Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Amsacrine”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mutations at arg486 and glu571 in human topoisomerase IIalpha confer resistance to amsacrine: relevance for antitumor drug resistance in human cells.

Human topoisomerase II, a nuclear protein involved in chromosome segregation, is the target of amsacrine and other clinically important anticancer drugs. The enzyme is expressed as alpha and beta isoforms whose mutation/down-regulation has been implicated in drug resistance. To understand the role of target mutations in cellular drug resistance, we have used yeast to select and characterize plasmid-borne human topoisomerase IIalpha mutants resistant to amsacrine. Single point changes of Glu571 to Lys (E571K) or Arg486 to Lys (R486K) in the conserved PLRGK motif, both of which reside in the GyrB homology domain of human topoisomerase IIalpha, were frequently selected and could be shown in vivo to confer >25-fold and >100-fold resistance, respectively, to amsacrine and approximately 3-fold cross-resistance to etoposide. Highly purified E571K and R486K human topoisomerase IIalpha proteins required 100-fold higher levels of amsacrine to induce DNA cleavage similar to that of wild-type protein, consistent with a resistance mechanism involving reduced cleavable complex formation. Our functional studies of the R486K mutation, previously identified in two amsacrine-resistant human cell lines and in human biopsy material, establish unequivocally that it confers resistance, and suggest mechanisms for its phenotypic expression in vivo. These results differ significantly from previous work using yeast topoisomerase II as a model system: introduction of the equivalent mutation to R486K (R476K) into the yeast enzyme did not give amsacrine resistance. We conclude that species-specific differences in topoisomerase II enzymes can affect the drug resistance phenotype of particular mutations and highlight the need to study the relevant human homolog.

Amsacrine↗
PubMed2001

Amsacrine and cisplatin in poor prognosis patients with metastatic transitional cell carcinoma of the urothelium: a phase-II study.

OBJECTIVES: Amsacrine, as a single agent, was reported to be effective in patients with metastatic transitional cell carcinoma of the urinary bladder. Amsacrine is also associated with a lower toxicity than cyclophosphamide, doxorubicin and cisplatin therapy and has similar activity. But amsacrine has been forgotten in clinical studies of transitional cell carcinoma of the urinary bladder. The aim of present study was to investigate the toxicity and efficacy of amsacrine and cisplatin in chemotherapy-naive patients with metastatic transitional cell carcinoma of the urinary bladder. METHODS: We have treated 54 patients (41 males/13 females) with a median age of 62 (38-72) years. Performance status was 0/2, I/27 II/17 and III/8. The treatment included: amsacrine 85 mg/ m(2), days 1-2, and cisplatin 30 mg/m(2), days 2-5. Cycles were repeated every 4 weeks. We applied 169 cycles (median 3/patient). Of 54 patients, 39 had previous surgery and 12 had previous radiotherapy. Histological tumor grade was I/7, II/27 and III/20. RESULTS: 51 patients were evaluable for response (3 patients refused further treatment during the first cycle): 2 complete remission (4%); 15 partial remission (29%); 23 stable disease (45%), and 11 progressive disease (22%). The response rate was 33% (95% CI 21-46). On an intent-to-treat basis the response was 32% (95% CI 19-44). Durations of complete and partial responses were 14 (range 12-16) and 6.5 (range 3-11) months, respectively. Median survival was 9 (range 3-21) months. All patients were evaluable for toxicity. Grades III-IV toxicity was as follows: anemia 11%; neutropenia 37%, and thrombocytopenia 20%. None of the patients was excluded from the study because of toxicity. CONCLUSION: The combination of amsacrine and cisplatin is a regimen with mild and manageable toxicity. The present regimen seems to be active. Randomized study of the present regimen versus another low-toxicity regimens are necessary, especially for poor prognosis patients including those with a low performance status.

Adult↗
PubMed2000

Design of two etoposide-amsacrine conjugates: topoisomerase II and tubuline polymerization inhibition and relation to cytotoxicity.

Topoisomerase II represents the main target for the antitumour drugs etoposide and amsacrine, which are both used clinically. Previous studies have shown that the glycoside moiety of etoposide is not necessary for cytotoxicity or DNA topoisomerase II inhibition. For this reason, we designed two epipodophyllotoxin derivatives for which the dispensable sugar moiety of etoposide has been replaced by a m-methoxy-methane-sulfonamide-anilino group analogous to the topoisomerase II-targeted domain of amsacrine. We report the synthesis of the hybrid molecules that have the epipodophyllotoxin and anilino groups directly linked (ICP-114) or connected by an ethylene spacer (ICP-147). Plasmid DNA relaxation and kinetoplast DNA decatenation assays were used to evaluate the effects of the drug on the catalytic activity of human topoisomerase II. We found that the hybrid ICP-147 was significantly more potent than both etoposide and amsacrine at stimulating DNA cleavage by the enzyme, whereas the hybrid ICP-114 lacking the linker chain was less potent. ICP-147 produces approximately 3 times more double-stranded breaks than ICP-114, suggesting that an ethylene spacer between the epipodophyllotoxin and amsacrine moieties is highly effective at inhibiting topoisomerase II. Sequencing data also supported the idea that the two moieties of ICP-147 participate to the interaction with topoisomerase II-DNA covalent complexes. Both hybrid compounds are more cytotoxic than etoposide but much less toxic than amsacrine toward L1210 leukemia cells. In addition to its effect on topoisomerase II, ICP-114 can inhibit tubulin polymerization, whereas ICP-147 is almost totally inactive in this assay. The unexpected capacity of ICP-114 to interfere with the polymerization of tubulin suggests that this compound can target tubulin dimers, as it is the case with certain antitumor sulfonamides. The design of etoposide-amsacrine hybrids may thus represent an opportunity for the discovery of dual inhibitors that target both topoisomerase II and tubulin.

Amsacrine↗
PubMed1990

Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, in mice, rats, rabbits, dogs, and humans.

The aim was to investigate interspecies relationships between body weight (W) (kg) and various pharmacokinetic parameters for the anti-tumor agents amsacrine and its 4-methyl-5-(N-methylcarboxamide) analogue, CI-921, and examine which pharmacokinetic parameter, if any, might be used to predict the toxicity of these agents. Pharmacokinetic, plasma protein binding, and toxicity data were available for CI-921 in mice, rats, rabbits, dogs, and humans. For amsacrine, similar interspecies pharmacokinetic data were available but toxicity and protein-binding data were available for only 3 species. Significant linear relationships were obtained for CI-921 between log W and log Vss (liters) (r = 0.971, P = 0.006), and log W and log Cl (liters/h) (r = 0.911, P = 0.031) resulting in the allometric equations Vss = 1.22W0.68 and Cl = 0.91W0.51. For amsacrine these corresponding equations were Vss = 3.37W0.81 (r = 0.996, P less than 0.001), and Cl = 2.28W0.46 (r = 0.952, P = 0.012). When interspecies differences in plasma protein binding were taken into account, the allometric relationships improved and the exponents of the power equations increased. For CI-921 the allometric equations for the kinetic parameters calculated from plasma "free" concentrations were: Vssfu (liters) = 247W0.93 (r = 0.984, P = 0.002) and Clu (liters/h) = 186W0.76 (r = 0.961, P = 0.009). The dog was a noticeable outlier in the relationship between the log maximum tolerated dose (MTD) (mg/kg) of CI-921 and log W. Omission of the latter resulted in a highly significant allometric relationship, MTD = 23.6W-0.14 (r = -0.988, P = 0.012). For amsacrine there was no significant allometric relationship between MTD and W. CI-921s prolonged t1/2 in the dog and the dog's increased susceptibility to CI-921 toxicity suggested a relationship between MTD and t1/2 (h). A significant linear relationship was observed between in MTD and t1/2 (r = -0.994, P less than 0.001), from which the following equation was developed MTD = 47.5e-0.51t1/2 Combining the amsacrine toxicity data in the latter relationship yielded a similar equation MTD = 44.7e-0.51t1/2 (r = -0.933, P less than 0.0001). It was concluded that allometric equations may be developed for CI-921 and amsacrine from animal pharmacokinetic data which allow a reasonable prediction of Cl and Vss in patients, despite these agents being eliminated mainly by biotransformation. However, similar relationships between toxicity and body weight were susceptible to variation between individual species. Species differences in the toxicity of these agents were predictable from the t1/2. This study emphasized the importance of pharmacokinetic data in preclinical toxicity and efficacy testing of antitumor agents.

Amsacrine↗
PubMed1994

Megabase pair deletions in mutant mammalian cells following exposure to amsacrine, an inhibitor of DNA topoisomerase II.

Amsacrine, [4'-(9-acridinylamino)-methanesulfon-m-auisidide], belongs to the class of cancer chemotherapeutic agents that target DNA topoisomerase II. We show that, over its cytotoxic range, amsacrine is a potent mutagen of the S1 phenotype in the AL (human x hamster) hybrid cell line. By contrast, amsacrine induction of the HPRT- phenotype in AL cells is at least two decades less frequent and is not concentration dependent. Such differential mutation frequencies are hypothesized to reflect the concomitant loss of essential genes neighboring the hprt locus. It may be that some amsacrine cytotoxicity is due to the inactivation of essential genes by large deletions. The AL mutation system is well suited for the detection and mapping of mutations which are large deletions because its MIC1 locus, which controls the expression of the selectable cell surface antigen S1, is on a single human chromosome. This human chromosome 11 is in addition to the genome of the Chinese hamster ovary cell and is basically nonessential. Since there are no sister human chromosomes in AL cells, deletions which extend beyond the MIC1 locus may be conveniently and unambiguously mapped. We have detected the presence or absence of 9 different chromosome 11 markers in 48 S1- mutants cloned from amsacrine-treated cultures. We find that almost all (92%) of the mutants have deletions of at least 1.5-2 megabase pairs in length. The distribution of marker loss frequencies flanking the MIC1 locus does not appear symmetric with respect to distance from that locus. We speculate that amsacrine-induced deletions are mediated by a series of subunit exchanges between overlapping topoisomerase II dimers at the bases of replicons or larger chromosomal structures such as replicon clusters or chromosome minibands.

Amsacrine↗
PubMed1993

Altered phosphorylation, biosynthesis and degradation of the 170 kDa isoform of topoisomerase II in amsacrine-resistant human leukemia cells.

Resistance to amsacrine in HL-60/AMSA is 50-100 fold compared to the parental HL-60/S cells. Synthesis and phosphorylation of topoisomerase II (TOPO II) were 2-3 fold lower in HL-60/AMSA compared to HL-60/S cells metabolically labelled with [32P]-orthophosphoric acid or [35S]-L-methionine. Incubating cells in radiolabel-free media following metabolic labelling for 4 hr revealed: (a) dephosphorylation of topoisomerase II at 4 hr was 70% and 20% in HL-60/S and HL-60/AMSA cells, respectively; and (b) degradation of topoisomerase II at 4 hr was 40% and 10% in HL-60/S and HL-60/AMSA cells, respectively, while at 8 hr degradation was 80% and 50% in HL-60/S and HL-60/AMSA cells, respectively. The magnitude of topoisomerase II band depletion in immunoprecipitates of amsacrine-treated cells labelled with [35S]-L-methionine or [32P]-orthophosphoric acid, correlated with the differential amsacrine sensitivity of HL-60/S and HL-60/AMSA cells, suggesting that the amount of newly synthesized and phosphorylated topoisomerase II may be contributing to amsacrine resistance. Thus, the attenuated synthesis and phosphorylation of TOPO II in HL-60/AMSA may contribute to the resistance of these cells to amsacrine.

Amsacrine↗
PubMed1996

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model.

The purpose of this study was to fabricate and investigate amsacrine containing polymeric rods for use in interstitial chemotherapy of malignant glioma. Ethylene vinyl acetate copolymer (EVAc) rods containing 40% amsacrine (AMSA) were fabricated successfully with an extrusion method. In vitro kinetic studies revealed a high level of reproducibility of the production process. The release of AMSA showed a biphasic pattern consistent with a matrix-type controlled-release system with an initial more rapid release rate followed by a slower and more linear release phase. Release of AMSA was observed for over 6 months and the rods continue to release in a stable fashion. In vitro studies using rat glioma (RG2) in cell culture showed that cells treated with AMSA released from the rods were killed in a dose dependent manner indicating that AMSA incorporated into the polymer remained biologically active. In vivo studies of rats with single AMSA rods implanted five days after RG2 tumour implantation revealed histological evidence of an anti-tumour effect as well as an increased survival (p < 0.0003). The mean survival of the amsacrine treated rats was 78 days with 50% still remaining alive > 5 months after implantation. All control animals developed tumours and died within 15-19 days after tumour implantation (mean = 17 days). Amsacrine implanted animals showed no significant histological or clinical evidence of toxicity. We conclude that amsacrine containing EVAc rods can be safely and efficaciously use against the RG2 experimental glioma in a rat model and warrant further investigation.

Amsacrine↗
PubMed1999

Carbamate analogues of amsacrine active against non-cycling cells: relative activity against topoisomerases IIalpha and beta.

PURPOSE: Methyl N-(4'-(9-acridinylamino)-phenyl)carbamate hydrochloride (AMCA) and methyl N-(4'-(9-acridinylamino)-2-methoxyphenyl)carbamate hydrochloride (mAMCA) are analogues of the topoisomerase II (topo II) poison amsacrine, and are distinguished from amsacrine by their high cytotoxicity towards non-cycling cells. Since mammalian cells contain two forms (alpha and beta) of topo II and the alpha isoform is down-regulated in non-cycling cells, we have considered whether these carbamate analogues target topo IIbeta selectively. METHODS: A drug permeable yeast strain (JN394 top2-4) was transformed using a shuttle vector containing either human top2alpha, human top2alpha or yeast top2 under the control of a GAL1 promoter. The strain was analysed at a non-permissive temperature, where only the plasmid-borne topo II was active. RESULTS: AMCA and mAMCA produced comparable levels of cell killing with human DNA topo IIalpha, human DNA topo IIbeta and yeast DNA topo II. Two other acridine derivatives N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its 7-chloro derivative, which like AMCA and mAMCA are able to overcome multidrug resistance mechanisms, were much more active against human DNA topo IIalpha than against human DNA topo IIbeta and yeast DNA topo II. A series of mutant Chinese hamster and human lines with defined topo lesions, including the HL60/MX2 line that lacks topo IIbeta expression, was also used to compare resistance to amsacrine, AMCA and etoposide. Loss of topo IIbeta activity had a greater effect on amsacrine and AMCA than on etoposide. Resistance of murine Lewis lung cultures in exponential and plateau phase was also measured. Loss of topo IIalpha activity, as measured in both mutant cells expressing lower amounts of enzyme and in cells in plateau phase, resulted in concomitant acquisition of resistance that was greatest for etoposide and least for AMCA. CONCLUSION: We conclude that the carbamate analogues of amsacrine recognize both topo IIalpha and beta in cells.

Acridines↗
PubMed1986

Nucleic acid binding drugs--XIV. The crystal structure of 1-methyl amsacrine hydrochloride; relationships to DNA-binding ability and anti-tumour activity.

The crystal structure of the 1-methyl derivative of the anticancer drug amsacrine [4'-(acridin-9-ylamino)-3'-methoxy-methanesulphonanilide+ ++] as its hydrochloride salt has been determined. The compound crystallizes in the monoclinic space group P21/n with cell dimensions a = 15.302(3), b = 8.035(2), c = 18.258(4) A and beta = 102.68(2) degrees, and has been refined to a final R of 0.055. The acridine chromophore is significantly non-planar, with a butterfly conformation about the C(9)-N(11) bond. The bonding geometry about the C(9) atom has been significantly altered compared to non-distorted amsacrine structures, as a result of this non-planarity. Energy calculations have been used to examine the flexibility of the molecule with respect to rotations about the C(9)-N(11) and N(11)-C(12) bonds, and with respect to intercalation into a dinucleoside duplex model for DNA. The latter calculations have been compared with solution DNA-binding and in vitro activity data for 1-methyl-amsacrine hydrochloride. The molecular modelling studies find that the energy of interaction between 1-methyl-amsacrine and a DNA intercalation fragment is significantly higher than for amsacrine itself, in accord with the biological data.

Amsacrine↗
PubMed1993

Further characterization of an amsacrine-resistant line of HL-60 human leukemia cells and its topoisomerase II. Effects of ATP concentration, anion concentration, and the three-dimensional structure of the DNA target.

The characterization of type II topoisomerases from amsacrine-sensitive (HL-60) and amsacrine-resistant (HL-60/AMSA) human leukemia cells was extended. The intercalator resistance and etoposide sensitivity of the HL-60/AMSA cells themselves were confirmed, and the stability of this pharmacologic phenotype over many hundreds of cell generations was demonstrated. Prolonging exposure of HL-60/AMSA cells to amsacrine did not alter their sensitivity relative to that of HL-60 cells. Improved methods of immunoblotting allowed clear demonstration that the topoisomerase II within these cells exhibited sensitivity and resistance characteristics that mirrored those of the cells and the isolated enzymes themselves. Additional biochemical characterization of the type II topoisomerases indicated that both enzymes relaxed supercoiled DNA in a distributive fashion and that the ATP concentrations at which optimal catalytic activity of the two enzymes was exhibited were identical. The enzymes differed, however, in their activity optima in buffers of various type and ionic strength. Furthermore, the inability of the HL-60/AMSA enzyme to exhibit enhanced DNA cleavage in the presence of amsacrine could be overcome if the DNA target molecule contained a bend cloned into its polylinker region. By contrast, a bend in a DNA plasmid containing no polylinker was resistant to amsacrine-enhanced cleavage in the presence of HL-60/AMSA topoisomerase II, as was a plasmid containing a polylinker with no bend. This suggests that an unusual DNA conformation (a bend) in a specific DNA context (a polylinker) may be a favored site for topoisomerase II action. It also suggests a mechanism by which the sites and extent of topoisomerase II activity can be controlled in cells.

Adenosine Triphosphate↗
PubMed1992

Sequence specificity of the binding of 9-aminoacridine- and amsacrine-4-carboxamides to DNA studied by DNase I footprinting.

DNase I footprinting has been used to probe the sequence selectivity of binding of a series of intercalating amsacrine-4-carboxamides and a related 9-aminoacridine-4-carboxamide to three DNA restriction fragments. These ligands have good experimental antileukemic activity, and for those members of the series that gave evaluable footprints, our principal finding is that they bind preferentially to GC-rich regions in agreement with the conclusion of equilibrium and kinetic measurements. The highest affinity sites generally occur in clusters of GC base pairs with runs of AT pairs being excluded from binding. It is important to appreciate that the 9-aminoacridine- and amsacrine-4-carboxamides exhibit a very high degree of selectivity for GC sites which, to our knowledge, has not been previously matched by acridine derivatives in footprinting experiments. The principal determinant of specificity appears to be the 4-carboxamide group itself since neither variations in the terminal funtionality of the 4-carboxamide sidechain nor the presence of the 9-anilino substituent modifies sequence preferences. The molecular origins of selectivity may be discerned in terms of potential hydrogen bonding interactions between the 4-carboxamide moiety and carbonyl oxygen and amino groups of GC base pairs in the DNA minor groove at CG dinucleotide sites. The related therapeutic agent amsacrine failed to inhibit cleavage by DNase I, so no conclusion can be drawn concerning its binding selectivity, save to note that amsacrine does not possess the 4-carboxamide group which appears to be the crucial determinant of GC specificity. Whether selectivity for binding to GC-rich sequences is an important element in the antitumor activity of both the 9-aminoacridine- and amsacrine-4-carboxamides remains to be determined.

Aminacrine↗
PubMed1987

Potential antitumor agents. 48. 3'-Dimethylamino derivatives of amsacrine: redox chemistry and in vivo solid tumor activity.

Structure-activity relationships for a series of acridine-substituted 3'-N(CH3)2 derivatives of the clinical antileukemic drug amsacrine (1) are reported. The parent (unsubstituted) compound 3 has activity against the Lewis lung solid tumor that is superior to amsacrine (1), the new clinical amsacrine analogue 4, and the recently developed 3'-NHCH3 derivative 2. Although the compounds generally bind less well to DNA and are less dose potent in vivo than either their amsacrine (3'-OCH3) or 3'-NHCH3 analogues, they show very high levels of antitumor activity, with the 4-OCH3 derivative capable of effecting 100% cures of the Lewis lung solid tumor. The broad structure-activity relationships for acridine substitution more closely resemble those of the amsacrine than the 3'-NHCH3 series, with 4-substituted and 4,5-disubstituted compounds showing the highest activity.

Amsacrine↗
PubMed1984

High-dose amsacrine (AMSA) therapy of relapsed and refractory adult acute nonlymphocytic leukemia. A phase II study.

Amsacrine (AMSA) has been shown to be an effective therapeutic agent in the treatment of adult acute nonlymphocytic leukemia (ANLL). The Eastern Cooperative Oncology Group studied the efficacy and toxicity of high-dose amsacrine (200 mg/m2/day for 5 days) in 38 adult patients with refractory and relapsed ANLL. The complete remission rate was low (8%). This dose level of amsacrine caused severe mucositis in 24% of patients and marked liver function abnormalities in 11%. Seizures did not occur, and two reversible cardiac events were not clearly attributable to amsacrine administration. Escalation of amsacrine beyond currently recommended total doses of 600-750 mg/m2 is unlikely to be of benefit.

Acute Disease↗
PubMed1998

Transcriptional down-regulation of c-myc expression in an erythroleukemic cell line, K562, and its doxorubicin-resistant variant by two topoisomerase II inhibitors, doxorubicin and amsacrine.

We have evaluated the effect of two topoisomerase II (Topo II) poisons, amsacrine and doxorubicin, on the expression of the c-myc oncogene, both at the mRNA and protein levels, in the leukemia cell line, K562, and its doxorubicin-resistant counterpart, K562 DoxR. We report in this study a concentration-dependent decrease in c-myc mRNA levels upon exposure of both cell lines to amsacrine and doxorubicin, with a more pronounced effect for amsacrine in the resistant line. In either case, c-myc down-regulation closely paralleled the drug-induced growth inhibition. We have also used the technique of PCR stop-assay to detect the occurrence of DNA breaks within the P2 promoter of the c-myc gene. We have shown that Topo II-mediated breaks induced by amsacrine are probably responsible for the down-regulation of c-myc in the resistant line. In addition, amsacrine induced apoptosis only in the resistant line while doxorubicin did not induce apoptosis in any cell line. These results suggest that c-myc is not involved in the resistance of K562 DoxR cells, but can induce the apoptosis pathway in these cells, while no drug-induced apoptosis could be detected in the sensitive line.

Amsacrine↗
PubMed1986

The binding of amsacrine to human plasma proteins.

Determination of amsacrine plasma protein binding by both equilibrium dialysis and ultracentrifugation gave similar results and indicated that amsacrine is highly bound (approximately 97%) in human plasma. This binding is independent of amsacrine concentration over the range 1-100 mumol litre-1, but is very sensitive to plasma pH and, to a lesser extent, to temperature. Approximately 20% of the drug appeared to be covalently bound to plasma proteins. Amsacrine was bound by all plasma proteins investigated including albumin, alpha 1-acid glycoprotein and various gamma-globulins. The binding to albumin appeared to occur by two processes, a saturable process at a single site with a KD of 13.9 mumol litre-1 and a non-saturable process. Despite differences in individual protein concentrations, no significant difference was observed in the unbound amsacrine fraction in plasma from patients receiving this drug for treatment of acute myelogenous leukaemia and plasma from healthy individuals.

Aminoacridines↗
PubMed1986

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.

Adolescent↗
PubMedDate not supplied

Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: a phase I-II trial of the Southeastern Cancer Study Group.

The Southeastern Cancer Study Group conducted a phase I-II trial of sequentially administered 5-azacitidine and amsacrine in patients with refractory adult acute leukemia from September 1980 to March 1983. The 5-azacitidine was administered by continuous iv infusion on Days 1-4 at doses ranging from 112 to 200 mg/m2/day, while amsacrine was given at doses ranging from 75 to 150 mg/m2/day on Days 5-8. The doses of 5-azacitidine and amsacrine were alternately escalated through six dose levels during the phase I portion of the trial. Of 128 patients entered, 102 (80%) were evaluable for response. Remission was achieved in 13 of 80 evaluable patients with acute myeloid leukemia, in one of 12 evaluable patients with acute lymphoid leukemia, and in none of 11 patients with blastic transformation of chronic granulocytic leukemia. Three remissions occurred in patients with acute myeloid leukemia who were refractory to initial induction chemotherapy with cytarabine and anthracycline combination chemotherapy. Remissions were relatively durable, lasting a median of 28 weeks in the 13 patients with refractory acute myeloid leukemia (range, 14-54 weeks). Toxic effects included universal severe myelosuppression, hyperbilirubinemia at a frequency and severity similar to those seen with amsacrine used as a single agent, moderately severe stomatitis and diarrhea, three incidents of amsacrine-related cardiac dysrhythmia, and a single case of probable drug-related cardiomyopathy. This combination has activity in the treatment of myeloid leukemia, which is primarily resistant to cytarabine and anthracyclines, and could have a role in primary management.

Adolescent↗
PubMed1987

Experimental antitumor activity of the amsacrine analogue CI-921.

CI-921 is a di-substituted analogue of amsacrine currently in phase 1 clinical trial. CI-921 was developed to clinical trial largely on the basis of a series of studies at five cancer research laboratories that demonstrated its improved spectrum and degree of activity relative to those of amsacrine against murine tumor models. The tumor models studied included lung, colon, and mammary carcinomas and encompassed a wide range of biologic properties and chemosensitivities. CI-921 had significant activity against 16 of 19 (84%) tumor models examined. The activity of CI-921 was superior to that of amsacrine in 10 of 14 tumor systems that were sensitive to at least one of the agents and for which comparable data existed. In the remaining four systems, CI-921 and amsacrine were equivalent in activity. CI-921 was found to be roughly equipotent with amsacrine on a milligram-per-kilogram (body wt) basis and was found to have significantly higher activity when given orally.

Amsacrine↗