Potentiation of adriamycin accumulation and effectiveness in adriamycin-resistant cells by aclacinomycin A

Tapiero, Haïm; Boulé, Dominique; Trincal, G; Fourcade, A; Lampidis, Théodore J.

doi:10.1016/0145-2126(88)90060-4

Cited by 10 publications

(6 citation statements)

References 12 publications

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“…ACM, an antineoplasic agent (Umezawa et al, 1987), has been shown to circumvent anthracycline resistance at the high dose of 10 pgml-l (Tapiero et al, 1988). Moreover, a significant synergistic effect of cytotoxicity against P388 leukaemia has been observed with the associations ACM-cyclophosphamide and ACM-vincristine (Fugimoto et al, 1979).…”

Section: Doxorubicin Resistance Reversal By Aclacinomycinmentioning

confidence: 98%

“…A previous report showed that high ACM levels (10pgrml'), in combination with DOX or daunomycin, increased the intracellular amount of the latter compounds with concomitant increased cytotoxicity against resistant cells (Tapiero et al, 1988). In this paper, we have extended these inhibition growth studies with non-toxic doses of ACM against DOX-resistant K562 cells in order to determine which kind of exposure with ACM and DOX, simultaneously or sequentially, produced the most cytotoxicity.…”

mentioning

confidence: 98%

“…Because of the rapid accumulations of ACM into sensitive and multidrug resistant lines (Seeber et al, 1980;Tapiero et al, 1988), the ACM intracellular deposition might in turn affect the DOX efflux. In contrast, another agent (forskolin) which reversed resistance to DOX, with increase of DOX cellular amounts, has virtually no effect on the rate of drug efflux (Wadler & Wiernik, 1988).…”

Section: Doxorubicin Resistance Reversal By Aclacinomycinmentioning

confidence: 99%

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Role of the aclacinomycin A – doxorubicin association in reversal of doxorubicin resistance in K562 tumour cells

Millot¹,

Rasoanaivo²,

Morjani³

et al. 1989

Br J Cancer

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Summary Acquired resistance to anthracyclines is characterised by a lower sensitivity to these agents, associated with impaired accumulation of drug. We have examined the ability of aclacinomycin A (ACM) associated with doxorubicin (DOX), to increase intranuclear DOX concentrations and, consequently, to enhance cytotoxic effects against drug resistant cells in vitro. A recently developed microspectrofluorometric technique is used to measure intranuclear DOX concentrations in sensitive and DOX-resistant K562 cells treated with DOX and ACM. Fluorescence emission spectra are collected from a microvolume of single living cell nuclei. From both DOX and ACM model fluorescence spectra (free, DNA-bound and metabolites), the intranuclear spectral profile is analysed according to the amount of each component. This quantitative analysis determines intranuclear DOX concentrations with an error of 10%. Non-cytotoxic doses of ACM, in combination with DOX, increase cytotoxic activity of DOX against K562 resistant cells. When DOX-resistant cells are exposed simultaneously to ACM and DOX, significant increases in intranuclear DOX concentrations are found compared with the case of exposure to DOX alone. The measure of the intranuclear retention of DOX shows that ACM partly blocks the DOX efflux in resistant cell nuclei, resulting in enhanced accumulation of DOX. These data lead us to conclude that ACM-DOX association partly reverses the DOX resistance at clinically achievable concentrations.A major obstacle to successful use of anthracyclines and other cytotoxic drugs in cancer chemotherapy is the development of clinical drug resistance. Tumour cell modifications (resulting in multidrug resistance) are characterised by a complex phenotype of cross-resistance to antineoplasic agents Bradley et al., 1988). These are accompanied by gene amplification, a deficient accumulation of drug, an enhanced drug efflux function and a build up of an integral membrane glycoprotein with a molecular weight of 170,000-180,000 (P-glycoprotein) . A study with DNA transfectants (Riordan et al., 1985) has demonstrated that the P-glycoprotein was intimately involved in resistance and might be serving as an active efflux pump to remove the drug from the cell. One way to overcome in vitro resistance to anti-cancer drugs has been to use simultaneously calcium channel blockers (Tsuruo et al., 1983) or calmodulin inhibitors (Ganapathi et al., 1984) together with the anti-cancer drug. The mechanism of the resistance reversal appears to be related to the inhibition of outward drug transport which subsequently leads to increased intracellular drug levels.With the recent development of microspectrofluorometry, we have studied fluorescence signals from microvolumes within a single living cell (Ginot et al., 1984;Manfait et al., 1987). DOX concentrations in nuclei of sensitive and DOXresistant K562 human leukaemia cell lines may thus be determined (Tsuruo et al., 1986;Sugimoto & Tsuruo, 1987). Cell growth and viability were determined by phase contrast microscop...

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Section: Doxorubicin Resistance Reversal By Aclacinomycinmentioning

confidence: 98%

mentioning

confidence: 98%

Section: Doxorubicin Resistance Reversal By Aclacinomycinmentioning

confidence: 99%

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Role of the aclacinomycin A – doxorubicin association in reversal of doxorubicin resistance in K562 tumour cells

Millot¹,

Rasoanaivo²,

Morjani³

et al. 1989

Br J Cancer

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“…Exhibiting relatively low levels of cross-resistance with doxorubicin and daunorubicin, 6,7 aclarubicin is a promising alternative to older anthracyclines and may be less hampered in impairing cytotoxicity by the expression of p-glycoprotein. 8,9 The topoisomerase-II inhibitor etoposide reveals substantial antileukemic efficacy as single agent with only limited toxicity 10,11 and is rarely used in first-line treatment.…”

Section: Introductionmentioning

confidence: 99%

Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial

et al. 1998

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In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m 2 /day and etoposide 100 mg/m 2 /day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia Ͻ500/ l was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

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“…Aclacinomycins A and B (Figure 1) are members of the anthracycline family of antibiotics with potent anticancer activity (Oki et al, 1981). Aclacinomycin A has been used in combination with doxorubicin to enhance the effectiveness of doxorubicin toward cancer cells which have acquired drug resistance (Millot et al, 1989;Tapiero et al, 1988). Aclacinomycin A has an antagonistic effect on DNA cleavage by topoisomerase II stimulated by daunorubicin (Jensen et al, 1991).…”

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confidence: 99%

Structure by NMR of Antitumor Drugs Aclacinomycin A and B Complexed to d(CGTACG)

Yang

Wang

1994

Biochemistry

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Aclacinomycins A and B are anthracycline antibiotics with potent antitumor activity. Each consists of an alkavinone aglycon chromophore and a trisaccharide (rhodosamine-deoxyfucose-cinerulose A or B) tail attached at the C7 of ring A of the alkavinone. The structures of the 2:1 aclacinomycin-d(CGTACG) complexes have been studied in solution by 2D NMR spectroscopy using nuclear Overhauser effect data. SPEDREF refinement procedure (incorporating simulated annealing within the program X-PLOR) was used to obtain an ensemble of refined structures which reveal that the elongated alkavinone is intercalated between the CpG steps and the trisaccharide lies in the minor groove. In the complex, the two GC Watson-Crick base pairs (C1:G12 and G2:C11) that wrap around the aglycon have large buckles, consistent with those seen in the crystal structures of other anthracycline-DNA complexes. The intercalation geometry of aclcainomycin is a hybrid between those of daunorubicin and nogalamycin. Ring D of alkavinone is sandwiched by the C1 and C11 bases. The deoxyfucose ring of the trisaccharide is close to the DNA backbone at the A4 nucleotide, forcing the DNA helix to kink toward the major groove (with the opening in the minor groove). The kink between two adjacent A-T base pairs (T3-A10 and A4-T9) causes the adenine A4N6 to form two hydrogen bonds to T9O4 (interstrand) and T3O4 (intrastrand) simultaneously. There is a small unwinding of the helix resulting from the intercalated aclacinomycin. Several potential hydrogen bonds exist between the drug and the guanine bases in the minor groove of the helix.(ABSTRACT TRUNCATED AT 250 WORDS)

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Potentiation of adriamycin accumulation and effectiveness in adriamycin-resistant cells by aclacinomycin A

Cited by 10 publications

References 12 publications

Role of the aclacinomycin A – doxorubicin association in reversal of doxorubicin resistance in K562 tumour cells

Role of the aclacinomycin A – doxorubicin association in reversal of doxorubicin resistance in K562 tumour cells

Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial

Structure by NMR of Antitumor Drugs Aclacinomycin A and B Complexed to d(CGTACG)

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