Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: CAS:80841-48-1 (CI-921)
 43 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Comparison of the cytotoxicity of amsacrine and its analogue CI-921 against cultured human and mouse bone marrow tumour cells. 213 78

Murine P388 (P) leukemia cell lines resistant to amsacrine (P/AMSA), dactinomycin (P/DACT), and doxorubicin (P/DOX) were compared with the parental strain in their sensitivity to a number of derivatives of amsacrine. The P/DACT cell line, which shows the characteristics of a transport-mediated multidrug-resistant cell line, was cross-resistant to vincristine, doxorubicin, etoposide, and a number of acridine-substituted amsacrine derivatives, but was sensitive in vitro and in vivo to amsacrine and its analog CI-921. The P/DOX cell line was cross-resistant to amsacrine but showed a similar pattern of cross-resistance to that of P/DACT in its in vitro response to amsacrine derivatives. In contrast, the P/AMSA line was substantially cross-resistant (from 27- to 146-fold) to all acridine-substituted amsacrine derivatives. However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome. Derivatives with low cross-resistance ratios were tested in vivo against the P/AMSA leukemia and, in contrast to amsacrine and CI-921, were found to be active. Since the target enzyme for amsacrine action, topoisomerase II, is thought to be structurally modified in the P/AMSA line as well as in some other multidrug-resistant lines, these results suggest the feasibility of tailoring topoisomerase II-directed drugs specifically for the altered enzymes in resistant cells. New drug design approaches are therefore available for overcoming two major types of multidrug resistance.
 ...
PMID:Design of DNA intercalators to overcome topoisomerase II-mediated multidrug resistance. 215 84

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.
 ...
PMID:Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs. 256 Oct 99

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316) is a chemically novel antitumour agent which is thought to interact with DNA topoisomerase II and which has DNA binding properties which are distinct from other acridine derivatives such as amsacrine and its disubstituted analogue CI-921. AC is one of the most active agents, experimental or clinical, against the Lewis lung carcinoma in mice. AC is the first acridine derivative in our hands to show higher activity against cultured Lewis lung cells than against leukaemia lines. AC is more active against two human leukaemia cell lines (U-937 and Jurkat) than against a melanoma line (MM-96) and is inactive against the HT-29 human colon line. With all cell lines tested, cytotoxicity was higher at AC concentrations of 3-6 microM than at 15-20 microM. AC at a concentration of 20 microM inhibited the cytotoxicity of amsacrine and CI-921, but not that of another topoisomerase-directed drug doxorubicin. A Lewis lung line which had been cultured for a long period was less sensitive than a line freshly isolated from mice, but sensitivity of the cultured line recovered after it was multiply passaged in vivo. Long-term cultures may therefore be less appropriate than short-term cultures for predicting effectiveness of AC in vivo.
 ...
PMID:Selectivity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide towards Lewis lung carcinoma and human tumour cell lines in vitro. 270 82

Antitumor activity against the Lewis lung carcinoma in mice is reported for the series of 36 acridine-substituted derivatives of the antileukemia agent amsacrine. This series is the one from which the analogue N,5-dimethyl-9-[(2-methoxysulfonylamino)phenylamino]-4-acridinecarboxamide (CI-921), presently in clinical trial, was chosen. The analogues also were tested in vitro by comparing growth inhibition data [IC50 values (concentration required to reduce growth of cultured cells to 50% of that of untreated cultures)], using L1210 murine leukemia cells and HCT-8 human colon carcinoma cells. Determined IC50 values were highly dependent on the culture medium used, and it was found that the presence of ascorbate in the medium had a major effect on the stability of compounds to oxidation. A survey of 115 analogues of amsacrine indicates that a low ratio of IC50 values (HCT-8/L1210) is necessary but not sufficient for good antitumor activity against the solid tumor. DNA binding constants did not in themselves predict activity, although they were related to dose potency. Other factors, such as drug lipophilicity, acridine base strength, and drug solubility, also are involved, probably in providing effective drug distribution. It is concluded that in vitro assay data provide information useful for drug design but that other factors also are important for in vivo activity.
 ...
PMID:Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma. 334 11

A number of new anilino ring variants of the anti-tumour drug amsacrine have been synthesised and their anti-tumour activity evaluated. In vitro selectivity, as measured by the logarithmic ratio of IC50 growth inhibition assays against P388 leukaemia and Lewis lung carcinoma cells, was significantly correlated with the increase in life span in vivo with the P388 leukaemia and Lewis lung lines, whereas the growth inhibition IC50 values alone correlated with the dose potency in mice. It was thus possible to predict both in vivo anti-tumour activity and dose potency, identifying compounds with high therapeutic activity, using a combination of two in vitro assays. Two new compounds have been identified which provide, along with an acridine-substituted analogue of amsacrine which is at present in clinical trial (CI-921), a high proportion of cures against the Lewis lung tumour in vivo. Since amsacrine is thought to interact with the enzyme topoisomerase II, and because the anilino group of 9-anilinoacridine derivatives is thought to project from the DNA intercalation site of the drug-DNA complex, these compounds may be of particular interest in mode of action studies.
 ...
PMID:In vitro and in vivo assessment of activity of new anilino-substituted analogues of amsacrine against Lewis lung carcinoma. 345 Feb 94

The activity of several clinical agents (5-fluorouracil, methotrexate, adriamycin, daunorubicin, mitoxantrone and amsacrine) and of a number of analogues of amsacrine, including the 4-methyl,5-(N-methyl)carboxamide derivative (CI-921) which is at present in clinical trial, has been compared in vivo against Lewis lung carcinoma (LL) and P388 leukaemia in mice, and against corresponding cell lines in cell culture. All derivatives were active against i.p. inoculated P388 leukaemia whereas only some were active against i.v. inoculated LL cells. The relative in vitro activities in the two cell lines, as measured by growth inhibition (IC50) assays, varied from equitoxic to 26-fold more active with P388 cells than with LL cells. The in vivo activity of these drugs against i.v. inoculated LL relative to i.p. inoculated P388 could be predicted with a high degree of significance from the ratio of in vitro activities in the 2 cell lines. However, this correlation did not appear to reflect cell line selectivity alone, since, when P388 cells were inoculated i.v. rather than i.p., drug sensitivity closely matched that of the LL tumour. This observation suggests a dominant role for pharmacological variables in determining the in vivo activity of amsacrine analogues, and underlines the importance of standardising tumour site in the determination of antitumour spectrum. Nevertheless, the correlation of selective in vitro toxicity for cultured LL cells with high activity against remotely implanted tumours demonstrates the utility of in vitro tests in identifying amsacrine analogues with improved clinical potential.
 ...
PMID:Comparison of in vivo and in vitro drug sensitivities of Lewis lung carcinoma and P388 leukaemia to analogues of amsacrine. 365 85

Eight human haematopoietic cell lines and four human carcinoma lines were used to compare the activity of a number of cytotoxic drugs including amsacrine, the amsacrine analogue CI-921, methotrexate, nitracrine, doxorubicin, daunorubicin and 5-fluorouracil. Activity was assessed by means of semiautomated microculture growth inhibition assays. Cell density of the non-adherent cell lines was measured using the technique of Mosmann (J Immunol Methods 1983, 65, 55-63), in which the dye thiazolyl blue (MTT) is metabolised to a dark blue formazan product. This technique gives similar results to those obtained by direct cell counting in an electronic cell counter, and when applied to some adherent cell lines gives similar results to those obtained by the methylene blue staining technique previously developed (Anal Biochem 1984, 139, 272-277). Both methylene blue and MTT methods were used to investigate cytotoxicity in conjunction with semi-automated 96-well microculture plate techniques. The results show that the three T-cell leukaemia lines (CCRF-CEM, Jurkat and MOLT-4) are more sensitive to DNA-binding drugs (excluding nitracrine) than are the colon carcinoma lines (HCT-8, HT-29, SW480 and SW620). The more resistant haematopoietic lines are intermediate in drug sensitivity between the T cell leukaemia and carcinoma lines. The DNA binding drugs show remarkably similar patterns of differential activity against the different cell lines.
 ...
PMID:Comparison of in vitro activity of cytotoxic drugs towards human carcinoma and leukaemia cell lines. 375 82

The 4-methyl-5-(N-methyl)carboxamide derivative (CI-921; NSC 343499) of the clinical antileukaemia agent amsacrine is highly active towards P388 leukaemia and Lewis lung carcinoma in mice. When administered intraperitoneally at the optimal schedule and dose, CI-921 provided 5/650-day survivors in leukaemic mice and 10/11 60-day survivors in mice previously inoculated intravenously with Lewis lung cells. An intermittent (every 4 days X 3) schedule was superior to single dose, daily X 5 or daily X 9 schedules. Although intraperitoneal dosage was superior to intravenous or oral dosage for the treatment of intraperitoneally inoculated P388 leukaemia, all three routes of administration provided similar results with intravenously inoculated Lewis lung or subcutaneously implanted P388 cells. Daily intraperitoneal dosage schedules provided sharper dose-response relationships than intermittent schedules, and with daily schedules 1.5-fold rather than 2-fold dose increments were necessary for reliable detection of activity against Lewis lung carcinoma.
 ...
PMID:Schedule dependence of activity of the amsacrine analogue CI-921 towards P388 leukaemia and Lewis lung carcinoma. 384 Oct 68

CI-921, the 5-methyl-4-carboxamide analog of amsacrine, in combination with cisplatin produced a 6-fold better cell kill in vitro than expected based on additive effects. The combination of CI-921 and cisplatin was subsequently evaluated in three in vivo model systems: intraperitoneally (TP) and intravenously (IV) implanted P388 leukemia, and advanced stage subcutaneously (SC) implanted LC-12 squamous cell carcinoma. All drug treatments were administered IP on an intermittent treatment schedule which was optimal for both agents. Combination therapy was superior to therapy with the best single agent alone, CI-921, in all three model systems. Against IP implanted P388 leukemia, combination therapy produced greater than 8 logs of net tumor cell kill with 60-day survivors (cures). This level of activity was 50-fold greater (1.7 log) than that obtained with CI-921 alone. An IV implant of P388 leukemia was used in a confirmatory study to provide a more rigorous evaluation against disseminated disease. Combination therapy against IV implanted P388 leukemia produced greater than 7.7 logs of net tumor cell kill, which was 630-fold greater (2.8 logs) than that obtained with CI-921 therapy alone. Against advanced stage LC-12 (200-1000 mg tumors at initial treatment), combination therapy improved tumor cell kill by 0.6 log (4-fold) over that obtained with CI-921 therapy alone and also produced greater numbers of 120-day survivors than did single agent therapy with CI-921. The combination of carboplatin and CI-921 was also evaluated against IV implanted P388 leukemia to determine if the enhanced therapeutic effect of CI-921 and cisplatin could be extended to include CI-921 and carboplatin. Combination therapy with CI-921 and carboplatin increased net log tumor cell kill by 0.8 and 1.5 log in two separate tests (6- and 32-fold, respectively) over that obtained with CI-921 therapy alone. The data indicate that combination therapy with CI-921 and platinum containing anticancer agents may have clinical application.
 ...
PMID:Enhanced therapeutic effect of amsalog (CI-921) in combination with cisplatin in vitro and in vivo. 2159 29


1