously induced signs of toxicity following its repeated administration stresses the importance of immediate and permanent cessation of cytosine arabinoside therapy, when signs of cerebellar dysfunction develop.

Cerebellar Diseases↗

PubMed1989

Behenoyl cytosine arabinoside, aclacinomycin A, 6-mercaptopurine, and prednisolone combination therapy for acute non-lymphocytic leukaemia in adults.

38 consecutive, previously untreated adult patients with acute non-lymphocytic leukaemia (ANLL) were treated with BHAC-AMP (N4-behenoyl-1-beta-D-arabinofuranosyl-cytosine, aclacinomycin A, 6-mercaptopurine, and prednisolone) therapy between March 1980 and February 1985. 25 patients (65.8%) achieved complete remission (CR). Median CR duration and median survival of patients who achieved CR were 14, and 24 months, respectively. The Kaplan-Meier analysis revealed a probability for remaining in CR of 18.0% at 5 years. Analysis of failure cases revealed that most of them were due to resistant disease. Major toxicities were infection, diarrhoea, liver dysfunction, nausea and vomiting but these were acceptable. The results indicate that BHAC-AMP therapy is comparable to the regimen with daunorubicin and cytosine arabinoside and a further clinical trial is necessary for previously untreated adult patients with ANNL.

Aclarubicin↗

PubMedDate not supplied

Cytosine arabinoside as a single agent for the induction of remission in canine lymphoma.

Cytosine arabinoside (AraC) was administered as a continuous IV infusion to 15 dogs with malignant lymphoma at a dose of 300 mg/m2/d for 2 consecutive days. Dogs were re-examined 7 d after treatment for response to therapy and for hematologic toxicity. Regardless of response, all dogs were started on combination chemotherapy at this time. Other toxicities were reported by owners. No dog responded objectively to Ara-C treatment, although 1 dog with circulating lymphoblasts had partial regression of lymphadenopathy but persistent blastemia. Thrombocytopenia (platelet count < 200,000/microL) 7 days posttreatment was the most commonly encountered hematologic toxicity, occurring in 10 of 14 dogs. Three of these 10 dogs were also mildly neutropenic (neutrophil counts of 2000 to 3000 cell/microL). Nonhematologic toxicity occurred in 8 of 15 dogs and was principally gastrointestinal in nature and mild in severity. Cytosine arabinoside at a dose of 300 mg/m2/day was not considered an active drug for the induction of remission in dogs with lymphoma.

Animals↗

PubMed1980

Tumoricidal response induced by cytosine arabinoside after plasma perfusion over protein A.

In dogs with spontaneous mammary adenocarcinomas, a single nontoxic infusion of cytosine arabinoside after extracorporeal perfusion of plasms over immobilized protein A resulted in a necrotizing response rapid in onset and specific for tumorous tissue. Gross tumoricidal reactions 12 hours after this combined treatment exceeded the algebraic sum of responses to cytosine arabinoside and protein A perfusion treatments alone in the same dogs, implying a synergistic effect between the two. The magnitude, rapidity, and specificity of the tumoricidal response after the combined treatment suggests that it may be an effective chemimmunotherapeutic approach to breast adenocarcinoma.

Adenocarcinoma↗

PubMed2003

Flucytosine-fluconazole cross-resistance in purine-cytosine permease-deficient Candida lusitaniae clinical isolates: indirect evidence of a fluconazole uptake transporter.

An unusual interaction between flucytosine and fluconazole was observed when a collection of 60 Candida lusitaniae clinical isolates was screened for cross-resistance. Among eight isolates resistant to flucytosine (MIC >/= 128 micro g/ml) and susceptible to fluconazole (0.5 < MIC < 2 micro g/ml), four became flucytosine-fluconazole cross resistant when both antifungals were used simultaneously. Fluconazole resistance occurred only in the presence of high flucytosine concentrations, and the higher the fluconazole concentration used, the greater the flucytosine concentration necessary to trigger the cross-resistance. When the flucytosine- and fluconazole-resistant cells were grown in the presence of fluconazole alone, the cells reversed to fluconazole susceptibility. Genetic analyses of the progeny from crosses between resistant and sensitive isolates showed that resistance to flucytosine was derived from a recessive mutation in a single gene, whereas cross-resistance to fluconazole seemed to vary like a quantitative trait. We further demonstrated that the four clinical isolates were susceptible to 5-fluorouracil and that cytosine deaminase activity was unaffected. Kinetic transport studies with [(14)C]flucytosine showed that flucytosine resistance was due to a defect in the purine-cytosine permease. Our hypothesis was that extracellular flucytosine would subsequently behave as a competitive inhibitor of fluconazole uptake transport. Finally, in vitro selection of spontaneous and induced mutants indicated that such a cross-resistance mechanism could also affect other Candida species, including C. albicans, C. tropicalis, and C. glabrata. This is the first report of a putative fluconazole uptake transporter in Candida species and of a possible resistance mechanism associated with a deficiency in the uptake of this drug.

Antifungal Agents↗