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PubMed1992

Relative activity of structural analogues of amsacrine against human leukemia cell lines containing amsacrine-sensitive or -resistant forms of topoisomerase II: use of computer simulations in new drug development.

Anilino analogues of amsacrine showed increased activity against amsacrine (AMSA)-resistant cell lines when compared with the parent compound, but the mechanisms of amsacrine resistance in these lines were unknown (Finlay, G. J., Baguley, B. C., Snow, K., and Judd, W., J. Natl. Cancer Inst., 82: 662-667, 1990). We tested the cytotoxic and DNA-cleaving activities of two amsacrine analogues which were derivatives of 9-anilinoacridine (1'-methylcarbamate and 1'-benzenesulfonamide) against an amsacrine-resistant human leukemia cell line (HL-60/AMSA) whose resistance is due to an amsacrine-resistant topoisomerase II. Neither agent could overcome the amsacrine resistance of HL-60/AMSA. Neither agent could induce HL-60/AMSA topoisomerase II-mediated cleavage of DNA in an isolated biochemical system, although at high concentrations the two analogues could inhibit HL-60/AMSA topoisomerase II-mediated DNA strand passage. Both analogues were at least as active, if not more active, than amsacrine against amsacrine-sensitive HL-60 and its topoisomerase II. Comparison of the cellular and biochemical results with those from computer simulation of the energy-minimized structures of amsacrine, its inactive isomer o-AMSA, and the two new active analogues suggests the following possibilities: (a) the positioning of the potential topoisomerase II-binding site (1'-anilino group) of the two new drugs resembles the positioning of this site in amsacrine; (b) the HL-60 topoisomerase II has a binding site which interacts with amsacrine and the two anilino analogues but not with o-AMSA, an analogue with altered positioning of the methoxy group; (c) the HL-60/AMSA topoisomerase II interacts with reduced affinity with amsacrine and the two anilino analogues, although HL-60/AMSA topoisomerase II still interacts with the structurally distinct topoisomerase II-reactive nonintercalator, etoposide; (d) because of their higher DNA binding affinity or the greater possible positions of their side groups in comparison to amsacrine, the two analogues can, at high concentrations, inhibit the strand-passing activity of HL-60/AMSA topoisomerase II.

Amsacrine↗

PubMed1997

A carbamate analogue of amsacrine with activity against non-cycling cells stimulates topoisomerase II cleavage at DNA sites distinct from those of amsacrine.

AMCA (methyl N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), an amsacrine analogue containing a methylcarbamate rather than a methylsulphonamide side chain, contrasts with amsacrine, doxorubicin and etoposide in its relatively high cytotoxicity against non-cycling tumour cells. AMCA bound DNA more tightly than amsacrine, but the DNA base selectivity of binding, as measured by ethidium displacement from poly[dA-dT].[dA-dT] and poly[dG-dC].[dG-dC], was unchanged. AMCA-induced topoisomerase cleavage sites on pBR322, C-MYC and SV40 DNA were investigated using agarose or sequencing gels. DNA fragments were end-labelled, incubated with purified topoisomerase II from different mammalian sources and analysed after treatment with sodium dodecylsulphate/proteinase K. AMCA stimulated the cleavage activity of topoisomerase II, but the DNA sequence selectivity of cleavage was different from that of amsacrine and other topoisomerase inhibitors. It was similar to that of the methoxy derivative of AMCA, indicating that the changed specificity resulted from the carbamate group rather than from the methoxy group. The pattern of DNA cleavage induced by AMCA was similar for topoisomerase II alpha and II beta.

Amsacrine↗

PubMed1990

Disposition of amsacrine and its analogue 9-([2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921) in plasma, liver, and Lewis lung tumors in mice.

9-([2-Methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921), an analogue of the clinical antileukemia drug amsacrine with improved solid tumor activity in mice, is currently being evaluated in patients. In order to determine whether CI-921 possesses any advantages over amsacrine in terms of tissue delivery, the pharmacokinetics of amsacrine and CI-921 were determined following i.v. injection in male B6D2F1 mice. Plasma kinetics in normal mice were measured following administration of 14.4, 28.9, and 57.7 mumol/kg. The kinetics in s.c. Lewis lung tumors, and in plasma and livers of normal and tumor-bearing mice were measured following administration of 57.7 mumol/kg. CI-921 and amsacrine were quantitated by high-performance liquid chromatography after extraction from plasma and from liver and tumor homogenates. In experiments with appropriate 3H-labeled compounds, both total and covalently bound radioactivity (determined after precipitation and washing with acetonitrile) were measured in plasma and in liver homogenates. Over this dose range, nonlinear kinetics were observed in plasma for unchanged CI-921 and amsacrine, and a reasonable fit was obtained with Michaelis-Menten kinetics to a one-compartment model for CI-921 (Km 3.7 mumol/liter; Vmax 18 mumol/h/kg; V ss 3.3 liter/kg) and a two-compartment model for amsacrine (Km 3.6 mumol/liter; Vmax 76 mumol/h/kg; Vss 4.8 liter/kg). The area under the concentration-time curve (AUC) for plasma following a dose of 57.7 mumol/kg was 31 mumol.h/liter for CI-921 and 6.3 mumol.h/liter for amsacrine. However, equilibrium dialysis measurements indicated high plasma protein binding with free drug fractions for CI-921 and amsacrine of 0.63 and 6.7%, respectively. In the liver, unchanged drug concentrations and total radioactivity for both compounds were approximately 10-fold those in plasma, and the tissue half-life of CI-921 was approximately 4-fold longer for CI-921 than for amsacrine. Plasma and liver kinetics in mice with s.c. Lewis lung tumors were similar to those in normal mice. Tumor half-lives of unchanged CI-921 and amsacrine were 3.9 and 2.7 h, respectively, considerably longer than those for plasma (1.2 and 0.30 h respectively) or liver (1.2 and 0.28 h, respectively). Tumor AUC values for CI-921 and amsacrine were 68 and 37 mumol.h/liter, respectively, as compared to the calculated AUC values for free drug in plasma of 0.19 and 0.42 mumol.h/liter, respectively. It is concluded that the uptake into tumors from the plasma free drug fraction is more efficient for CI-921 than for amsacrine.

Amsacrine↗

PubMedDate not supplied

Review of amsacrine, an investigational antineoplastic agent.

The pharmacology, chemistry, pharmacokinetics, clinical studies, and adverse effects of amsacrine, an investigational antineoplastic agent, are reviewed. Amsacrine's mechanism of action is not clearly understood, although the drug is known to inhibit DNA synthesis. As an investigational NCI "Group C" agent, amsacrine is available to physicians for the treatment of adult patients with refractory acute nonlymphocytic leukemia (ANLL) under an established protocol. Following intravenous administration, amsacrine has a biphasic plasma clearance. It is extensively metabolized by the liver to inactive compounds that are excreted in the bile. Phase I studies indicated that amsacrine was potentially effective in patients with solid tumors and acute leukemias. Patients with solid tumors could tolerate much lower doses of amsacrine than leukemia patients because of dose-limiting bone-marrow suppression in the former. In Phase II studies, amsacrine appeared effective in treating the acute leukemias, with response rates of 31% and 23% for acute lymphocytic leukemia and ANLL, respectively. Patients with other types of cancers have not responded to amsacrine therapy. Frequently occurring adverse effects of amsacrine include leukopenia and thrombocytopenia in patients with solid tumors; nausea, vomiting, and diarrhea; mucositis in patients receiving higher doses (leukemia patients); alopecia; hepatotoxicity; and phlebitis. The clinical usefulness of amsacrine appears limited to treatment of the acute leukemias. Studies of combination therapies that include amsacrine are currently underway and should further define the therapeutic role of amsacrine.

Aminoacridines↗

PubMed1999

Inhibition of the action of the topoisomerase II poison amsacrine by simple aniline derivatives: evidence for drug-protein interactions.

The action of the anticancer drug amsacrine appears to involve molecular interactions with both DNA and topoisomerase II. It has been shown previously that DNA intercalators can inhibit the action of amsacrine and several other topoisomerase II poisons, presumably as a result of interference with the DNA binding sites for the enzyme. We show here that drug molecules such as N-phenylmethanesulfonamide, which mimic the anilino side chain of amsacrine, inhibit the cytotoxicity against cultured Lewis lung murine carcinoma of amsacrine, amsacrine analogues including asulacrine and DACA (N-[2-(dimethylamino)-ethyl]acridine-4-carboxamide dihydrochloride), and etoposide. In contrast, the cytotoxicity of doxorubicin was slightly increased by co-incubation with N-phenylmethanesulfonamide. The cytotoxicity of amsacrine was also modulated in human Jurkat leukemia, HCT-8 colon, and HT-29 colon cell lines. Because o-AMSA, an amsacrine analogue containing a methoxy group in the ortho rather than in the meta position, is known to be inactive as an antitumor drug, the abilities of the ortho and meta methoxy-substituted derivatives of methyl-N-phenylcarbamate to reverse the cytotoxicity of amsacrine, asulacrine, and DACA were compared. The ortho substitution decreased activity while meta substitution slightly increased it, suggesting that the side chains were binding to a similar site to that occupied by amsacrine. To determine whether the side chain variants actively inhibited the formation of DNA-topoisomerase II covalent complexes, cultured cells were treated with amsacrine or asulacrine, harvested, and lysed directly on acrylamide gels before electrophoresis and Western blotting to identify non-DNA-bound topoisomerase II. Extractable topoisomerase II was depleted in cells incubated with amsacrine but partially restored by coculture with methyl-N-phenylcarbamate. The findings are consistent with the hypothesis that low molecular weight molecules can modulate the effects of topoisomerase II poisons by directly interacting with the enzyme.

Amsacrine↗

PubMed1992

Oxidative metabolism of amsacrine by the neutrophil enzyme myeloperoxidase.

Oxidative metabolism of the anti-cancer drug amsacrine 4'-(9-acridinylamino) methane-sulphan-m-anisidide has been suggested to account for its cytotoxicity. However, enzymes capable of oxidizing it in non-hepatic tissue have yet to be identified. A potential candidate, that may be relevant to the metabolism of amsacrine in blood and its action in myeloid leukaemias and myelosuppression, is the haem enzyme myeloperoxidase. We have found that the purified human enzyme oxidizes amsacrine to its quinone diimine, either directly or through the production of hypochlorous acid. In comparison, the 4-methyl-5-methylcarboxamide derivative of amsacrine, CI-921 9-[[2-methoxy-4[(methylsulphonyl)-amino]phenyl]amino)-N, 5-dimethyl-4-acridine carboxamide, reacted poorly with myeloperoxidase, although it was oxidized by hypochlorous acid. Detailed studies of the mechanism by which myeloperoxidase oxidizes amsacrine revealed that the semiquinone imine free radical is a likely intermediate in this reaction. Oxidation of amsacrine analogues indicated that factors other than their reduction potential determine how readily they are metabolized by myeloperoxidase. Both amsacrine and CI-921 inhibited production of hypochlorous acid by myeloperoxidase. CI-921 acted by trapping the enzyme as the inactive redox intermediate compound II. Amsacrine inhibited by a different mechanism that may involve conversion of myeloperoxidase to compound III, which is also unable to oxidize Cl-. The susceptibility of amsacrine to oxidation by myeloperoxidase indicates that this reaction may contribute to the cytotoxicity of amsacrine toward neutrophils, monocytes and their precursors.

Amsacrine↗

PubMed1991

Effects of amsacrine in combination with other anticancer agents in human acute lymphoblastic leukemia cells in culture.

Effects of amsacrine in combination with other anticancer agents at ID80 were evaluated by cell growth assay using a human T-cell leukemia cell line (MOLT-3). The data were analyzed with the aid of an improved isobologram, using the concept of an envelope of additivity. A supra-additive effect was observed for amsacrine in combination with cytosine arabinoside and mitoxantrone. An additive effect was observed in its combinations with bleomycin, CPT-11, cisplatin, daunorubicin, doxorubicin, etoposide, 5-fluorouracil, homoharringtonine, mitomycin C, or vincristine. 6-Mercaptopurine had an additive effect with amsacrine at ID80 but a sub-additive to protective effect at ID90. A sub-additive to protective effect was shown for amsacrine in combination with methotrexate. These data suggest that cytosine arabinoside and mitoxantrone are the best of the anticancer agents we studied for use in combination with amsacrine. Bleomycin, cisplatin, CPT-11, doxorubicin, cytosine arabinoside, homoharringtonine, mitomycin C, and vincristine also yielded favorable results when administrated simultaneously with amsacrine. Simultaneous administration of amsacrine with 6-mercaptopurine and methotrexate is not appropriate. If amsacrine is combined with 6-mercaptopurine and methotrexate, other suitable schedules should be explored. These results may provide a rationale for the design of clinical protocols combining amsacrine with other anticancer agents.

Amsacrine↗

PubMed1988

Involvement of glutathione in the metabolism of the anilinoacridine antitumour agents CI-921 and amsacrine.

4'-(9-Acridinylamino)methanesulphon-m-anisidide (amsacrine) and CI-921, the 4-methyl-5-(N-methyl-carboxamide) derivative of amsacrine, are two anilinoacridine antitumour agents in clinical use or trial. The elimination of these agents has been investigated in male BDF1 mice. 74% and 86% of the dose of [acridinyl-G-3H]-amsacrine and -CI-921, respectively, was excreted in the faeces of mice by 72 hr after i.v. injection. Administration of both compounds also resulted in significant depletion of glutathione (GSH) in mouse liver, although the effect of CI-921 was delayed and reduced compared with amsacrine. In mouse bile, radiolabelled products which cochromatographed with amsacrine GSH conjugates at both the 5'- and 6'-positions of the anilino ring were present in similar amounts and constituted approximately 70% of the excreted radioactivity, the balance being minor, more polar metabolites. With hepatic microsomal fractions, both conjugates of amsacrine were formed but only the 6'- and not the 5'-conjugate was increased in the presence of cytosol. Preliminary evidence indicates the presence in mouse bile of at least the 5'-GSH conjugate of CI-921, and several other GSH derived products not seen with amsacrine. It is concluded that the elimination of CI-921 occurs by a mechanism similar to that of amsacrine. Further, the possible involvement of GSH transferase in the conjugation of amsacrine may have consequences for the hepatotoxicity of this agent.

Amsacrine↗

PubMed1986

The effect of buthionine sulphoximine, cimetidine and phenobarbitone on the disposition of amsacrine in the rabbit.

Evidence suggests that the main elimination pathway for amsacrine is hepatic oxidation to the quinone diimine derivative followed by conjugation with glutathione (GSH) and excretion in the bile. If this is so, amsacrine elimination should be susceptible to induction by phenobarbitone (PB) and inhibition by cimetidine (CT) and perhaps by buthionine sulphoximine (BSO), a specific depleter of tissue GSH. This study was carried out in groups of six rabbits. Each rabbit acted as its own control and received pretreatment with saline or PB, CT, or BSO, followed by an amsacrine infusion. Blood (8 X 3 mL) was collected up to 12 h and total plasma amsacrine concentrations determined by HPLC. PB pretreatment resulted in a significant increase in amsacrine's Cl (mean 46%, range 25%-70%) and also in the Vd (mean 58%, range 25%-117%), but had no effect on t1/2 alpha, t1/2 beta or MRTni. In addition, there was no change in the plasma protein binding of amsacrine after PB pretreatment. CT pretreatment had the opposite effect, resulting in a significant decrease in amsacrine's Cl (mean 33%, range 21%-38%) and a decrease in Vd, although this latter decrease was not significant at the 5% level. As with PB, the time parameters were not significantly changed. BSO pretreatment resulted in a significantly reduced Cl (mean 22%, range 15%-30%), no effect on Vd or on t1/2 alpha, but significantly prolonged t1/2 beta and MRTni. BSO pretreatment was also associated with a significant reduction in red blood cell GSH concentration. These results are consistent with the involvement of the hepatic mixed function oxidase system and GSH status in the elimination of amsacrine in the rabbit.

Amsacrine↗

PubMed1990

The possible role of electron-transfer complexes in the antitumour action of amsacrine analogues.

Amsacrine is a DNA intercalating agent which is active against a number of tumours in mice and is used for the treatment of leukaemia in humans. In its DNA-bound form, amsacrine efficiently quenches the fluorescence of ethidium. Fluorescence lifetime studies demonstrate two populations of DNA-bound ethidium. The first, whose fluorescence lifetime is constant at approx. 3 ns and whose proportion increases with increasing amsacrine binding ratio, may comprise molecules bound in close proximity to amsacrine. The second, whose fluorescence lifetime is longer and variable (10-24 ns) and whose proportion decreases with increasing amsacrine binding ratio, may comprise molecules three or more base-pairs away from ethidium. Studies with a number of derivatives of 9-anilinoacridine containing different anilino substituents suggest that the observed wide variation in quenching capacity is correlated with the magnitude of the substituent dipole moment in a particular direction. Consideration of the geometry of the DNA-binding complex indicates that the negative pole of a dipole established in the anilino ring is directed towards a positively charged site on the ethidium molecule. Quenching of ethidium fluorescence may therefore occur where an electron-transfer complex has formed between ethidium and amsacrine molecules. To ascertain whether electron-transfer complex formation is biologically important in the amsacrine series, ethidium quenching has been quantitated and compared with activity against a transplantable neoplasm in mice, the Lewis lung carcinoma. Compounds which strongly quench ethidium fluorescence are in general highly active antitumour agents. The results are discussed in terms of a model where amsacrine has both a DNA-binding and a protein-binding domain, the latter possibly interacting by formation of an electron-transfer complex. The most likely protein-binding domain is on the enzyme topoisomerase II, the target for its cytotoxic activity.

Amsacrine↗

PubMed1997

Cellular responses to methyl-N-[4-9-acridinylamino)-2-methoxyphenyl] carbamate hydrochloride, an analogue of amsacrine active against non-proliferating cells.

The acridine derivative m-AMCA (methyl-N-[4-(9-acridinylamino)-2-methoxyphenyl]carbamate hydrochloride), a carbamate analogue of the topoisomerase II poison amsacrine, is distinguished by its high cytotoxicity against non-cycling tumour cells. We compared the response of cultured Lewis lung carcinoma cells to m-AMCA, amsacrine and the topoisomerase I poison camptothecin. The DNA polymerase inhibitor aphidicolin reversed the cytotoxicity of camptothecin fully, that of amsacrine partially, and that of m-AMCA minimally. The ability of m-AMCA to induce the enzyme poly(ADP-ribose)polymerase (PARP) was markedly lower than that of camptothecin or amsacrine. Cell cycle responses to m-AMCA and amsacrine were similar, with slowing of progress through S-phase and arrest in G2-phase. These cell cycle changes were also observed when plateau phase cultures were exposed to drug for 1 h, washed free of drug and cultured in fresh medium, with m-AMCA having a more pronounced effect than amsacrine and camptothecin having no effect. We also examined the role of p53 protein in the response using cultured human H460 cells. Both m-AMCA and amsacrine induced p53 protein expression in proliferating but not in non-proliferating H460 cells, and induced p21WAF1 regardless of proliferation status. Both induced G1-phase cell cycle arrest. It is suggested that two cytotoxicity mechanisms can be distinguished using these drugs. The first is specific for S-phase cells, is reversed by aphidicolin and induces PARP activity. The second is cell cycle non-specific, does not induce PARP and is unaffected by aphidicolin. Camptothecin activates only the first, m-AMCA primarily the second and amsacrine activates both.

Amsacrine↗

PubMed1986

Comparison of the pharmacokinetics and protein binding of the anticancer drug, amsacrine and a new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenyl-amino] -4-acridinecarboxamide in rabbits.

Amsacrine (NSC 249 992) is a new anticancer drug which, although effective for the treatment of various disseminated tumors, has shown disappointing activity against most solid tumors. A new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino] -4-acridine-carboxamide (CI-921, NSC 343 499) has been identified, which might offer a broader clinical antitumor spectrum. This analogue is more lipophilic (0.5 log p units) and is also a considerable weaker base (pKa 6.40) than amsacrine (pKa 7.43). This study compared the pharmacokinetics of total and unbound amsacrine and CI-921 in plasma after equimolar dose infusions (12.7 mumol/kg) in a balanced crossover design in six rabbits. Drug concentrations were determined by high-pressure liquid chromatography and the unbound fraction by equilibrium dialysis. Threefold higher total plasma concentrations were achieved with CI-921 than with amsacrine. However, the unbound fraction was significantly less for CI-921 (0.33% +/- 0.04) than for amsacrine (2.78% +/- 0.53). There was no significant difference between distribution and elimination half-life and mean residence time, but the apparent volume of distribution (means, 121 vs 45 l/kg) and clearance (means, 46.6 vs 16.3 l h-1 kg-1) of unbound CI-921 were threefold greater than the corresponding parameters for unbound amsacrine. We suggest that despite higher binding in plasma, the greater distribution or tissue uptake of CI-921 may be partly responsible for its greater anticancer activity in vivo.

Aminoacridines↗

PubMed1985

Pharmacokinetics of amsacrine in patients receiving combined chemotherapy for treatment of acute myelogenous leukemia.

The pharmacokinetics of amsacrine have been studied after the first and third infusions (200 mg . m-2) in 10 patients receiving combined chemotherapy for the treatment of acute myelogenous leukaemia (AML). Postinfusion amsacrine elimination was best described by a biexponential expression with a mean t1/2 alpha of 0.8 h and a terminal t1/2 beta of 5.3 h. After the third infusion there was a significant reduction (P less than 0.05) in the plasma clearance (Cl) and a prolongation of the terminal half-life (t1/2 beta) (P less than 0.01), but no change in the initial half-life (T1/2 alpha) or volume of distribution (Vd). No significant overall changes were recorded in any of the biochemical indices of renal or hepatic function between the first and third infusions, but the patient who exhibited the largest reduction in Cl showed a marked increase in AST levels and a reduction in albumin concentration. Two distinct groups were apparent after the first infusion, patients with a Cl greater than 294 and those with a Cl less than 208 ml . h-1 . kg-1. The latter patients were significantly older (P less than 0.05), and four of the five had subnormal albumin concentrations. Urinary determination of amsacrine indicated that renal elimination plays a minor role in the total clearance of this drug. Amsacrine was also found to be highly bound to plasma proteins (96.4%-97.7%), but changes in binding were not responsible for the reduced Cl and prolonged t1/2 beta observed between the first and third infusions. We suggest that the elimination of amsacrine may be susceptible to small changes in hepatic function, perhaps due to the high amsacrine concentrations (5-18 mumol . l-1) achieved with this regimen, which may be approaching saturation of the capacity for hepatic elimination.

Adult↗

PubMed1991

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Adolescent↗

PubMed1987

Electron donor properties of the antitumour drug amsacrine as studied by fluorescence quenching of DNA-bound ethidium.

The effect of the antitumour acridine derivative amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide] on the fluorescence lifetime of DNA-bound ethidium has been investigated using a synchronously pumped cavity dumped dye laser producing picosecond pulses for sample excitation and a time-correlated single photon counting detection system. As the proportion of DNA-bound amsacrine on the synthetic DNA polymer poly[deoxyadenylic-thymidylic acid] is increased, the fluorescence decay curve of ethidium can be accurately resolved into two exponential components. The short lifetime component, whose proportion increases with increasing proportions of DNA-bound amsacrine, has a lifetime of between 3 and 4 ns, significantly longer than that of ethidium in aqueous solution (1.63 ns). The magnitude of the long lifetime component decreases from 25.4 to 14 ns with increasing proportions of bound amsacrine. It is concluded that a new fluorescence state of ethidium (lifetime 3-4 ns) is present, probably resulting from reversible electron transfer between ethidium and amsacrine. The ability of various 9-anilinoacridine derivatives to quench the fluorescence of DNA-bound ethidium appears to be related to the electron donor properties of the substituents on the anilino ring, as well as to experimental antitumour activity. The electron donor properties of DNA-bound amsacrine may therefore be relevant to its antitumour action.

Acridines↗

PubMed1990

Comparison of the cytotoxicity of amsacrine and its analogue CI-921 against cultured human and mouse bone marrow tumour cells.

Human and mouse bone marrow cells were cultured for 1 h in the presence of either the antileukaemia drug amsacrine or its 4-methyl,5-[N-methyl]carboxamide disubstituted analogue CI-921, before being plated in methylcellulose medium to determine the survival of granulocyte-macrophage colony forming units (CFU-GM). The drug concentration required for 50% reduction in survival was approx. 0.4 microM for both drugs and was similar for both human and mouse cells. A comparison of the two drugs was then made, at an added drug concentration of 0.5 microM, using cultured mouse L1210 and P388 leukaemia, Lewis lung carcinoma cell lines LLAK and LLTC, human Jurkat leukaemia, human histiocytic lymphoma U937 and human colon carcinoma SW620. The sensitivity of the mouse lines for amsacrine was in the order L1210 greater than P388 greater than LLAK greater than LLTC, similar to the in vivo sensitivity. The selectivity of CI-921 for L1210 versus bone marrow, and for LLAK versus L1210 or P388, was greater than that of amsacrine, again in keeping with its in vivo properties. The sensitivity of the human Jurkat and U937 lines for amsacrine was intermediate between that of L1210 and P388, while SW620 was resistant. The selectivity of CI-921 for Jurkat and U937 versus bone marrow was greater than that of amsacrine, suggesting that CI-921 could have additional advantages over amsacrine in the treatment of some tumours.

Amsacrine↗

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↗

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↗