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Biomedical subjects

H Tapiero

Publications and source records attributed to H Tapiero.

At least 55 records · Page 3Linked to original sources
PubMed1988

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

Variants of Friend leukemia cells (FLC) selected for resistance to either adriamycin (ADM), daunorubicin (DNR) or aclacinomycin A (ACM) by step-wise exposure to each drug, were found to be cross-resistant to ADM and DNR but not to ACM. In addition, an epithelial cell line isolated from normal monkey kidney (CV-1) was found to be intrinsically resistant to ADM and DNR but not to ACM. In contrast, a human breast carcinoma cell line (MCF-7) was found to be sensitive to all three compounds. In these latter cell lines as well as in the FLC variants, lowered intracellular amounts of ADM and DNR correlated with resistance, but ACM levels were the same in sensitive and resistant cells. When cells with either acquired or intrinsic resistance were treated with ACM in combination with ADM or DNR, significant increases in the intracellular amounts of these latter compounds were found. Increased drug accumulation in resistant cells treated this way was accompanied by increased cytotoxicity. When resistant cells were exposed to ACM in combination with other anthracyclines, similar results were obtained. In comparison, these phenomena were not observed when either one of the sensitive cell types (parental FLC and MCF-7) were treated similarly. Since ADM and DNR resistant cells are sensitive to ACM and their resistance circumvented by ACM, this drug may have important clinical applications when used in combination with other anthracyclines.

Aclarubicin↗
PubMed1986

Cytogenetic modifications of Friend leukemia cells resistant to adriamycin.

Chromosome analysis was performed on adriamycin-sensitive and resistant Friend leukemia cells. Resistance to ADM is associated with an increased number of metacentric chromosomes. With increasing level of drug resistance additional metacentric chromosomes and several chromosomal markers were observed. Furthermore, the C-banding patterns and the heterochromatin distribution differed in resistant, as compared to sensitive cells. When sensitive cells were exposed to a toxic dose of ADM, multiple chromosomal breaks were observed in 62% of cells. In contrast, when ADM resistant cells were exposed to cytotoxic concentrations, the pulverization phenomenon was not observed and 75-80% of cells were without breaks. This striking difference suggests a different mechanism for cytotoxicity in sensitive and resistant cells.

Animals↗
PubMed1986

Reversal of intrinsic resistance to adriamycin in normal cells by verapamil.

Intracellular accumulation of adriamycin (ADM) was found to be increased in human breast carcinoma cell line (MCF-7) and cardiac-muscle cells as compared to an epithelial cell line derived from normal monkey kidney (CV-1) and non-muscle cells (fibroblasts) derived from the heart. This increase correlates with greater sensitivity of the carcinoma cell line to ADM. In CV-1, efflux of ADM contributes to low drug accumulation which correlates with the intrinsic drug resistance of the cells. Blockage of ADM efflux in this resistant cell line and subsequent increases in intracellular accumulation and sensitivity can be achieved by co-treatment with verapamil. ADM accumulation and sensitivity in MCF-7 however cannot be significantly increased by verapamil. These data demonstrate selectively for ADM in human breast carcinoma cell line, MCF-7 and cardiac-muscle cells in vitro. The reversal by verapamil of the normal cells' natural resistance, may have importance in the clinical use of verapamil as a resistance modulating agent.

Cell Line↗
PubMed1986

Relationship between the intracellular accumulation of anthracyclines and effectiveness in vitro and in vivo.

The relationship between accumulation, retention and cytotoxicity of various anthracyclines was investigated in Friend leukaemia cells growing in vitro. By comparison to that of adriamycin (ADM) and epi-adriamycin (Epi-ADM), the uptake of demethoxy-daunorubicin (DM-DNR) and THP-adriamycin (THP-ADM) is a rapid process. In cells exposed to DM-DNR or THP-ADM, a 50% accumulation is reached in less than 2 min, whereas 80 min and up to 4 hours are needed for epi-ADM or ADM, respectively. More than 95% of these anthracyclines are accumulated and retained in the nuclear fraction. Following a short cell exposure, the intracellular concentrations of the rapidly incorporated drugs (DM-DNR or THP-ADM) decrease with the cell density. After cell exposure to one of these drugs followed by growth in drug-free medium, the cytotoxic activity is related to the ease with which the anthracycline accumulates in cells. Since the pharmacological properties of these anthracyclines differ, and because cytotoxic activity correlates with these properties, plasma and intracellular concentrations of ADM and THP-ADM were studied after intravenous administration in leukaemic and non-leukaemic patients with various white blood cell concentrations. Since the pharmacokinetic studies in vivo correlated to in vitro parameters, it is concluded that administration modalities have to be determined, adapted to each patient, and considered differently according to the anthracycline used.

Adolescent↗
PubMed1986

Cellular pharmacology of anthracycline resistance and its circumvention.

Adriamycin-resistant cells express a multiple drug resistance phenotype characterized by cross-resistance to compounds of related and unrelated structure and action. The pharmacological determinants of this resistance, such as decreased drug uptake and/or decreased drug retention, are associated with biochemical alterations in the cells. To overcome multiple drug resistance, a calcium-channel blocking agent, verapamil, was used, which acted by increasing the amount of drug retained in resistant cells and consequently enhanced the cytotoxic effectiveness. The basis for this enhanced retention and cytotoxicity is not known. Whether these compounds sensitize the cells to the action of, or potentiate the effect of, anticancer drugs remains to be determined. The preliminary data tend to support the second possibility.

Animals↗
PubMed1986

An oriented phase II trial of THP-adriamycin in breast carcinoma.

THP-ADM is a new anthracycline with broad antitumor activity without cardiac toxicity or alopecia in experimental models. Phase I studies had established a proposed dose for phase II trials of 50 mg/m2 every three weeks. This modality gave an insignificant result in breast carcinoma. Cellular pharmacokinetics suggested that a longer time of administration could be more efficient. In this phase II trial oriented to advanced breast cancer, we have used 3 consecutive daily doses of 20 mg/m2/day in monthly cycles with dose escalation in each patient. We have observed 28% partial remissions (PR). Two patients previously treated with adriamycin had PR. Significantly less alopecia and no cardiac toxicity were observed.

Adult↗
PubMed1985

Interaction of rhodamine 123 with mitochondria isolated from drug-sensitive and -resistant Friend leukemia cells.

Mitochondria isolated from Friend leukemia cell lines sensitive (FS) and resistant (FR) to rhodamine 123 (Rho123), showed respiratory control and ADP/O ratios indicative of well-coupled oxidative phosphorylation activity. When Rho123 was added to mitochondria from both cell lines, respiratory State 4 increased. The increase was higher in mitochondria isolated from resistant than from sensitive cells. Respiratory State 3 was slightly more inhibited by Rho123 in resistant than in sensitive cell mitochondria (98 and 82% inhibition, respectively). While it is not clear how the uncoupling-like effects of Rho123 on State 4 contribute to cellular toxicity, our results indicate that differential cellular sensitivity to the drug does not correlate with inhibition of oxidative phosphorylation in mitochondria isolated from drug-sensitive and -resistant cells.

Animals↗
PubMed1985

Relationship between the intracellular level and growth inhibition of a new anthracycline 4'O-tetrahydropyranyl-Adriamycin in Friend leukemia cell variants.

The relationship between the intracellular amount of a new anthracycline derivative, 4'-O-tetrahydropyranyl-adriamycin (THP-ADM) and its cytotoxic activity in Friend leukemia cells (FLC) was investigated. By comparison to adriamycin (ADM), the uptake of THP-ADM is a very rapid process reaching maximal levels within 5 min. Both drugs are accumulated and retained in the nuclear fraction. The two main consequences associated to these different uptake rate are: following short-time cell exposure to comparable drug concentration, the higher cytotoxic effect of THP-ADM correlates to the ease with which it crosses the cell membrane; the intracellular amount of THP-ADM but not of ADM decreases with the cell density. These results emphasize the importance of considering drug uptake kinetics and its relationship to cytotoxicity. Studies comparing uptake and efflux of both drugs in ADM-resistant cells showed that THP-ADM extrusion correlate more to cytotoxicity than that of ADM. The relevance of these in vitro findings to clinical application is considered.

Animals↗
PubMed1985

Reversal of resistance to rhodamine 123 in adriamycin-resistant Friend leukemia cells.

Pleiotropic resistance to rhodamine 123 (Rho-123) in Adriamycin (ADM)-resistant Friend leukemia cells was circumvented by cotreatment with 10 microM verapamil. Increased cytotoxicity corresponded to higher intracellular Rho-123 levels. The verapamil-induced increase of drug accumulation in resistant cells is accounted for at least in part by the blockage or slowing of Rho-123 efflux from these cells. In contrast, accumulation and consequent cytotoxicity of Rho-123 in sensitive cells are not increased by verapamil. Similar results were obtained when ADM was used in this cell system. These results suggest that the efflux system for Rho-123 and ADM in sensitive cells is either reduced or absent. Although Rho-123 accumulates specifically in mitochondria and ADM mainly in the nucleus, the loss of these two different classes of compounds from resistant cells appears to occur via a similar or common mechanism. The similarities in drug transport between Rho-123 and ADM may have important implications when applied to an in vivo environment.

Animals↗
PubMed1984

Biochemical and cytotoxic properties of the isomeric forms of N,N'-bis[N-2-chloroethyl)-N-nitrosocarbamoyl] cystamine.

Three isomeric forms of a cystamine-containing chloroethylnitrosourea, N,N'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl]cystamine (CNCC), have been identified and separated by high pressure liquid chromatography. Isomer S, 3,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, was significantly less cytotoxic than isomer C, 1,1'-bis [N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, or isomer M, 1,3'-bis[N-(2-chloroethyl)-N-nitrosocarbamoyl] ethyl disulfide, in either a human Namalva lymphoblastoid or a rat Walker 256 carcinoma cell line. Both isomers S and C inhibited DNA synthesis at a 50 microM concentration. A structural analysis of the isomeric forms suggested that bioreduction of the disulfide bond would permit both isomers to produce isocyanate moieties which would carbamoylate intracellular proteins and depress nucleic acid synthesis. The reduced cytotoxic potential of isomer S is consistent with a prolongation in the half-life of production of alkylating carbonium species that lack the capacity to cross-link macromolecules. Overall, the relative position of the NH group within each of the nitrosourea isomers appears critical to the biological properties of the drug.

Animals↗
PubMed1984

Cross-resistance to rhodamine 123 in Adriamycin- and daunorubicin-resistant Friend leukemia cell variants.

Cross-resistance to rhodamine 123 (Rho-123) has been found in Adriamycin (ADM)-resistant and daunorubicin (DNR)-resistant Friend leukemia cell variants. Cytotoxicity in sensitive cells correlates with the intracellular amount of Rho-123, as determined by high-pressure liquid chromatography. Differential resistance coincides with Rho-123 accumulation which in sensitive cells was 20-fold higher than in resistant cells after 180 min of treatment. Sodium azide, which has been shown to inhibit ADM efflux and consequently increase drug accumulation in ADM-resistant cells, did not inhibit Rho-123 efflux. The difference in Rho-123 accumulation between sensitive and resistant cells correlates with cytotoxicity, which is in contrast to what has been found in these cells when treated with either ADM or DNR. Moreover, in contrast to the known effects of ADM and DNR on macromolecular synthesis, Rho-123 in sensitive cells was found to inhibit protein synthesis but had no effect on DNA or RNA synthesis. At Rho-123 doses which inhibited protein synthesis, drug localization changed from mitochondrial specific to generalized cytoplasmic. This effect was never achieved in resistant cells, even with prolonged drug exposure. The relevance of these findings is that different mechanisms of resistance to different drug types can be identified in the same cells even though similar resistance occurs. The similarity in resistance need not share a common mechanism. Although the drugs are effluxed more efficiently in resistant cells, the mechanisms for resistance in each case seem to differ. In the case of ADM and DNR, it appears to be multifactorial, whereas with Rho-123, total intracellular accumulation seems to be most important.

Animals↗
PubMed1984

Phase I-II study of aclarubicin for treatment of acute myeloid leukemia.

Aclarubicin (ACM) was administered as induction treatment to 40 patients with acute myeloid leukemia (AML) who were either refractory to initial induction chemotherapy or in relapse. Thirty-eight patients with AML, 2-80 years of age (mean +/- SE, 35.0 +/- 3.2), were evaluated during this study. Seventeen of these patients were given ACM after an unsuccessful attempt had been made to attain a complete remission (CR) with various regimens that included doxorubicin or daunorubicin; this group was considered resistant to these drugs. ACM was administered by rapid iv injection. Thirteen patients received a single course of ACM at a daily dose of 10-30 mg/m2 until a maximum total dose of 300 mg/m2 was reached or until unacceptable toxicity appeared. Of these patients, two (15%) attained a CR. The other 25 patients were given 10-day courses of ACM at a daily dose of 15 mg/m2 with 10-day intervals between courses; courses were repeated until the blast cells were cleared from peripheral blood and bone marrow or until progressive disease became evident. With this regimen, 11 patients (44%) attained a CR. The overall CR rate for the 38 patients was 34%. Total doses necessary to achieve a CR ranged from 150 to 600 mg/m2. A CR was attained by six patients who were previously resistant to a regimen containing moderate doses of doxorubicin. The incidence and severity of the toxic effects were related to the dose of ACM administered per course of therapy. The incidence of mucositis, diarrhea, vomiting, and infection in patients who received doses greater than 150 mg/m2/course was significantly higher than that observed in patients who received a dose of 150 mg/m2/course. In the latter patients, toxicity was within acceptable limits. Alopecia was not observed. Three patients had transient T-wave inversion, and reversible atrial flutter developed in one patient. Our results indicate that ACM is a major new drug for the treatment of AML.

Aclarubicin↗
PubMed1984

Phase I-II study of aclacinomycin for a treatment of acute myeloid leukemia.

Aclacinomycin A (ACM) was administered for induction treatment to 40 previously treated acute myeloid leukemia (AML) patients. 38 patients aged 2 to 80 years (mean +/- SE, 35.0 +/- 3.2 years) with overt AML were evaluated; of these, seventeen patients were given ACM after an unsuccessful attempt to obtain a complete remission (CR) with various regimens comprising adriamycin (ADM) or daunorubicin (DNR) and were considered resistant to these drugs. Thirteen patients received ACM at a daily dose of 10 to 30 mg/m2 IV bolus until the maximum total dose of 300 mg/m2 per course was reached or until unacceptable toxicity appeared; of these patients, 2 (15%) attained a CR. Twenty-five patients were given 10-day courses of ACM at the daily dose of 15 mg/m2 IV bolus with 10-day intervals between courses; with this regimen 11 patients (44%) attained a CR. The overall CR rate was 34%. Total doses necessary to attain a CR ranged from 150 to 600 mg/m2. CR was attained by 6 patients (35%) of the 17 who were previously resistant to ADM or DNR. The incidence and severity of the toxic effects such as mucositis, diarrhea, vomiting and infection were related to the dose of ACM administered during each course of therapy. However, in patients who received 150 mg/m2 per course the toxicity was within acceptable limits. Alopecia was not observed. Transient T-wave inversion was observed in 3 patients and atrial flutter developed in one patient. Therefore, we conclude that ACM is a new major drug in the treatment of AML.

Aclarubicin↗
PubMed1983

Membrane dynamics in human leukemia and lymphoma cells. pH dependency of diphenylhexatriene fluorescence polarization.

Membrane dynamics of human leukemia and lymphoma cell lines were analyzed by investigating the effect of pH on fluorescence polarization (P) of the lipophilic probe diphenylhexatriene (DPH). The degree of P varied as a function of pH, depending on the cell lines. These variations were not detected in phospholipid vesicles. In addition, they were prevented by treatments with glutaraldehyde, sodium azide or phenylmethylsulfanyl fluoride, a specific protease inhibitor. Therefore, these P value changes might be influenced by protein modification.

Cell Division↗
PubMed1983

Fate of aclacinomycin-A and its metabolites effect on cell growth and macromolecular synthesis.

The relationship between the structure and activity of aclacinomycin-A (ACM) metabolites was investigated in vitro in Friend leukaemia cells (FLC). The cytotoxic effect was related to the ease with which ACM and its metabolites accumulate in the nucleus. Cellular uptake and nuclear incorporation are influenced by the hexopyranoses linked to aklavinone (AKV) and by the two methyls linked to the L-rhodosamine amino groups. The effect of ACM and its metabolites on macromolecular synthesis depended on the drug concentrations and the exposure time. ACM was the most active in the inhibition of nucleic acid synthesis whereas it had no direct effect on protein synthesis even at high drug concentrations. When cells were treated for a short time with low drug concentrations (1 microM), RNA synthesis was inhibited to a greater extent than DNA synthesis. But when incubated for longer periods, inhibition of DNA synthesis increased further. RNA and DNA syntheses were both inhibited to about the same extent only when cells were exposed to the higher drug concentrations (10 microM). We conclude therefore that at low drug concentrations the effect on DNA synthesis is probably a consequence of RNA synthesis inhibition. The early DNA synthesis inhibition which occurs at higher drug concentrations may result from the direct action on the cellular genome.

Aclarubicin↗
PubMed1983

Serum-controlled membrane dynamic changes in growing human leukemia and lymphoma cells.

The relationship between membrane dynamics and cell growth in human leukemia-lymphoma cell lines of B, T or nonB-nonT phenotype was studied by fluorescence polarization (P) with the probe diphenylhexatriene. Cyclic variations in the degree of P were found as a function of time after subculture. The P value decreases within three hours, until a minimal value obtained before the phase of logarithmic growth. Then, P increases up to its presubculture value. The extent of these variations is not correlated to the differentiation phenotype of the cell lines, nor to their pathologic origin. Experiments with dialyzed or not depleted medium, show that these changes are seen only in the presence of fresh serum. Moreover, the P values vary with the ratio of serum concentration to cell number. These P value modulations are related to subsequent variations in proliferation rate, except in the immature non B-non T REH cells, which grow independently on the serum to cell ratio. It is concluded that changes in the dynamic organization of membrane components are specific for each cell line and are controlled by serum factors.

Animals↗