Acute polyneuropathy after high dose cytosine arabinoside in patients with leukemia

BACKGROUND: Peripheral nerve toxicity has been reported but is not a commonly recognized complication of high dose cytosine arabinoside (HDAC) therapy. This study was undertaken to estimate the prevalence and describe the clinical spectrum of acute polyneuropathy associated with HDAC therapy for leukemia. METHODS: Records of 153 acute leukemia patients who received 194 courses of HDAC at the City of Hope were reviewed for evidence of severe peripheral neuropathy with onset 2-3 weeks after HDAC therapy. RESULTS: Two patients were identified who developed motor disability 2-3 weeks after HDAC therapy, and the disability progressed in a monophasic course to quadriparesis. There was neurophysiologic evidence of peripheral nerve demyelination with slowed nerve conduction velocities and conduction block. One patient who was autopsied had demyelination identified in luxol-fast blue sections of peripheral nerve (with Bielschowsky-stained sections showing intact peripheral nerve axons). There were foamy macrophages in the peripheral nerve but no chronic inflammatory cells. For comparison, data from these two patients were combined with those from four published case reports of polyneuropathy associated with HDAC therapy. Quadriparesis occurred in five of six cases with the need for ventilatory support in four. Cerebrospinal fluid protein was elevated in five of six cases. Etiologic evidence incriminating HDAC included simultaneous cerebellar signs in two of six cases and a narrow interval of clinical onset after HDAC therapy. CONCLUSIONS: Demyelinating polyneuropathy occurs in approximately 1% of HDAC courses and produces severe motor disability. HDAC immunosuppression could trigger an immune-mediated neuropathy; alternatively, a direct neurotoxic effect of HDAC on Schwann cells is also an etiologic possibility.     

Pericarditis induced by high-dose cytosine arabinoside chemotherapy

Pericarditis is a rare side effect of chemotherapy. We report here the case of a patient treated with high-dose cytosine arabinoside (HD ara-c) who developed severe pericarditis. Interruption of HD ara-c and initiation of corticosteroid treatment were effective in resolving the pericardial effusion. This case illustrates this rare but potentially life-threatening cardiac complication of HD ara-c therapy as well as the beneficial effect of corticosteroid treatment.     

辛伐他汀联合阿糖胞苷对K562细胞增殖与凋亡的影响

目的 探讨辛伐他汀(SV)联合阿糖胞苷(Ara-C)对K562细胞增殖与凋亡的影响.方法 不同浓度SV和Ara-C单用或者联合处理K562细胞,对照组为K562细胞.药物作用24、48、72 h后收集细胞,分别观察各组细胞形态,采用MTT法检测不同组别细胞的生长抑制率,采用流式细胞术检测细胞早期凋亡率、细胞坏死比例.结果 SV联合Ara-C组与单药组相比细胞形态明显有核固缩现象,且可见凋亡小体形成,并且随着处理时间的增加,抑制率也增大.其中15 μmol/L SV联合20 μmol/LAra-C的细胞抑制作用最为显著,72 h细胞抑制率为(72±1)%,明显高于15 μmol/L SV组的(45±2)%和20μmol/LAra-C组的(44±0)%(P＜0.01),表现为协同抑制作用(24、48 h金氏Q值为1.24和1.19).流式细胞术检测发现20、15和10μmol/LSV组K562细胞早期凋亡率AnnexinV明显高于对照K562细胞(P＜0.01),而且随着时间延长和剂量的增大早期凋亡率也增加(P＜0.05).20和15 μmol/LSV组早期凋亡率均高于10 μmol/LSV组,而前两者之间差异无统计学意义(P＞0.05).晚期凋亡细胞率(PI)各组中差异均无统计学意义(P＞0.05).结论 SV体外抑制K562细胞增殖及诱导细胞凋亡,SV与Ara-C具有协同作用,增加了K562细胞对化疗药物的敏感性.15 μmol/L可能为SV体外最佳作用浓度.     

Mitoxantrone and cytosine arabinoside as treatment for acute myelogenous leukemia (AML) at first recurrence

A total of 107 patients with newly diagnosed acute myeloblastic leukemia (AML) were referred to the ICRF Department of Medical Oncology at St Bartholomew's Hospital between August 1986 and July 1989. Of those referred, 92 (87%) were treated with remission induction chemotherapy comprising: Adriamycin, cytosine arabinoside (ara-C) and 6-thioguanine if aged < 60 years (57 patients) or mitoxantrone (MTN) and ara-C if aged > 60 years (35 patients). Of those treated, 54 (58%) entered complete remission (CR). Recurrent AML developed in 38 out of these 54 patients (70%) of whom 25 aged 19-73 years (median 50 years) subsequently received MTN and ara-C as reinduction therapy. The 19 younger patients (under 60 years old) received MTN at 12 mg/m2, intravenously, daily for 5 days and ara-C at 100 mg/m2, intravenously, twice daily for 7 days. The six older patients received the same ara-C schedule but the dose of MTN was reduced to 10 mg/m2 for 5 days. Second CR was achieved in 16 out of 25 patients (64%) [12/19 (63%) and 4/6 (67%) for patients aged under or over 60 years, respectively]. Eight of the patients in whom second CR was achieved were aged under 50 years and were thus eligible for additional consolidation comprising myeloablative therapy with autologous bone marrow transplantation (ABMT). Four patients actually received the latter treatment: two remain in second CR at 21 and 46 months. Three of the remaining eight patients aged > 50 years in whom second CR was achieved remain in second CR 8 to 43 months later. Censored for myeloablative therapy + ABMT, the overall median duration of second CR was 5 months. Although remissions tended to be short, in younger patients the possibility of proceeding to myeloablative therapy with autologous bone marrow support makes the regimen worthwhile and, even in older patients, it was sometimes possible to achieve prolonged second remissions.     

Enhancement of cytosine arabinoside cytotoxicity by granulocyte/macrophage colony-stimulating factor and granulocyte colony-stimulating factor in a human myeloblastic leukemia cell line

Enhancement of the cytotoxicity of cytosine arabinoside (ara-C) by granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), and the mechanisms involved, were studied in the AML-193 human leukemia cell line. AML-193 cells require GM-CSF and G-CSF(CSFs) for optimum growth, and 24 h deprivation of CSFs decreased DNA synthesis measured in terms of 3H-thymidine incorporation. The DNA synthesis gradually recovered upon addition of CSFs. To examine the sensitivity to ara-C under different growth conditions, two groups of cell suspensions, one pretreated with CSFs after 24 h deprivation (CSFs(+) cells), and the other held continuously under CSFs-free conditions (CSFs(-) cells), were exposed to 1.0 microgram/ml of ara-C for 16 h. In clonogenic assays, CSFs(+) cells showed higher sensitivity to ara-C than CSFs(-) cells. These cell groups showed no significant difference in ara-C triphosphate accumulation or retention, though the amount of ara-C incorporated into the acid-insoluble fraction was two times greater in CSFs(+) cells than CSFs(-) cells, and that difference became even clearer in the retention pools. These data suggest that the enhancement of cytotoxicity by CSFs was due to the promotion of ara-C incorporation into DNA as a result of an increase of the cell fraction in the S phase.     

Treatment of human B-cell precursor leukemia in SCID mice using a combination of the investigational biotherapeutic agent B43-PAP with cytosine arabinoside

Combined immunochemotherapy regimens using the investigational biotherapeutic agent B43(anti-CD19)-poke-weed antiviral protein (PAP) immunotoxin may offer an effective treatment for refractory B-cell precursor leukemias. The purpose of the present study was to explore and identify effective combinations of B43-PAP with standard chemotherapeutic drugs, including the anthracyclin doxorubicin, the epipodophyllotoxin etoposide, the nitrosurea carmustine, and the antimetabolite cytosine arabinoside. Here, we report that the B43-PAP plus cytosine arabinoside combination has potent antileukemic activity against human B-cell precursor leukemia in SCID mice and leads to 100% long-term event-free survival from an otherwise invariably fatal leukemia. Surprisingly, none of the other treatment protocols tested, including combinations of B43-PAP with carmustine, doxorubicin, or etoposide, proved more effective than B43-PAP alone.     

Quantitation of resistance of leukemic cells to cytosine arabinoside from BrdUrd/DNA bivariate histograms

The cytotoxicity of ara-C derives from an inhibition of DNA synthesis after incorporation of ara-CTP into DNA. The rate of DNA synthesis can be determined from the amount of bromodeoxy-uridine (BrdUrd) incorporated into cells after a short exposure to BrdUrd. We developed a computer program to quantify the inhibition of the rate of DNA synthesis by analysis of the distribution of BrdUrd/DNA. Inhibition was evaluated in ara-C-sensitive and resistant cells after incubation with different doses of ara-C. An index of resistance to ara-C (RI) was expressed as the ratio of the amount of BrdUrd incorporated into S phase cells incubated with ara-C to that incorporated in the absence of ara-C. In the ara-C-sensitive and resistant HL60 cells, a linear relationship between RI and log ara-C concentration was observed. Small numbers of slightly resistant cells in mixtures of ara-C-sensitive and resistant cells could be determined using this method, making it suitable for clinical use to test the resistance of leukemic cells to ara-C.     

Calculation of individual dosage regimen of cytosine arabinoside (ara-C) based on metabolite levels in leukemic cells

Patients with acute nonlymphocytic leukemia (ANLL) were treated by continuous infusion of ara-C (100 mg/m2/d x 10 days). During ara-C treatment, cellular arabinofuranosyl cytosine triphosphate (ara-CTP) pharmacokinetics was assessed in the circulating blasts of these patients using a high-performance liquid chromatography (HPLC) and an associated radioimmunoassay. Since a strong correlation was found between achievement of complete remission and cellular ara-CTP levels, we propose a calculation scheme that allows steady-state adjustment of ara-CTP levels during administration of ara-C. To improve the complete remission rate in patients with low ara-CTP levels, we sought optimum ara-C dosing. In order to achieve an optimal therapeutic response, in vivo ara-CTP formation has to be > 50 microM in leukemic cells. Conversely, using the same pharmacokinetic approach, the infusion rate at which to administer ara-C in order to reach in vivo ara-CTP concentration threshold and to achieve complete remission could be calculated for each patient.     

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.     

Rescue of mesencephalic dopamine neurons by anticancer drug cytosine arabinoside

Nanomolar concentrations of cytosine arabinoside (ara-C), a structural analogue of 2'-deoxycytidine (2'dC) used in the chemotherapy of cancer, proved to be highly effective in preventing the death of postmitotic dopaminergic neurons that occurs spontaneously by apoptosis in mesencephalic cultures. The rescued cells were totally functional and highly differentiated. The trophic/neuroprotective effects of ara-C were (1) specific for dopaminergic neurons; (2) long-lived, remaining detectable several days after withdrawal of the nucleoside analogue from the culture medium; (3) still observed when the treatment was delayed after plating; (4) abolished by an excess of 2'dC or dCTP, or by exposure to the neurotoxin 1-methyl-4-phenylpyridinium; and (5) mimicked by ara-CTP, 5-fluoro-2'-deoxyuridine, and aphidicolin. Autoradiographic studies revealed that ara-C was incorporated exclusively into astrocyte nuclei, suggesting that the dopaminotrophic activity was indirect and resulted from the antiproliferative action of the modified nucleoside on glial cells at concentrations that were not neurotoxic. No evidence was found for putative deleterious or trophic molecules secreted by proliferating or ara-C-treated astrocytes, respectively, suggesting that neuroglial contact may play a role. Our results suggest a possible mechanism underlying neurodegeneration in Parkinson's disease, where selective loss of dopaminergic neurons in the mesencephalon is accompanied by astrogliosis.     

CD7 positive acute lymphoblastic leukemia successfully treated with high dose cytosine arabinoside and mitoxantrone: a case report

Primary Sjogren's syndrome (pSS) is a common autoimmune connective tissue disease in China yet without a universally accepted diagnostic criteria. In this study a new criteria was proposed and compared with other six sets of criteria. Fifty-five items in 112 pSS and 185 controls were evaluated. Results show the criteria we proposed contained one major and nine minor items. For the purpose of identifying patients in clinical studies, a major with at least three of the nine minor items or at least five of the minor items should be presented. The major item is anti-SSA/SSB(+) and the minors are, (1) dry eyes or dry mouth (> 3 months, persistently), (2) swollen salivary glands (recurrently or persistently), (3) rampant dental caries, (4) Schirmer test (< 5 mm in 5 min.) or corneal staining(+), (5) unstimulated salivary flow (< 0.03 ml/min) or abornal parotid sialography, (6) minor salivary gland biopsy (> or = 1 focus), (7) renal tubular acidosis, (8) hypergammaglobuminemia (gamma globulin > or = 30%) or hypergammaglobuminemic purpura, (9) RF > 1 : 20 or ANA > 1 : 20. Other connective tissure diseases, pre-existing lymphoma, AIDS, sarcoidosis, graft vs host disease must be excluded. The criteria we proposed had a high specificity of 98.2% and sensitivity of 94.1%.     

Induction therapy for acute myelogenous leukemia in patients over 60 years with intermediate-dose cytosine arabinoside, mitoxantrone and etoposide

Using a broth microtiter dilution method, the minimum inhibitory concentrations of antipseudomonal antibiotics were determined against 19 P. aeruginosa isolates. Two different concentration of inoculum, 10(5) and 10(8), were used to show the inoculum concentration effect of in vitro antibiotic susceptibility tests. On the basis of the MIC values and using Howard B.J. (1) breakpoints, the effect of inoculum density was most prominent for amikacin and aztreonam, intermediate for mezlocillin, ticarcillin, piperacillin, cefotaxime, cefoperazone, netilmicin, tobramycin, gentamicin, and least apparent for ciprofloxacin and carbenicillin respectively.     

Long term follow-up of patients with acute myelogenous leukemia who received the daunorubicin, vincristine, and cytosine arabinoside regimen

Some previous studies have suggested that the fast phenotype of the N-acetyltransferase NAT2 may confer susceptibility to colorectal cancer because of greater activation of dietary heterocyclic amines, particularly in individuals who also consume well-done red meat, but other studies have not supported this. We describe a large case-control study examining the interaction between dietary, smoking and drinking habits, and acetylation genotype in relation to susceptibility to colorectal cancer. One-hundred-and-seventy-four incident cases and 174 matched controls were recruited. Genotyping for polymorphisms in NAT2 was performed using a method that detects >95% of slow alleles and data on personal habits were collected using a standardized questionnaire. We found no difference in the frequency of the fast acetylator genotype between cases and controls [odds ratio = 0.95 (95% CI 0.61-1.49)], and analysis by sex, age and site also revealed no difference in acetylator genotype. There was, however, considerable heterogeneity in dietary risk factors between fast and slow acetylators. Analysis by acetylator type shows that recent smoking was more frequent in slow acetylator cases than matched controls [OR = 2.31 (1.16-4.6)] and that heavy alcohol consumption was also more frequent in the slow acetylator cases than controls [OR = 2.5 (1.02-7.29)]. In contrast, frequent fried meat intake was seen more frequently in fast acetylator cases than matched controls [OR = 6.0 (1.34-55)]. The odds ratio for the combination of fast acetylator status and frequent fried meat consumption in cases was 6.04 (1.6-26). Our study suggests that there may be different risk factors for colorectal cancer in slow and fast acetylators, and reveals a new observation that slow acetylators may be at risk of colon cancer from smoking. In our community, the overall effect of acetylator status on colorectal cancer risk is neutral.     

Treatment of relapsed adult acute lymphoblastic leukemia with fludarabine and cytosine arabinoside followed by granulocyte colony-stimulating factor (FLAG-GCSF)

The aim of the present study was to evaluate the efficacy of the combination of fludarabine 30/mg/m2 + cytarabine 2g/m2 followed by the administration of G-CSF to achieve a complete remission (CR) in patients with relapsed acute lymphoblastic leukemia (ALL). We treated twelve patients in first relapse, overall 10 patients achieved a second CR, one patient showed resistant disease and one patient died during remission induction. The regimen was well tolerated and we observed a short period of neutropenia with a low incidence of myelosuppression-associated problems. Eight patients in second CR received the same chemotherapeutic regimen as consolidation used for the reinduction. In six patients the chemotherapeutic regimen was well tolerated, two patients died, (cerebral hemorrhage in one patient and sepsis in the other). In conclusion the combination of fludarabine, cytarabine and G-CSF has significant antileukemic activity and non hematological toxicities were acceptable. The addition of G-CSF reduced the period of neutropenia obtaining a low incidence of myelosuppression-associated problems.     

Herpes simplex encephalitis: treatment with surgical decompression and cytosine arabinoside

Herpes simplex encephalitis in a 21-year-old man presented as a flu-like illness, followed by inappropriate behaviour, drowsiness and focal neurologic signs. Investigations indicated a lesion in the right temporal lobe. The diagnosis was confirmed by isolation of the virus from a cerebral biopsy. Pronounced clinical improvement was noted when cytosine arabinoside therapy was started in the postoperative period. This report supports the observation by some authors that cytosine arabinoside may be of value in the treatment of herpes simplex encephalitis.     

Transfection of C6 glioma cells with the bax gene and increased sensitivity to treatment with cytosine arabinoside

BACKGROUND: Prolonged dialysis is associated with acquired cystic kidney disease (ACKD) and also higher incidence of renal cell carcinoma. Relationship among dialysis, tubular cell proliferation, development of cystic change and neoplastic transformation is not clearly known. Whether dialysis causes additional stress on tubular cells is also conjectural. Study of heat shock protein (HSP) expression which are rapidly synthesized in cells in response to a variety of stresses may be helpful in this regard. METHODS: To evaluate dialysis induced early changes in end stage renal disease (ESRD), kidneys from eight adult autopsied patients were examined (group I) who were on weekly maintenance haemodialysis for 3-12 months. The heat shock protein (HSP 72/73) expression of tubular epithelial cells and their proliferating cell nuclear antigen (PCNA) labelling index (LI) were studied by immunohistochemistry using monoclonal antibodies. For comparison similar study was carried out in 10 cases of ESRD (Group II) of similar age and sex distribution who were not dialysed. The atrophic tubules were subtyped morphologically into (1) classic, (2) thyroid, (3) endocrine and (4) super tubules. RESULTS: In the dialysed group (I) the percentage of hyperplastic super tubules (10.6 +/- 4.1%) was significantly higher than in the non-dialysed group (II) (5.2 +/- 1.3%) with a higher PCNA LI (6.8 +/- 2.04%) (group II 4.9 +/- 1.9%) (P < 0.01 to < 0.001). Though grossly not detected, but microscopic cysts and microadenoma like areas were seen in all the cases in group I with a mean diameter of 522.66 +/- 315.25 microns and 494.85 +/- 262.46 microns respectively. They were seen in one case of group II. PCNA LI of the cells in microadenoma (7.2 +/- 3.1%) and microcysts (6.6 +/- 2.6%) were similar to that of super tubules in group I. Quantitation of HSP expression by image analysis (optical density 2.309 +/- 0.155) showed a positive correlation (r = 0.7555) (P < 0.001) with PCNA LI in super tubules indicating a higher induction in the dialysed group. CONCLUSIONS: This study suggests that haemodialysis may cause injury to tubular cells and aggravate stress on an already compromised situation of ESRD leading to increased cell proliferation and more hyperplastic supertubule formation which may be the forerunner of cyst formation as well as neoplastic transformation.     

Maintenance of remission in adult acute nonlymphoblastic leukemia using intermittent courses of cytosine arabinoside (NSC-63878) and 6-thioguanine (NSC-752)

In seven of 30 consecutive patients with the adult respiratory distress syndrome, disseminated intravascular coagulation (DIC) developed. Increasing respiratory dysfunction characterized by decreased effective static compliance and increased hypoxemia coincided with the development of DIC. Patients in whom DIC developed were characterized by a high incidence of bleeding, gangrene of the extremities, renal dysfunction, mortality and autopsy evidence of fibrin microthrombi in the lungs, kidney and skin. In 12 of 23 patients who did not meet the criteria for DIC, the platelet count decreased by at least 50 per cent of the initial values at some time during their illness. Fibrin microthrombi were found in the lungs in the majority of the patients subjected to autopsy. These data support the concept that depostion of platelet on damaged pulmonary capillary endothelium may be more common in the adult respiratory distress syndrome than the DIC syndrome.     

Drug resistance to 5-aza-2''-deoxycytidine, 2'',2''-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells

Squamous metaplasia can be demonstrated in about 4% of all invasive carcinomas of the breast. Primary squamous cell carcinomas of the breast are rare, since they occur in less than 1% of all primary invasive breast carcinomas. In order to classify a breast tumor as a primary squamous cell carcinoma one must exclude an epidermal origin, especially from the nipple region and the possibility of metastatic infiltration of the breast by a squamous cell carcinoma from a different location. Causative and formal pathogenesis of primary squamous cell carcinoma of the breast is not clear. A pluripotent embryonal stem cell origin is discussed, considering the phylogenetic descent of the mammary gland from skin appendages. Squamous metaplasia is also suggested to be a precursor of squamous cell carcinoma. Here endocrine stimulation and chronic inflammation may both play an inductive role. The number of published cases of squamous cell carcinomas developing years and decades after implantation of silicon prostheses has increased in recent years. These tumors probably develop on top of squamous metaplasia induced by the inflammatory pseudocapsule. Estimating the prognosis and therapeutic management in patients with squamous cell carcinoma of the breast should follow the same guidelines as for other squamous cell cancers.