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PubMed1990

Schedule-dependent interaction of cytarabine plus doxorubicin or cytarabine plus mitoxantrone in acute myelocytic leukemia cells in culture.

Schedule-dependent interaction of 1-beta-D-arabinofuranosylcytosine (ara-C, cytarabine) plus doxorubicin or ara-C plus mitoxantrone was studied in vitro using HL-60 human acute myelocytic leukemia cell line. The cells were exposed for 1 hr to each drug simultaneously, or sequentially (up to a 28-hr interval), and cell kill effects were determined by clonogenic assay. The results were compared with controls in which cells were exposed to the individual drug only and seeded after appropriate intervals. Simultaneous exposure to two drugs produced lethal effects, but no more than those produced by doxorubicin or mitoxantrone alone. Ara-C followed by doxorubicin produced time-dependent increases in cell kill that was parallel to the doxorubicin alone control, indicative of no true potentiation. In contrast, ara-C followed by mitoxantrone produced striking increases in cell kill effects. Thus, ara-C followed by mitoxantrone resulted in more than 10-fold increases in cell kill at the intervals of greater than or equal to 8 hr between exposures, and the strong cell kill effects were maintained. Our data indicate that: (a) simultaneous exposure to ara-C and doxorubicin or mitoxantrone is less than additive; (b) ara-C followed by doxorubicin is probably only additive; and (c) ara-C followed by mitoxantrone is more than additive, and cell kill effects are sustained.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

[A late phase II comparative study of idarubicin + cytarabine and daunorubicin + cytarabine in adult patients with acute non-lymphocytic leukemia. Idarubicin Study Group].

In adult patients with acute non-lymphocytic leukemia (ANLL), idarubicin (IDA) and daunorubicin (DNR) were compared for efficacy and safety in combination with cytarabine (Ara-C). IDA 12 mg/m2/day and DNR 40 mg/m2/day were administered iv bolus for 3 consecutive days (day 1-3), respectively, in combination with Ara-C 80 mg/m2 given by 2-hour intravenous infusion, every 12 hours for 7 consecutive days. The number of evaluable patients was 32 for each group previously untreated. The rates of complete remission (CR) were 59.4% (19/32) in the IDA group and 40.6% (13/32) in the DNR group. The clinical equivalence test with delta = 10% demonstrated that the IDA group is equal or superior in remission rates (p = 0.010) compared to the DNR group. In addition, the Cochran-Mantel-Haenszel test for response means with scores of 3 (CR), 2 (PR) and 1 (NR) showed the significant superiority (p = 0.044) of the IDA group to the DNR group. The duration needed to attain less than 5% leukemic cells in bone marrow tended to be shorter in the IDA group (p = 0.072), and in the CR patients the number of days needed to reach the nadir value in leukemic cells were significantly fewer in the IDA group (p = 0.037). The nadir value of WBC was significantly lower in the IDA group (p = 0.022). As for adverse reactions, high incidences of diarrhea and stomatitis were observed in the IDA group, while the incidences of other adverse reactions were similar between the two groups. When effects of the drug on the ECG were examined, significant changes in ECG parameters were observed in the DNR group after treatment but not in the IDA group. From the above, remission induction in adult AN LL, IDA + Ara-C therapy showed better efficacy than DNR + Ara-C therapy, and IDA was considered to be a drug of first choice in the treatment of ANLL patients.

Adolescent↗
PubMed1996

A phase II comparative study of idarubicin plus cytarabine versus daunorubicin plus cytarabine in adult acute myeloid leukemia.

In previously untreated adult patients with acute non-lymphocytic leukemia (ANLL), idarubicin (IDA) and daunorubicin (DNR) were compared for efficacy and safety when used in combination with cytarabine (Ara-C). IDA 12 mg/m2/d and DNR 40 mg/m2/d were administered by intravenous (i.v.) bolus for 3 consecutive days (days 1 to 3), respectively, in combination with Ara-C 80 mg/m2 given by 2-hour i.v. infusion, every 12 hours for 7 consecutive days. The number of assessable patients was 32 for each group. The rate of complete remission (CR) was 59.4% (19/32) in the IDA group and 40.6% (13/32) in the DNR group. The clinical equivalence test with delta = 10% demonstrated that the remission rate in the IDA group was equal or superior (P = .010) to the DNR group. In addition, the Cochran-Mantel-Haenszel test for response means with scores of 3 (CR), 2 (partial response [PR], and 1 (no response [NR]) showed the IDA group to be significantly superior (P = .044) to the DNR group. The duration needed to attain less than 5% leukemic cells in the bone marrow tended to be shorter in the IDA group (P = .072), and in CR patients, the number of days needed to reach the nadir value for leukemic cells was significantly fewer in the IDA group (P = .037). The nadir value for WBC count was significantly lower in the IDA group (P = .022). As for adverse reactions, high incidences of diarrhea and stomatitis were observed in the IDA group, while the incidences of other adverse reactions were similar between the two groups. When the effects of the drug on the ECG were examined, significant changes in ECG parameters were observed after treatment in the DNR group but not in the IDA group. Based on these findings, it was surmised that the combination of IDA plus Ara-C is the treatment of first choice for adult ANLL patients.

Adolescent↗
PubMed2006

A pharmacokinetic study of intra-CSF administered encapsulated cytarabine (DepoCyt) for the treatment of neoplastic meningitis in patients with leukemia, lymphoma, or solid tumors as part of a phase III study.

INTRODUCTION: Cytarabine liposome injection (DepoCyt), a sterile suspension of the antimetabolite cytarabine, encapsulated into multivesicular, lipid-based particles, has been developed to improve the treatment of neoplastic meningitis (NM) through sustained release of cytarabine. The objective of this study was to determine the pharmacokinetics (PK) of cytarabine after intrathecal administration of 50 mg encapsulated cytarabine (DepoCy) in patients with neoplastic meningitis up to 336 h (14 days) after dosing. METHODS: This was an open-label study wherein two 50-mg doses of DepoCyt were administered 14 days apart via the intraventricular (IVT) route or by lumbar puncture (LP). Cerebrospinal fluid (CSF) samples were collected from eight adult patients at various times up to 14 days after each dose. Plasma samples were also collected within the same time period. CSF samples were analyzed for unencapsulated (free) and encapsulated cytarabine and the cytarabine metabolite, ara-U. Plasma samples were analyzed for free cytarabine and ara-U. The limit of detection was 0.003 microg/mL cytarabine and 0.016 microg/ml for ara-U. RESULTS: The concentration of free and encapsulated cytarabine in the ventricular and lumbar CSF ranged from 0.01 to 1500 microg/mL and were detectable up to 14 days post-dosing. Free cytarabine concentrations in plasma were only sporadically detectable. CSF and plasma concentrations of ara-U were low in all samples. CONCLUSIONS: The administration of intrathecal encapsulation cytarabine prolongs sustained tumor exposure to cytotoxic concentrations of cytarabine (>0.02 microg/ml) with a slow continuous release of cytarabine from the DepoFoam particles, so drug exposure is prolonged over time, resulting in lower peak cytarabine levels and a longer duration of exposure compared with standard cytarabine (Ara-C).

Adult↗
PubMed2006

Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome.

BACKGROUND: Progressive or higher-risk myelodysplastic syndrome (MDS) is often treated with intensive chemotherapy regimens used for acute myelogenous leukemia (AML). Patients with MDS are often older and may have contraindications to anthracycline-based regimens. Topotecan-cytarabine regimens have shown encouraging results in higher-risk MDS. The aim of this study was to analyze the long-term results with topotecan-cytarabine versus other intensive chemotherapy regimens in higher-risk MDS. METHODS: Five hundred ten patients with higher-risk MDS treated with intensive chemotherapy were reviewed. Their median age was 63 years; 82% had intermediate 2 or high-risk MDS; 32% had secondary MDS; 40% had chromosome 5 or 7 abnormalities. Therapy was: topotecan-cytarabine in 77; idarubicin-cytarabine regimens in 270; topotecan-cytarabine and cyclophosphamide in 67; fludarabine-cytarabine in 96. Univariate and multivariate analyses were conducted to evaluate the independent associations of different variables, and most important, the treatment regimen, with complete response, induction mortality, and survival. RESULTS: The overall complete response (CR) rate was 55%, induction mortality 17%, and 5-year survival rate 8%. The 5-year survival rate was 11% for patients younger than 65 years old and 17% for patients with a normal karyotype. Among 82 patients younger than 65 years with a normal karyotype, the CR rate was 67%, 5-year survival rate 27%, and 5-year CR duration rate 33%. Topotecan-cytarabine regimens were equivalent to idarubicin-cytarabine regimens in relation to CR rates and survival rates, but were associated with a lower induction mortality. Multivariate analysis confirmed that treatment regimens were not associated with independent significant differences in CR rates or survival. However, topotecan-cytarabine regimens were still selected to be associated with lower induction mortality rates. CONCLUSIONS: This analysis suggests that topotecan-cytarabine regimens are equally effective to other AML regimens in higher-risk MDS and may be less toxic. Topotecan-cytarabine may be considered a reasonable alternative to idarubicin-cytarabine in higher-risk MDS, particularly in older patients with contraindications to anthracyclines.

Age Factors↗
PubMed1993

Hematologic remission and cytogenetic improvement after treatment of stable-phase chronic myelogenous leukemia with continuous infusion of low-dose cytarabine.

Prolonged exposure to low concentrations of cytarabine preferentially inhibits in vitro growth of neoplastic myeloid progenitors from patients with chronic myelogenous leukemia (CML) compared to that of normal myeloid progenitors. Continuous infusions of cytarabine in doses of 15-30 mg/m2/day were therefore administered for extended periods to patients with CML in stable phase to determine if this treatment could achieve selective cytoreduction of Philadelphia chromosome (Ph)-positive cells. Five patients demonstrating > 90% Ph-positive metaphases before treatment received a total of 43 cycles of cytarabine infusional therapy. Cytarabine was administered on an outpatient basis using a portable, battery-operated syringe pump until the total leukocyte count reached 2500/microliters or the platelet count reached 75,000/microliters. A new cycle was begun when the total leukocyte count exceeded 4,000/microliters and the platelet count exceeded 100,000/microliters. The median duration of cytarabine administration per cycle was 29 days (range 15-72 days). Leukocytosis was readily controlled by low-dose cytarabine therapy in all patients. All five patients experienced complete hematologic responses during cytarabine therapy. The fraction of Ph-positive metaphases in the marrow of the five patients was reduced to 0, 10%, 43%, 72%, and 84%, respectively, during therapy. The median time to achieve optimal cytogenetic response was 4.8 months (range 2.8-8.6 months). One patient demonstrated a complete cytogenetic response after three cycles of cytarabine. Another patient demonstrated persistent cytogenetic improvement during 20 cycles of cytarabine, with a median 38% Ph-positive marrow metaphases (range 10-53%) over 32 months. Cytarabine therapy was generally well-tolerated, but was discontinued in one patient because of persistent asymptomatic elevations in hepatic enzymes, which resolved within 2 months after discontinuing therapy. There were no episodes of fever during neutropenia, and platelet transfusions were not required. However, symptomatic anemia requiring transfusion of red cells occurred during most cycles of treatment. In summary, treatment of CML with low-dose cytarabine can induce prolonged cytogenetic improvement in some patients with acceptable toxicity. Further evaluation is needed to ascertain the effect of this treatment on duration of stable phase and overall survival.

Adult↗
PubMed1992

Recombinant human interferons alpha, beta and gamma reduce the antiproliferative action of cytarabine in K562 human myeloid leukaemia clonogenic cells.

The effects of recombinant human interferons alpha, beta and gamma (IFN) on the antiproliferative activity of cytarabine in K562 human myeloid leukaemia clonogenic cells were studied in an agar capillary microassay. The addition of IFN-alpha did not affect the antiproliferative activity of cytarabine in K562 cultures treated with low concentrations of cytarabine (10-50 nM), whereas in those treated with high concentrations (100-150 nM) IFN alpha increased the IC50 of cytarabine on day 5 from 102 nM to 214 nM, i.e., cytarabine combined with IFN alpha was about two-fold less potent than cytarabine alone. Similarly, low concentrations of IFN beta and IFN gamma did not affect the antiproliferative activity of cytarabine on K562 colonies, but high concentrations of these two interferons: 4 x 10(3) U/ml and 10(4) U/ml respectively, increased the IC50 of cytarabine on day 5 to 304 nM and to 316 nM respectively, i.e. cytarabine combined with IFN beta or IFN gamma was about threefold less potent than cytarabine alone. The evaluation of the present negative interactions of interferons with cytarabine is warranted in fresh cells from myeloid leukaemia patients in primary culture.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

The toxicity of cytarabine.

The principal toxicity of standard induction regimens for acute non-lymphocytic leukemia (ANLL) [including cytarabine (ARA-C) 100 mg/m2 for 7 days plus an anthracycline] is myelotoxicity, leading to death in at least 25% of cases during induction in non-selected patients. The complete remission rate is less than 35% in patients over 65 years of age, due in part to an age-related increase of myelotoxicity. The other important adverse effect of standard-dose cytarabine is gastrointestinal toxicity, especially oral mucositis, diarrhoea, intestinal ulceration, ileus and subsequent Gram-negative septicaemia. Idiosyncratic reactions like exanthema, fever and elevation of hepatic enzymes are relatively frequent, but do not represent therapeutic problems. Intermittent high-dose cytarabine (3 g/m2 in 8 to 12 doses) is extremely myelosuppressive. Similarly, the gastrointestinal toxicity is formidable and dose-limiting. Severe, and sometimes irreversible, cerebellar/cerebral toxicity in 5 to 15% of courses of treatment limits the peak dose of cytarabine. The pathogenesis, prophylactic and therapeutic measures are unknown. These major toxicities are age-related and prohibitive to the use of high-dose cytarabine therapy in patients older than 55 to 60 years. Subacute noncardiogenic pulmonary oedema occurs in some patients, with an incidence of about 20%, and seems to have an intriguing coincidence with precedent streptococcal septicaemia; high-dose systemic steroids may be beneficial. Corneal toxicity is very frequent in high-dose cytarabine therapy but is always reversible. It is largely preventable with prophylactic steroid or 2-deoxycytidine eyedrops. Fever, exanthema and hepatic toxicity have an incidence similar to that in standard dosage. The maximum tolerable cumulated dose of cytarabine is significantly lower when the agent is administered as a continuous infusion, due to myelosuppression and gastrointestinal toxicity. Conversely, continuous infusion may be less neurotoxic. The antileukaemic effect of continuous infusion high-dose cytarabine is less well established. The only significant toxicity of low-dose cytarabine is myelosuppression. Given the generally poor condition of leukaemia patients, low-dose cytarabine therapy is well tolerated, although occasional cases of diarrhoea, reversible cerebellar symptoms, peritoneal and pericardial reactions, and ocular toxicity have been reported. Continuous infusion may be more toxic than the usual intermittent dosage. It is concluded that the toxicity of the standard induction regimen for ANLL is acceptable in patients younger than 60 to 65 years with no concurrent disease. Low dose cytarabine is tolerable for virtually all ANLL patients, but the overall therapeutic efficacy still needs to be defined and compared to standard therapy in the relevant age groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗
PubMed1977

Reduction of erythropoietic toxicity to cytarabine by pentobarbital.

The erythropoietic toxicity of cytarabine was reduced when mice were maintained in the anesthetized state by pentobarbital starting 1 hr before and lasting 1 hr after a series of doses of cytarabine given over a 4 hr period. Erythropoietic toxicity was determined by injecting 59Fe 48 or 72 hr after the last dose of cytarabine and measuring 59Fe in the circulating red blood cells 24 hr later (24 hr 59Fe uptake). Although pentobarbital alone had no effect on 24 hr 59Fe uptake either 48 or 72 hr after pentobarbital, the barbiturates reduced erythropoietic toxicity when cytarabine was given as 3 doses of 50 or 100 mg/kg every 2 hr and the effect was evaluated 48 hr after the last dose. Neither single nor multiple doses of cytarabine inhibited 59Fe uptake when 24 hr 59Fe uptake was measured 72 hr after cytarabine. However, if an initial dose of cytarabine (150 mg/kg) was given 12 hr prior to the multiple doses and 24 hr 59Fe up take was measured 72 hr after drug treatment, 59Fe uptake was inhibited, suggesting that the initial dose of cytarabine induced hemopoietic stem cells in the resting GO state to go into active cell cycle. Pentobarbital also protected against these latter effects of multiple doses of cytarabine. In contrast to the above, pentobarbital did not protect against the inhibitory effects of a single dose of cytarabine on 59Fe uptake. The above data show that pentobarbital protects against the cytotoxic effect of cytarabine on pronormoblasts and hemopoietic stem cells in cell cycle.

Animals↗
PubMed1992

A randomized study of intermediate versus conventional-dose cytarabine as intensive induction for acute myelogenous leukaemia.

The optimal dose of cytarabine for induction chemotherapy is unknown. Most studies have utilized doses of 100-200 mg/m2/d, although higher doses have been proposed to increase the concentration of the active metabolite ara-CTP within leukaemia cells. To address this question 101 adults with newly diagnosed acute myeloid leukaemia were randomized to receive treatment with daunorubicin and either conventional-dose cytarabine (200 mg/m2/d by continuous infusion) or an intermediate-dose of cytarabine (500 mg/m2 every 12 h). 36/51 (71%) patients assigned to conventional-dose cytarabine achieved complete remission compared to 37/50 (74%) who achieved remission with intermediate-dose cytarabine (P = 0.9). Patient age significantly affected remission rate. 8/17 patients age greater than 60 assigned to conventional-dose cytarabine and 10/17 assigned to intermediate-dose cytarabine achieved complete remission compared to 27/33 patients under age 60 assigned to the conventional dose and 28/34 patients assigned to the intermediate dose arm (P = 0.004). Actuarial 4-year disease-free survival for patients assigned to conventional-dose cytarabine was 20 +/- 16% versus 28 +/- 17% for patients assigned to intermediate-dose cytarabine (P = 0.9). We conclude that intermediate dose cytarabine did not substantially improve results of induction chemotherapy for acute myeloid leukaemia.

Adolescent↗
PubMed2002

Clinical pharmacokinetics of cytarabine formulations.

Cytarabine (cytosine arabinoside, Ara-C) is an effective chemotherapeutic agent for the treatment of acute myelogenous leukaemia and lymphocytic leukaemias. As cytarabine is an S-phase-specific drug, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. However, the activity of cytarabine is decreased by its rapid deamination to the biologically inactive metabolite uracil arabinoside. This rapid deamination is the reason for the ongoing search for effective formulations and derivatives of cytarabine that cannot be deaminated and exhibit better pharmacokinetic parameters. Protection of cytarabine from fast degradation and elimination has been investigated by encapsulating the drug into pharmaceutically acceptable carriers. Cytarabine derivatives have shown promise in vitro and in animal models. For example, ancitabine (cyclocytidine), enocitabine and cytarabine ocfosfate have been used clinically in Japan. Cytarabine encapsulated into multivesicular liposomes has been approved in several countries for the intrathecal treatment of lymphomatous meningitis. Although many compounds have been investigated, few cytarabine derivatives are currently available for clinical use. Further research is needed to improve the efficacy of cytarabine against haematological and solid tumours.

Animals↗
PubMed2000

Chitosan microspheres in PLG films as devices for cytarabine release.

Cytarabine was included in chitosan microspheres and several of these microspheres were embedded in a poly(lactide-co-glycolide) (PLG) film to constitute a comatrix system, to develop a prolonged release form. Chitosan microspheres, in the range of 92+/-65 microm, having good spherical geometry and a smooth surface incorporating cytarabine, were prepared. The cytarabine amount included in chitosan microspheres was 43.7 microg of ara-C per milligram microsphere. The incorporation efficiency of the cytarabine in microspheres was 70.6%. Total cytarabine release from microspheres in vitro was detected at 48 h. Inclusion of cytarabine-loaded microspheres in poly(lactide-co-glycolide) film initiated a slower release of the drug and, in this way, the maximum of cytarabine released (80%) took place in vitro at 94.5 h. Comatrices, with 8.7 mg of cytarabine, signifying a dose of 34.5 microg/kg, were subcutaneously implanted in the back of rats. Maximum plasma cytarabine concentration was 18.5+/-1.5 microg/ml, 48 h after the device implantation and the drug was detected in plasma for 13 days. The histological studies show a slow degradative process. After 6 months of implantation, most of the microspheres of the matrix seemed to be intact, the comatrix appeared surrounded by conjunctive tissue and small blood vessels and nerve packets were detected in the periphery of the implant.

Animals↗
PubMed2002

Enhancement of cytarabine sensitivity in squamous cell carcinoma cell line transfected with deoxycytidine kinase.

BACKGROUND: Cytarabine is the most effective agent known for the treatment of acute myeloid leukemia. Its antitumor effect is expressed by combining with DNA during replication and then destroying the DNA chain. However, cytarabine has only limited activity against most solid tumors, including squamous cell carcinoma of the head and neck. The reason for this is thought to be that in cell lines of solid tumors the expression of cytidine deaminase, an enzyme that degrades cytarabine, is high, whereas the expression of deoxycytidine kinase (dCK), which phosphorylates cytarabine (a prodrug), is weak. OBJECTIVE: To determine whether head and neck squamous cell carcinomas can be made more sensitive to the cytotoxic effects of cytarabine by shifting the balance from the degradative to the activation pathway. METHODS: Human SCC-25 squamous carcinoma cells were transfected by either retroviral vector or adenoviral vector containing DCK gene and were identified for dCK expression by Northern blot analysis. In vitro cytotoxic assay after cytarabine exposure was performed using these cells. RESULTS: Both retroviral and adenoviral vector-mediated transduction of the dCK complementary DNA resulted in marked sensitization of tongue squamous carcinoma cell lines to the cytotoxic effects of cytarabine in vitro. CONCLUSION: The dCK-cytarabine system may be a useful approach for gene therapy of squamous cell carcinomas of the head and neck.

Adenoviridae↗
PubMed1996

Acute pancreatitis associated with continuous infusion cytarabine therapy: a case report.

BACKGROUND: While acute pancreatitis is a recognized complication of numerous drugs, cytarabine's role in causing this complication is controversial. Approximately 15 cases have been reported to the Food and Drug Administration linking cytarabine with pancreas-related toxicities. Previous case reports have been complicated by comorbid illnesses and the coadministration of other drugs associated with acute pancreatitis. METHODS: This report describes the clinical course of a patient with acute myelogenous leukemia (AML) who developed recurrent pancreatitis associated with cytarabine therapy. RESULTS: A male age 36 years with French-American-British M5B acute myelogenous leukemia received induction cytarabine (200 mg/m2/day) by continuous infusion for 7 days, and subsequently developed acute pancreatitis. The patient was rechallenged with intermittent, bolus, high dose cytarabine (HDAC) (3 g/m2bid administered over 3 hours) during the following intensification treatment, but did not develop clinical acute pancreatitis. Retreatment with continuous infusion cytarabine at a later time resulted in recurrence of acute pancreatitis. CONCLUSIONS: This case illustrates that cytarabine treatment may cause acute pancreatitis, and that this toxicity may be schedule dependent. In those with known sensitivity to cytarabine, altering the administration technique may avoid this complication.

Acute Disease↗
PubMed2007

Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose cytarabine chemotherapy in a patient with acute myeloid leukemia.

A 56-year-old man was admitted to our hospital with leukocytosis, anemia, and thrombocytopenia. Acute monoblastic leukemia was diagnosed. Two subsequent courses of consolidation chemotherapy consisted of conventional doses of cytarabine and intermediate-dose cytarabine. Intermediate-dose cytarabine was infused intravenously every 12 hr for 6 days. On day 15 after the final infusion of cytarabine, the patient suffered headache, and on day 21, he experienced a decrease in sensation on the sole of his left foot. Magnetic resonance imaging (MRI) of the brain revealed widespread areas of white matter edema. Cerebrospinal fluid (CSF) examination revealed an increase in the number of cells to 31 mm(-3); the majority were lymphocytes. No infiltration of leukemia cells was seen. After 2 months, brain MRI findings were normal. The clinicoradiologic features of the case were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). RPLS in the present case was unlikely to have been caused by direct neurotoxicity because (1) the doses of cytarabine (500 mg/m(2); total dose 9.2 g) were much smaller than those in reported cases and were repeatedly infused until RPLS developed; (2) the RPLS developed 21 days after the final infusion of cytarabine, a much longer period than previously reported; (3) the slight leukocytosis in the CSF observed on day 33 might also have been related to the cellular immune responses evoked by the infused cytarabine. These details suggest not only that direct cerebral neurotoxicity of cytarabine but also that some type of allergic response may have been involved in the development of RPLS.

Antimetabolites, Antineoplastic↗
PubMedDate not supplied

Synthesis and biological evaluation of a cytarabine phosphoramidate prodrug.

Recently, we reported a novel approach for the intracellular delivery of the anti-cancer nucleotide 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) using phosphoramidate-based prodrugs. These phosphoramidate prodrugs contain an ester group that undergoes intracellular activation, liberating phosphoramidate anion, which in turn undergoes spontaneous cyclization and P-N bond cleavage to yield the nucleoside monophosphate quantitatively. This approach has now been extended to cytarabine [1-beta-D-arabinofuranosylcytosine (Ara-C)], an anti-cancer nucleoside that is limited in its utility because of poor intracellular transport characteristics and weak activity as a substrate for tumor cell kinases. The cytarabine phosphoramidate prodrug 1 has been synthesized and evaluated in comparison with cytarabine for growth inhibitory activity against wild-type, nucleoside transport-deficient, and nucleoside kinase-deficient CEM leukemia cell lines. The prodrug was comparable in growth inhibitory activity (IC50 = 32 nM) to cytarabine (IC50 = 16 nM) in wild-type CCRF-CEM cells following drug treatment for 72 h. The nucleoside transport-deficient CEM/AraC8C exhibited a high level of resistance (6400-fold) to cytarabine but was more sensitive (210-fold resistant vs CCRF-CEM cells) to prodrug 1. Similarly, the deoxycytidine kinase-deficient cell line (CEM/dCK-) was highly resistant to cytarabine (13900-fold) but more sensitive (106-fold resistant vs CCRF-CEM cells) to prodrug 1. These results indicate that prodrug 1 is significantly more potent than cytarabine against transport- and kinase-deficient cell lines and are consistent with a mechanism involving intracellular delivery of cytarabine 5'-monophosphate.

Amides↗