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Biomedical subjects

M Israel

Publications and source records attributed to M Israel.

At least 37 records · Page 2Linked to original sources
PubMed1998

Cellular resistance against the novel hybrid anthracycline N-(2-chloroethyl)-N-nitrosoureidodaunorubicin (AD 312) is mediated by combined altered topoisomerase II and O6-methylguanine-DNA methyltransferase activities.

N-(2-Chloroethyl)-N-nitrosoureidodaunorubicin (AD 312), a novel semisynthetic compound with combined anthracycline and nitrosourea alkylating functionalities, circumvents resistance conferred by either reduced DNA topoisomerase II (topo II) or increased P-glycoprotein expression with less myelosuppression and cardiotoxicity than adriamycin (doxorubicin; ADR). Cellular resistance to AD 312 could arise from a novel mechanism that confers resistance to both functions simultaneously, or one or more mechanisms common to anthracyclines and/or alkylating agents. The mechanism contributing to AD 312 resistance was investigated following selection of AD 312-resistant murine J774.2 macrophage-like cells and human NCI-H460 non-small-cell lung carcinoma cells. Murine J/312-400 (> 4.7-fold) and human H/312-40 cells (6.3-fold) were cross-resistant to topo II inhibitors (ADR, teniposide, etoposide) and nitrosoureas (carmustine, lomustine) but remained sensitive to vinblastine, colchicine, and camptothecin. There was approximately a twofold decrease in topo II decatenation activity and protein. Decreased net intracellular drug accumulation was not observed. There were no increases in glutathione content or glutathione-S-transferase activity. Increased O6-methylguanine-DNA methyltransferase (MGMT) activity (2.3-fold) was detected in J/312-400, and AD 312 resistance was partially reversed by O6-benzylguanine, a potent inhibitor of MGMT activity. The results suggest that AD 312 resistance arose through selective pressure by both cytotoxic functions in a serial manner.

Animals↗
PubMed1998

Extremely low frequency electric and magnetic fields as risk factors in chemical industry.

OBJECTIVES: The risk assessment for staff in the chemical industry is usually related to accident hazards, production emergencies, blast and fire danger, or to the adverse effects of toxic substances. The combined effect of electric and magnetic fields with other factors combined with other hazards and working conditions, has not yet been studied. In all branches of industry, the members of staff who endure the most exposure to electric and magnetic fields, are electricians. This group is considered at high risk because of the increased probability of cancer. METHODS: We studied electric and magnetic fields with low frequencies in the nitrogen chemical fertilizer plant "HIMCO", Vratza. Sources of extremely low frequency fields (50 Hz) are local thermal power plants, substations, open (110 kV) and closed (6 kV and 0.4 kV) distribution devices, transformers, compressors and turbocompressors, command halls, and video display units. The methods used for assessing exposure of low frequency electric and magnetic fields were based on the separate measurement of the electric and magnetic components of the field, using spot measurements and evaluation of the real time duration of exposure for different staff groups. RESULTS: The measured values for the different staff groups were within the limits of national and international standards. The measured magnetic flux densities in the "HIMCO" plant exceeded 3 mG, a value which is considered by many investigations in the literature, as a possible carcinogenic factor. CONCLUSIONS: The prolonged exposure to low frequency electric and magnetic fields determines the place of these physical factors in the complex of hazardous environmental factors for the staff. The simultaneous performance of combined investigations of all risk factors would result in the complete risk assessment for staff in the chemical industry. Electricians are considered to be a professional group who have an increased risk of contracting cancer. Extensive measurement and assessment of exposure of the low frequency electric and magnetic fields is needed using individual dosimeters and retrospective analysis to determine this. It is important to study all types of nonionizing radiation in the whole of the Bulgarian chemical industry, especially within petroleum refineries.

Bulgaria↗
PubMed1997

Circumvention of P-GP MDR as a function of anthracycline lipophilicity and charge.

From a number of studies it has been suggested that positive charge and degree of lipophilicity dictate, or at least influence, whether anthracyclines are recognized by the apparently clinical important mechanism of tumor cell resistance, i.e., P-gp-mediated multidrug resistance. Using a selected series of analogs in which lipophilicity and or positive charge are altered we find the following: (1) Positively-charged anthracyclines as compared to their neutral counterparts are better recognized by MDR+ cells. (2) With increasing lipophilicity charge becomes less important for MDR recognition. (3) In MDR+ cells with a resistance index to Adriamycin (ADR) of 4534, as compared to an MDR- parental line, almost all of the resistance is circumvented (resistance index = 3) with an anthracycline which does not contain a protonatable nitrogen and is highly lipophilic (partition coefficient, log p = > 1.99). (4) As lipophilicity is increased to log p > 1.99 and nuclear binding is decreased, anthracycline localization switches from nuclear to cytoplasmic which most likely indicates a different cytotoxic target and mechanism of action. (5) Cytoplasmically localized anthracyclines appear to distribute also in mitochondria which suggests these organelles as possible new anthracycline targets. In contrast, ADR shows no mitochondrial localization. (6) Photoaffinity analysis suggests that the highly lipophilic analogs, regardless of charge, interfere with NASV-Vp binding to P-gp. This is consistent with the idea that highly lipophilic anthracyclines act as modulators of MDR which may contribute to their mechanism of overcoming this form of resistance. The possible clinical significance of these data is that highly lipophilic anthracyclines are shown to circumvent MDR which most likely reflects their ability to localize in the cytoplasm and affect targets other than nuclear DNA, i.e., mitochondria, and to act as self modulators of MDR. Thus, a new approach to circumventing MDR and other mechanisms of resistance which involve nuclear targets is the use of active anthracyclines which are highly lipophilic and localize in the cytoplasm/mitochondria.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

Administration, Intravesical↗
PubMed1997

The effects of CO2, Nd:YAG and Er:YAG lasers with and without surface coolant on tooth root surfaces. An in vitro study.

The objective of this study was to compare and contrast the morphologic changes in tooth root surfaces treated in vitro by scaling and root planing followed by irradiation with the Er:YAG laser using air/water surface cooling and the CO2 and Nd:YAG lasers, both with and without surface coolant. The experimental unit consisted of 42 freshly extracted teeth which were divided equally and randomly assigned to the following 7 treatment groups: untreated control, S/RP only, CO2 laser with and without air/water surface cooling, Nd:YAG laser with and without/air water surface cooling, and Er:YAG laser with air/water surface coolant. Specimens treated with CO2 laser irradiation were subjected to energy densities ranging from 100 to 400 J/cm2; those treated with the Nd:YAG from 286 to 1857 J/cm2; and the Er:YAG was used within a range of 20 to 120 J/cm2. The degree of morphologic change following CO2 and Nd:YAG irradiation appeared directly related to energy density but unrelated to the use of surface coolant. Laser induced surface changes included cavitation, globules of melted and resolidified mineral, surface crazing, and production of a superficial char layer. In contrast, the Er:YAG laser produced root surface changes that might be expected from acid etching, i.e., removal of the smear layer and exposure of the collagen matrix. In addition, sharply defined microfractures of the mineralized structure were noted and unlike the CO2 and Nd:YAG lasers, there was no evidence of melting or surface char. Given the parameters of this study, it appears that both the CO2 and Nd:YAG lasers alter the root surface in an undesirable manner. The Er:YAG laser, however, when used at low energy densities shows sufficient potential for root surface modification to warrant further investigation.

Acid Etching, Dental↗
PubMed1996

Quantal acetylcholine release induced by mediatophore transfection.

Mediatophore is a protein of approximately 200 kDa able to translocate acetylcholine in response to calcium. It was purified from the presynaptic plasma membranes of the electric organ nerve terminals. Mediatophore is a homooligomer of a 16-kDa subunit, homologous to the proteolipid of V-ATPase. Cells of the N18TG-2 neuronal line are not able to produce quantal acetylcholine release. We show here that transfection of N18TG-2 cells with a plasmid encoding the mediatophore subunit restored calcium-dependent release. The essential feature of such a release was its quantal nature, similar to what is observed in situ in cholinergic synapses from which mediatophore was purified.

Acetylcholine↗
PubMed1996

Phase 1 trial of intraperitoneal AD-32 in gynecologic malignancies.

AD-32 (N-trifluoroacetyladriamycin-14-valerate), an analogue of doxorubicin, was examined for intraperitoneal (ip) administration in a phase 2 trial involving 25 patients with advanced gynecologic malignancies. At an AD-32 dose of 600 mg/m2, the limiting toxicity was grade 4 neutropenia (64% of patients), while severe abdominal pain was relatively uncommon (12%). Intraperitoneal AD-32 administration was associated with a 200-fold pharmacokinetic advantage for cavity exposure, compared to the systemic compartment. At the 600 mg/m2 dose level, 4 of 9 patients (44%) with ascites experienced control of malignant fluid reaccumulation. Based on the results of this phase 1 trial, further exploration of a possible role for the ip administration of AD-32 in individuals with gynecological malignancies appears indicated, particularly in patients with either small volume residual disease after initial systemic chemotherapy or in those with intractable ascites.

Aged↗
PubMed1996

Pharmacology of N,N-di(n-butyl)adriamycin-14-valerate in the rat.

Lipophilic N-alkylanthracyclines such as AD 198 (N-benzyladriamycin-14-valerate) or AD 201 [N,N-di(n-propyl)adriamycin-14-valerate], which exert their cytotoxicity through mechanisms which are not yet fully defined, possess inherent abilities to circumvent multidrug resistance in vitro and in vivo, possibly though alterations in normal intracellular drug trafficking. As part of structure-activity studies with this class of agent, we have now examined the pharmacology of AD 202 [N,N-di(n-butyl)adriamycin-14-valerate], another analog possessing superior antitumor activity to doxorubicin in vivo and an ability to circumvent multidrug resistance in vitro. Following the administration of AD 202 (20 mg/kg, i.v.) to anesthetized rats, rapid drug distribution (T1/2 5 min) was followed by more gradual elimination (T1/2 3.6h). Plasma clearance of AD 202 (224 +/- 63.6 ml/min per kg) and steady state volume of distribution (25.7 +/- 11.1 l/kg) were indicative of extensive tissue sequestration and/or a large degree of extra-hepatic metabolism. The parent drug predominated in plasma until 20 min, thereafter N,N-di(n-butyl)adriamycin became the principal circulating anthracycline. The systemic exposure to this biotransformation product (area under the plasma concentration-time curve from time zero to 480 min AUC(0-480) 28 1672 ng.min/ml) was > tenfold higher than for the other detected plasma products (N-butyladriamycin-14-valerate, N-butyladriamycin, and three unidentified fluorescent signals; P1-3). Total urinary elimination over 8h was limited (1.9% of dose), occurring predominantly as N,N-di(n-butyl)adriamycin (1.2% of dose), N-butyladriamycin (0.4% of dose), and their corresponding 13-carbinol metabolites (<0.1% of dose each). Low levels of adriamycin (ADR), aglycones and two unidentified products were also seen. Parental AD 202 was found in urine only up to 1h. By contrast, hepatic elimination of parent drug was seen, albeit at low levels, through 8h. Excretion by this route (22% of dose) occurred principally as N-butyl-adriamycin (8% of dose), N-butyladraimycinol (2.1% of dose) with lower levels of N,N-di(n-butyl)adriamycin (1.6% of dose), N,N-di(n-butyl)adriamycin (0.8% of dose), and aglycones (4.3% of dose, combined). Other products included ADR (1.1% of dose) and two unidentified signals (3.4% of dose, combined). The relatively poor mass balance in these studies is attributed to prolonged intracellular retention (elimination T1/2 24.2h) of N,N-di(n-butyl)adriamycin. Thus, in common with other N-alkylanthracyclines, the pharmacology of AD 202 is complex but its therapeutic properties clearly are not derived from an ADR prodrug effect. Significant differences continue to be noted as to the metabolic fate of congeners of this class of anthracycline analogs.

Animals↗
PubMed1996

Enhancement of quantal transmitter release and mediatophore expression by cyclic AMP in fibroblasts loaded with acetylcholine.

Neuronal properties such as neurotransmitter uptake and release can be expressed in non-neuronal cells. We show here that fibroblasts-mouse cell line L-M(TK-)-are able to take up acetylcholine from the external medium and to release it in response to a calcium influx. Release was assessed biochemically by a luminescence method, but it was also elicited from individual fibroblasts and recorded in real-time using a Xenopus myocyte as an acetylcholine detector. After treatment for three to six days with dibutyryl-cyclic AMP, the cells changed their shape and acetylcholine release was greatly enhanced. Surprisingly, in differentiated fibroblasts the time-course transmitter release exhibited a high degree of variability even for the successive responses evoked from the same cell; many currents recorded in myocytes on electrical stimulation of fibroblasts had an extremely long duration (up to 1 s or more). This suggested that the release sites were kept open for a very long time. Cyclic AMP treatment also caused a marked increase in the expression of mediatophore 16,000 mol. wt proteolipid in fibroblast membranes. Mediatophore is an acetylcholine-translocating protein which is abundant in cholinergic presynaptic plasma membranes. It is concluded that cyclic AMP differentiation of fibroblasts prolongs the duration of acetylcholine release at individual sites and enhances the expression of the 16,000 mol. wt proteolipid-forming mediatophore.

Acetylcholine↗
PubMed1995

Use of the carbon dioxide laser in retarding epithelial migration: a pilot histological human study utilizing case reports.

Predictable regeneration of tooth-supporting tissues lost to periodontal disease is the aim of periodontal therapy. Often the result of conventional treatment is healing with a long junctional epithelium along the root surface and little regeneration of the complete attachment apparatus. The purpose of this pilot study was to evaluate whether de-epithelialization with a CO2 laser at the time of flap surgery and at 10-day intervals over the first 30 days of healing has the potential to enhance the formation of a connective tissue attachment. Six mandibular incisors in two patients were selected for the study. Each patient received oral hygiene instruction and initial therapy prior to surgery. The teeth were splinted together, open flap debridement was performed on all teeth, a notch was placed on the roots at the height of the crest of the alveolar bone, and the flaps were sutured in place. The test side received controlled de-epithelialization of the outer (oral) gingiva with the carbon dioxide laser, and the inner gingival flap. The de-epithelialization was repeated on the test side at 10, 20, and 30 days postsurgically. Controls received open debridement only. Block sections were taken at 90 days and processed for histologic analysis. The results showed that for both patients, junctional epithelium (JE) was formed on both test and control teeth. In all control teeth, the JE extended the entire length of the root to the base of the reference notch.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Structural requirements of analogues of polyamines for migration and growth of IEC-6 cells.

Healing of gastrointestinal mucosal lesions occurs through two processes: an early one involving cell migration and a later one in which cell division replaces lost cells. Both processes require the presence of polyamines, but the mechanism of action of these compounds is unknown. In the present study, we examined the ability of analogues of spermidine and spermine to support migration and growth of IEC-6 cells that have been grown in alpha-difluoromethylornithine to inhibit polyamines. All analogues of spermidine with the general formula x-3 (referring to the numbers of carbon atoms on either side of the central nitrogen), where x = 2-12, competed with spermidine for entry into the cells. However, in addition to spermidine (x = 4), only compounds for which x = 2, 3, or 6 supported migration and only those for which x = 2 or 7 supported growth. Spermine analogues 3-x-3, for which x = 3, 6, 9, or 12, competed for entry into the cells, but only compounds for which x = 3 or 6 supported migration and only the compound for which x = 3, in addition to spermine (x = 4), supported growth. In addition, analogues 2-3-2, 3-2-3, and 2-(3)2, a branched compound, supported both migration and growth but entered the cell via a mechanism different than that for spermidine and spermine. These data define some of the specific structural requirements for polyamines to produce their physiological effects.

Animals↗
PubMed1994

Analysis of phenoxazine chemosensitizers: an electron ionization and keV-ion beam bombardment mass spectrometry study.

The mass spectral behavior of a set of eight 2- and 10-disubstituted phenoxazines putatively possessing anticancer drug enhancer properties was investigated. Both electron ionization (EI) and keV-ion beam bombardment (liquid secondary ion mass spectrometry, LSIMS) were used. As expected, EI led to extensive fragmentation to produce structurally characteristics ions. Except in one example, the molecular ions were reasonably abundant. Two different liquid matrices--sulfolane and 3-nitrobenzyl alcohol--were used to obtain LSIMS data. The use of the latter produced more stable molecular ions. Ion beam bombardment also produced several structure-specific fragments. A unique feature of the LSI spectra obtained using either of the above matrices is production of both M+. and [M + H]+ ions, with the former being more abundant in most cases. Adduct formation with the liquid matrices was also observed for many compounds.

Neoplasms↗
PubMed1994

Use of the CO2 laser in soft tissue and periodontal surgery.

The use of laser energy is by now established in some areas of the medical and dental professions. This article reviews the history of the carbon dioxide laser and discusses the advantages, indications, and contraindications of laser in soft tissue and periodontal surgery. Four clinical cases are presented to illustrate laser techniques in excisional biopsy, gingivectomy, coagulation of graft donor site, and a frenectomy procedure. The learning objective of this article is to familiarize the reader with this relatively new addition to oral surgical procedures.

Adolescent↗
PubMed1992

Synthesis and chemical characterization of N-substituted phenoxazines directed toward reversing vinca alkaloid resistance in multidrug-resistant cancer cells.

A series of 21 N-substituted phenoxazines has been synthesized in an effort to find more specific and less toxic modulators of multidrug resistance (MDR) in cancer chemotherapy. Thus, N-(omega-chloroalkyl)- and N-(chloroacyl)phenoxazines were found to undergo iodide-catalyzed nucleophilic substitution on reaction with various secondary amines, including N,N-diethylamine, N,N-diethanolamine, morpholine, piperidine, pyrrolidine and (beta-hydroxyethyl)piperazine. Products were characterized by UV, IR, 1H-, and 13C-NMR, mass spectral data, and elemental analyses. All of the compounds were examined for cytotoxicity and for their ability to increase the accumulation of the vinca alkaloids, vincristine (VCR) and vinblastine (VLB) in multidrug-resistant GC3/Cl (human colon adenocarcinoma) and KBChR-8-5 (HeLa variant) cell lines. Compounds were compared to the standard modulator verapamil (VRP). Substitutions on the phenoxazine ring at position 10 were associated with an increase in antiproliferative and anti-MDR activities. Modification of the length of the alkyl bridge and the type of amino side chain also influenced the potency of these effects. From among the compounds examined, 10 derivatives were found to increase the accumulation of VCR and VLB in GC3/Cl and KBChR-8-5 cells relative to the effect of VRP, suggesting that with the exception of pyrrolidinyl, the tertiary amine attachments to the phenoxazine nucleus linked through a three- or four-carbon alkyl chain resulted in enhanced anti-MDR activity. On the basis of their 50% growth inhibitory (IC50) values, five of the ten compounds, namely, 10-(3'-chloropropyl)phenoxazine, 10-[3'-[N-bis(hydroxyethyl)- amino]propyl]phenoxazine, 10-(3'-N-morpholinopropyl)phenoxazine, 10-(4'-N-morpholinobutyl)phenoxazine and 10-(N-piperidinoacetyl)phenoxazine were selected as relatively nontoxic chemosensitizers. These modulators, at nontoxic concentrations, potentiated the cytotoxicity of VCR and VLB in GC3/Cl and KBChR-8-5 cells. Further, two compounds 10-(3'-N-morpholinopropyl)phenoxazine, and the butyl derivative, enhanced accumulation of VLB in GC3/Cl, KBChR8-5 and highly resistant KB-V1 cells to a level significantly greater than the maximal level achieved with VRP. Additional experiments to understand the mechanism of action of these agents in modulating MDR are in progress.

Drug Resistance↗
PubMed1992

Resistance to N-benzyladriamycin-14-valerate in mouse J774.2 cells: P-glycoprotein expression without reduced N-benzyladriamycin-14-valerate accumulation.

N-Benzyladriamycin-14-valerate (AD 198) is a highly lipophilic analogue of Adriamycin with novel cytotoxic mechanisms, greater in vivo antitumor activity, and the ability to circumvent multidrug resistance due to P-glycoprotein-mediated drug efflux or decreased topoisomerase II activity. To identify the mechanism(s) which may confer AD 198 resistance, J774.2 mouse macrophage-like cells were selected for growth in cytotoxic levels of AD 198 (AD 198R). AD 198R cells exhibited over-expression of the mdr1b (P-glycoprotein) gene, cross-resistance to Adriamycin and vinblastine, and potentiation of drug cytotoxicity by verapamil. However, net intracellular accumulation of AD 198 in AD 198R cells was unchanged compared to parental cells, while Adriamycin and vinblastine accumulations were reduced 40% and 95%, respectively. AD 198 was localized in the perinuclear region of the cytoplasm in both parental and AD 198R cells, with additional vesicular compartmentalization in AD 198R cells. Verapamil-induced reversal of AD 198 resistance coincided with some drug redistribution from cytoplasmic vesicles, but without redistribution of AD 198 into the nucleus. These results suggest that AD 198 resistance was not conferred through a P-glycoprotein-mediated reduction in intracellular drug accumulation but through other cytoplasmic mechanisms, including, but not limited to, drug compartmentalization.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Activation of human leukemia protein kinase C by tumor promoters and its inhibition by N-trifluoroacetyladriamycin-14-valerate (AD 32).

N-Trifluoroacetyladriamycin-14-valerate (AD 32), a lipophilic, DNA non-binding analog of Adriamycin (ADR), was found to be a potent inhibitor of the membrane-bound enzyme, protein kinase C (PKC). PKC was isolated and purified from human leukemia ML-1 cells, and the enzyme activity was shown to be activated by the tumor promoters 12-O-tetradecanoylphorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate (PDBu). AD 32, nevertheless, inhibited the activation of PKC by TPA or PDBu. The IC50 values for AD 32 inhibition of PKC activation were 0.85 microM for TPA and 1.25 microM for PDBu. Under the same assay conditions, ADR demonstrated much higher IC50 values: 550 microM for TPA and greater than 350 microM for PDBu. The inhibition of PKC by AD 32 was further shown to be competitive in nature; AD 32 inhibited the binding of [3H]PDBu to PKC. Therefore, AD 32 competes with the tumor promoter for the PKC binding site and prevents the latter from both interacting with the phospholipid and binding to PKC. These effects of AD 32 were reproduced in situ; incubation of human leukemia ML-1 cells with TPA showed an increased phosphorylation of cellular proteins, and the TPA-induced protein phosphorylation was inhibited by the addition of AD 32 to the cultured cells.

Binding, Competitive↗
PubMed1992

N-benzyladriamycin-14-valerate and drug resistance: correlation of anthracycline structural modification with intracellular accumulation and distribution in multidrug resistant cells.

N-Benzyladriamycin-14-valerate (AD 198) is a highly hydrophobic analogue of Adriamycin (ADR) which can circumvent multidrug resistance (MDR) in various cell lines. Unlike ADR, AD 198 avoids extrusion by P-glycoprotein (P-gp) in AD 198-resistant murine macrophage-like J774.2 cells and localizes in the cytoplasm. To determine the structural modification(s) responsible for these different characteristics, intracellular accumulation and distribution of ADR, AD 198, and the two half-substituted AD 198 congeners. N-benzyladriamycin (AD 288) and adriamycin-14-valerate (AD 48), were analyzed in AD 198-sensitive (J774.2) and -resistant (A300) cells. A300 cells exhibited cross-resistance to and reduced accumulation of ADR, AD 48, and AD 288. ADR and AD 288 rapidly localized in the nuclei of parental and A300 cells, while AD 48 and AD 198 localized in the cytoplasm. AD 48 redistributed into nuclei and cytoplasm of both cell lines, but AD 198 maintained a punctate cytoplasmic distribution in A300 cells. These results suggest that both the N-benzyl and C14-valerate substitutions of AD 198 are required for P-gp circumvention and stable cytoplasmic localization in A300 cells, probably as a result of differing intracellular drug trafficking.

ATP Binding Cassette Transporter, Subfamily B, Mem↗