Evaluation of the safety of C-1311 (SYMADEX) administered in a phase 1 dose escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumours.

PURPOSE: C-1311 is a member of the novel imidazoacridinone family of anticancer agents. This phase 1 trial was designed to investigate the safety, tolerability and preliminary anti-tumour activity of C-1311. PATIENTS AND METHODS: This was a phase 1, inter-subject dose escalating and pharmacokinetic study of intravenous (IV) C-1311, administered weekly during 3consecutive weeks followed by 1week rest (constituting 1 cycle) in subjects with advanced solid tumours. RESULTS: Twenty-two (22) patients were treated with C-1311, the highest dose given was 640mg/m(2). All subjects experienced one or more treatment-related adverse events (AEs). The most frequently observed treatment-related AEs were neutropaenia and nausea (50% each), followed by vomiting (27%), anaemia (23%), asthenia (23%) and diarrhoea (18%). Most treatment-related AEs were of Common Terminology Criteria for Adverse Events (CTCAE) grades 1-2, except for the blood and lymphatic system disorders, which were primarily of grades 3-4. The recommended dose (RD) of C-1311 administered as once weekly IV infusions for 3weeks every 4weeks is 480mg/m(2), with the dose limiting toxicity (DLT) being grade 4 neutropaenia lasting more than 7days. Treatment at this dose offers a predictable safety profile and excellent tolerability. CONCLUSION: The safety profile and preliminary anti-tumour efficacy of C-1311, observed in this broad-phase dose-finding study, warrants further evaluation of the compound.

Nanoparticle coated emulsions as novel dermal delivery vehicles.

The dermal delivery characteristics of hydrophilic silica nanoparticle coated medium chain triglyceride oil-in-water emulsions are reported and correlated with the physicochemical and interfacial properties of the emulsion based drug carriers. The synergistic drug/stabiliser/nanoparticle interactions are demonstrated to be a function of the charge and concentration of the initial emulsion stabiliser; charge and initial loading phase of nanoparticles and physicochemical properties of the drug molecule. The improved physical stability of the emulsions and the chemical stability of two model lipophilic agents (all-trans-retinol and acridine orange 10-nonyl bromide) confirm that engineered nanoparticle layers can enhance the shelf-life of liable lipophilic agents. Nanoparticle coatings are shown to control the in-vitro release of active agents from emulsions and significantly promote skin retention. The lipophilic agents distributed into the deeper viable skin layers without permeation through full-thickness skin and hence systemic exposure. Nanoparticle-coated submicron oil-in-water emulsions can serve as novel dermal carriers with controlled release kinetics and targeted drug delivery.

Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer.

BACKGROUND: Single-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy. METHODS: A meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X (X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation. RESULTS: The meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio (HR) of 0.91 (95% CI: 0.85 - 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 (I2 = 0%). The analysis of platinum-based combinations indicated a HR of 0.85 (95% CI: 0.76 - 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 - 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed (HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status (PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 - 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR = 1.08; 95% CI: 0.90 - 1.29, p = 0.40). CONCLUSION: The meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis (representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.

Pharmaceutical development of a parenteral lyophilised dosage form for the novel anticancer agent C1311.

C1311 (5-[[2-(diethylamino)ethyl]amino]-8-hydroxyimidazo [4,5,1-de]-acridin-6-one-dihydrochloride trihydrate) is the lead compound from the group of imidazoacridinones, a novel group of rationally designed anticancer agents. C1311 shows significant cytotoxic activity in vitro and in vivo toward a range of colon tumours. The aim of the present study is to develop a sterile and stable, injectable pharmaceutical product for C1311 to be used in phase I clinical trials. C1311 drug substance was structurally and analytically characterised by chromatographic, spectrometric, and diffraction techniques. C1311 was freely soluble in water, and its stability was investigated in several liquid and lyophilised formulations with or without the use of buffering, tonicity, and bulking agents. The final product, containing 100 mg/vial C1311 (as anhydrous free base), was stable for at least 3 months under accelerated storage conditions and at the designated long-term storage condition of 5 +/- 3 degrees C in the dark. The drug is currently used in phase I clinical trials.

Pharmacokinetics and tissue distribution of the imidazoacridinone C1311 in tumour-bearing mice.

C1311 is the most active member of a new series of rationally designed anti-cancer agents, the imidazoacridinones, which has shown promising pre-clinical anti-tumour activity in vitro and in vivo against a variety of human colon cancers and is a strong candidate for clinical trials. Data are not available on the pharmacokinetic properties of this compound; therefore, the main aim of this project was to study the plasma pharmacokinetics and tissue and tumour distribution of C1311 in mice and to assess, prior to potential clinical application, whether these pharmacokinetics were linear with respect to the dose. The distribution of C1311 in whole blood was also studied. NMRI or NCR-Nu mice were used throughout the study. C1311 was given i.p. at doses of 15, 50, 100 and (the maximum tolerated dose, (MTD) 150 mg kg(-l) i.p. Plasma, tissue and tumour levels were monitored over a 24-h period using high-performance liquid chromatography (HPLC) with fluorescence detection. The distribution of C1311 in murine and human whole blood was studied using both HPLC and fluorescence microscopy. C1311 was quickly cleared from the plasma (47410 ml min kg(-1)) and rapidly distributed into the tissues at all doses. Tissue-to-plasma ratios were large, ranging from 8 in the liver (15 mg kg(-l)) to 600 (50 mg kg(-1)) in the spleen. Overall concentrations were ranked in the order of plasma << liver < kidney < fat < small intestine < spleen. Tumour concentrations were similar to those measured in the liver and kidney, with AUCs being 186 (MAC15A) and 94.4 microg h ml(-l)(HT-29). Plasma pharmacokinetics were linear at doses of 15-100 mg kg(-1), but disproportionate increases were seen in plasma and tissue concentrations at doses above 100 mg kg(-l). C1311 distributed unevenly in both mouse and human blood, with higher concentrations occurring in the cellular fraction than in plasma. Nucleated cells accounted for a large proportion of this localised drug. In conclusion, C1311 is quickly cleared from the plasma and rapidly distributed into the tissues, with tissue concentrations being far higher than plasma levels. The plasma pharmacokinetics are linear up to but not above doses of 100 mg kg(-1). Concentrations of C1311 are greater in the cellular fraction of the blood than in the plasma, with disproportionately high concentrations occurring in the nucleated fraction.

Cell killing by the novel imidazoacridinone antineoplastic agent, C-1311, is inhibited at high concentrations coincident with dose-differentiated cell cycle perturbation.

We have studied the actions of C-1311, an imidazoacridinone analogue with potent in vivo antitumour activity, against a human tumour line (HeLa S3), in an examination of the events associated with the lethality of this agent. Continuous exposures (24 h) induced complete G2 arrest, although the concentration range of this effect was narrow, with elevation of the drug level inducing additional and increasing impediment to S-phase transit. Acute treatments (3 h) revealed that cells exposed to drug levels, which first induced persistent G2 arrest (0.5 microgram ml-1), subsequently died from this compartment, while doses exceeding these levels (1.0 microgram ml-1), paradoxically, did not cause the same extensive cell death. We explain our findings on the proposition that this particular mode of cell death is dependent upon inappropriate activation of the primed mitotic machinery-specifically the hyperphosphorylated p34cdc2/cyclin B complex-assembled within G2, but that impediment to genomic replication at higher doses inhibits assembly of this complex, and hence prevents cell death. Our results demonstrate that high dose does not necessarily correlate with increased cell death, while at the same time providing further evidence for the importance of events normally associated with the G2/M transition in DNA damage-induced tumour cell death.

Preclinical evaluation of novel imidazoacridinone derivatives with potent activity against experimental colorectal cancer.

Novel imidazoacridinone derivatives, C1310 and C1311, have been evaluated for their potential to inhibit tumour cell growth in vitro and in vivo. A cell line panel, including seven human and murine colon carcinoma cell lines and three in vivo models, was used. The compounds were found to be potent inhibitors of tumour cell growth with IC50 values ranging between 10 nM and 2 microM in human colon cancer cell lines. Statistically significant tumour growth delay (P < 0.01) was observed after a single intraperitoneal (i.p.) dose of C1311 (100 mg kg-1 body weight) in MAC15A, MAC29 murine and HT29 human adenocarcinomas of the colon. Rapid accumulation of fluorescence of both C1310 and C1311 was seen in the nuclei of HT29 human colon tumour cells in culture. C1311 was also found to bind into calf thymus DNA as shown by spectrophotometric titration and thermal denaturation and to cause early inhibition of thymidine incorporation in HT29 cells in vitro. The results of this study suggest that C1311 should be considered as a candidate for clinical development.

Tumour profile of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide after intraperitoneal administration in the mouse.

N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC) is an experimental antitumour agent that is being considered for phase I trials. After i.p. administration of 150 mg/kg [3H]-AC to tumour-bearing mice, AC was absorbed rapidly into the plasma and tissues such as the heart, liver, kidney and brain but more slowly into the s.c. tumour. The maximal AC concentration (86 +/- 36 mumol/kg) in the tumour occurred at 35-60 min and was 3-fold the maximal plasma concentration, which occurred at 15 min. Although higher maximal concentrations were observed in other tissues, these concentrations fell rapidly in parallel with plasma concentrations. In contrast, AC concentrations in the tumour remained elevated, the t1/2 value (16.3 h) and mean residence time (MRT, 9.5 h) being prolonged in comparison with those in the plasma and other tissues (t1/2 range, 1.0-2.9 h; MRT, 1.2-1.4 h). AC concentrations were not detectable by our high-performance liquid chromatographic (HPLC) method (limit of detection, 0.02 mumol/l) in the plasma or other tissues at 24 or 48 h after administration but were measurable in the tumour (1.6 +/- 0.8 and 0.6 +/- 0.3 mumol/kg, respectively). Radioactivity concentrations in the plasma, tissues and tumour were very variable but were greater than the corresponding levels of unchanged parent AC. By 24 h, radioactivity concentrations in the plasma, tissues and tumour had fallen to similar levels with prolonged elimination profiles. Thus, the exposure of the s.c. implanted tumour to a threshold AC concentration for a prolonged time (> 24 h) tumour, whereas the shorter period of exposure of blood and other tissues may explain its low haematological toxicity.

Pharmacokinetics of acridine-4-carboxamide in the rat, with extrapolation to humans.

The pharmacokinetics of N-[2-(dimethyl-amino)ethyl]acridine-4- carboxamide (AC) were investigated in rats after i.v. administration of 18, 55 and 81 mumol/kg [3H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (+/- SD) model-independent pharmacokinetic parameters were: clearance (Cl), 5.3 +/- 1.1 1 h-1 kg-1; steady-state volume of distribution (Vss), 7.8 +/- 3.0 l/kg; mean residence time (MRT), 1.5 +/- 0.4 h; and terminal elimination half-life (t1/2Z), 2.1 +/- 0.7 h (n = 10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1-8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05-0.10; 95% confidence limits) 1 h-1 kg-1 and a Vss value of 0.63 (range, 0.2-1.1) l/kg for total drug concentrations in humans.

Pharmacokinetics and toxicity of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide after i.v. administration in the mouse.

The pharmacokinetics, tissue distribution and toxicity of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide(AC) were studied after i.v. administration to mice. Over the dose range of 9-121 mumol/kg (3-40 mg/kg), AC displayed linear kinetics with the following model-independent parameters: clearance (C), 21.0 +/- 1.9 1 h-1 kg-1; steady-state volume of distribution (Vss), 11.8 +/- 1.4 l/kg; and mean residence time (MRT), 0.56 +/- 0.02 h. The plasma concentration-time profiles for AC fitted a two-compartment model with the following parameters: Cc, 19.4 +/- 2.3 1 h-1 kg-1; Vc, 7.08 +/- 1.06 l/kg; t1/2 alpha 13.1 +/- 3.5 min; and t1/2Z, 1.60 +/- 0.65 h. AC displayed moderately high binding in healthy mouse plasma, giving a free fraction of 15.9%-25.3% over the drug concentration range of 1-561 microM. After the i.v. administration of 30 mumol/kg [3H]-AC, high radioactivity concentrations were observed in all tissues (especially the brain and kidney), showing a high t1/2c value (37-59 h). At 2 min (first blood collection), the AC concentration as measured by high-performance liquid chromatography (HPLC) comprised 61% of the plasma radioactivity concentration (expressed as AC equivalents/l). By 48 h, 73% of the dose had been eliminated, with 26% and 47% of the delivered drug being excreted by the urinary and faecal routes, respectively; less than 1% of the total dose was excreted as unchanged AC in the urine. At least five distinct radiochemical peaks were distinguishable by HPLC analysis of plasma extracts, with some similar peaks appearing in urine. The 121-mumol/kg dose was well tolerated by mice, with sedation being the only obvious side effect and no significant alterations in blood biochemistry or haematological parameters being recorded. After receiving a dose of 152 mumol/kg, all mice experienced clonic seizures for 2 min (with one death occurring) followed by a period of sedation that lasted for up to 2 h. No leucopenia occurred, but some mild anaemia was noted. There was no significant change in blood biochemistry. A further 20% increase in the i.v. dose (to 182 mumol/kg) resulted in mortality, with death occurring within 2 min of AC administration.

Intraperitoneal administration of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in the mouse: bioavailability, pharmacokinetics and toxicity after a single dose.

The pharmacokinetics, tissue distribution and toxicity of the antitumour agent N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide (AC) were studied after i.p. administration of [3H]-AC (410 mumol/kg) to mice. The latter is the optimal single dose for the cure of advanced Lewis lung tumours. AC was rapidly absorbed into the systemic circulation after i.p. administration, with the maximal concentration (Cmax) occurring at the first time point (5 min). There was no reduction in bioavailability as compared with previous i.v. studies, but the shape of the plasma concentration-time profile was considerably different, reflecting a 3-fold lower Cmax value (20.9 +/- 3.6 mumol/l) and a longer t1/2 value (2.7 +/- 0.3 h) as compared with that observed after i.v. administration (1.6 +/- 0.6 h). Model independent pharmacokinetic parameters after i.p. administration were: clearance (C), 17.5 l h-1 kg-1; steady-state volume of distribution (Vss), 14.1 l/kg; and mean residence time (MRT), 1.46 h. High but variable tissue uptake of AC was observed, with tissue/plasma AUC ratios being 5.7 for heart, 8.4 for brain, 18.9 for kidney and 21.0 for liver but with similar elimination t1/2 values ranging from 1.3 to 2.7 h. All radioactivity profiles in plasma and tissues were greater than the respective parent AC profiles and showed prolonged elimination t1/2 values ranging from 21 h in liver to 93 h in brain. However, tissue/plasma radioactivity AUC ratios were near unity, ranging from 0.7 to 1.57, with the exception of the gallbladder (15.6), which contained greater amounts of radioactivity. By 48 h, approximately 70% of the total dose had been eliminated, with the faecal to urinary ratio being approximately 2:1. This i.p. dose was well tolerated by mice, with sedation being the only obvious side effect. No major change was observed in blood biochemistry or haematological parameters. Comparisons of Cmax, tmax and AUC values determined for AC in brain after its i.p. and i.v. administration suggest that the reduction in acute toxicity after i.p. administration is not due to reduced exposure of the brain to AC as measured by AUC but may be associated with the lower Cmax value or the slower rate of entry of AC into the brain after i.p. administration.

Application of a brain-targeting chemical delivery system to 9-amino-1,2,3,4-tetrahydroacridine.

Several chemical delivery systems (CDS) were synthesized for the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroacridine (THA). The derivatives prepared were substituted with a 1,4-dihydropyridine in equilibrium pyridinium salt redox system at the amino functionality. These compounds were synthesized by acylation of the 9 amino group of THA with nicotinic anhydride under forced conditions, followed by a selective N-alkylation of the pyridine ring and regioselective reduction of the resulting quaternary salts. Lipophilicity parameters indicated increased lipophilic indices for various CDS's compared to the THA. Oxidation studies showed that dihydronicotinamides readily converted to the quaternary salt, both chemically and enzymatically. The transport forms of THA were also shown not to interact with acetylcholinesterase in vivo. In vivo distribution studies in the rat indicated that high and sustained levels of the pyridinium quaternary ion derivative were present in the central nervous system (CNS). In addition, THA was produced in the CNS from the quaternary salt precursor in low concentrations, indicating a slow but sustained release. The CDS for THA were found to be less acutely toxic than THA.

Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. Results of a Canadian double-blind, crossover, multicenter study.

We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

Oral tacrine administration in middle-aged monkeys: effects on discrimination learning.

We studied the effect of chronic, oral administration of 1,2,3,4 tetrahydro-9-aminoacridine (THA), an anticholinesterase, on the acquisition of a color discrimination task in five monkeys (Macaca radiata), aged 13-19 years. A two-phase experiment was performed: initially, one animal was used and served as his own control in a multiple dose, crossover, placebo controlled trial, designed to establish a dose-response curve and an optimal dose range based on THA serum concentrations. Thereafter, four monkeys were given the optimal dose of THA (5.0 mg/day) determined previously while learning up to four color pair discriminations. They also learned up to four other color pair discriminations while on placebo. Two monkeys received THA first, then placebo; the others received placebo first, then THA. No order effects were noted. When combined scores for THA tests were compared to their placebo scores, the difference was significant at p less than 0.01 with all four THA treated monkeys requiring fewer trials to reach learning criterion. These results indicate that THA has a significantly positive effect on the acquisition of a color discrimination task.

Long-term oral administration of memory-enhancing doses of tacrine in mice: a study of potential toxicity and side effects.

Recently, tacrine (1, 2, 3, 4-tetrahydro-9-aminoacridine; THA; TAC) has received international attention as an oral agent capable of relieving some of the cognitive symptoms accompanying Alzheimer's disease (AD). When given acutely and parenterally (by injection), tacrine has also enhanced memory retention in animals and man. This study evaluates the clinical potential of this agent by assessing toxicity and major side effects of a memory-enhancing dose of tacrine in mice. Groups of mice received either tacrine or vehicle (placebo) orally for 4 to 6 months. A lack of toxicity after this prolonged treatment with TAC was indicated by: (a) no significant impairment on a battery of behavioral toxicity tests; (b) improved memory retention; (c) a significant but only slight elevation of ornithine transcarbamylase activity in blood serum; (d) no abnormality as revealed with light microscopy of liver tissue; and (e) no gross organ pathology in visceral organs.

Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type.

We treated 17 patients who had moderate to severe Alzheimer's disease with oral tetrahydroaminoacridine (THA), a centrally active anticholinesterase, in a three-phase study. In the nonblinded first phase of the study, significant improvement occurred in subjects who received the drug, as compared with their pretreatment status, on the global assessment (P = 0.001), the Orientation Test (P = 0.001), and the more sophisticated Names Learning Test (P = 0.001). During the second phase, the subjects served as their own controls in a double-blind, placebo-controlled, cross-over study in which the order of administration of the drug and placebo was randomly assigned. Among the 14 subjects completing Phase II, THA treatment produced significantly better results than placebo on the global assessment (P = 0.003), the Orientation Test (P = 0.004), the Alzheimer's Deficit Scale (P = 0.003), and the Names Learning Test (P = 0.001). Twelve subjects have entered Phase III, which involves long-term administration of oral THA. The average duration of treatment in these subjects at present is 12.6 months; symptomatic improvements have occurred, and no serious side effects attributable to THA have been observed. These encouraging initial results suggest that THA may be at least temporarily useful in the long-term palliative treatment of patients with Alzheimer's disease. We stress that further observations will be required before a clear assessment of the role of this agent can be made.

Amsacrine-associated cardiotoxicity: an analysis of 82 cases.

Amsacrine is an antileukemia drug being widely used in North America, Europe, Australia, and New Zealand. In the initial clinical trials, patients treated with amsacrine developed occasional instances of acute cardiac arrhythmias and cardiomyopathy. We review and analyze the features of cardiac abnormalities associated with amsacrine in 82 patients, 27 of whom have not been previously reported. The rest have been reported in the literature, but we have included a large amount of additional information about these patients in our analysis. We conclude that amsacrine-related cardiac events are less common than those related to anthracycline chemotherapeutic agents. Manifestations of such toxicity include ECG abnormalities, ventricular and atrial arrhythmias, sudden death, and congestive heart failure. There is little or no cumulative dose effect. Hypokalemia may be a risk factor for development of serious tachyarrhythmias, but such problems can occur despite a normal serum potassium level. Amsacrine appears to affect depolarization and repolarization of the heart, but the mechanism is unknown.

[A new drug and current strategy in the treatment of acute non-lymphocytic leukemia in adults].

Among new drugs being studied currently, AMSA and mitoxantrone have shown significant usefulness against acute non-lymphocytic leukemia in adults. Remission induction therapy consisting of daunomycin and cytosine arabinoside has been commonly selected as the first line of treatment and the complete remission rate obtained has exceeded 70%. Postremission therapy consolidation has been judged to be necessary while the clinical roles of maintenance and intensification remain to be clarified and appear to still require an investigational approach.