Biomedical subjects

J F Prost

Publications and source records attributed to J F Prost.

At least 19 recordsLinked to original sources

PubMed1999

Isolation, cloning, and expression of a new murine zinc finger encoding gene.

With the aim of identifying genes involved in cartilage differentiation, we have used a subtractive hybridization strategy with cDNAs from a chondrocytic cell line (MC615) and mRNAs from a mesenchymal precursor cell line (10T1/2). We have isolated a cDNA clone representing a novel mouse gene. The predicted 368-amino acid protein, designated ZF-12, contains four C(2)H(2)-type zinc finger motifs and one region homologous to the LeR domain, a finger-associated structural domain. ZF-12 mRNAs are expressed during embryonic development and in different organs in adult, including rib cartilage. These data suggest that ZF-12 might play an important role not only in cartilage differentiation, but also in basic cellular processes.

Amino Acid Sequence↗

PubMed1999

Detection of an extended-10 element in the promoter region of the pckA gene encoding phosphoenolpyruvate carboxykinase in Escherichia coli.

The regulation of transcription of the pckA gene coding for phosphoenolpyruvate carboxykinase in Escherichia coli was analysed by site-directed mutagenesis of the promoter region and measurement of in vitro transcription initiation. Mutation of the guanine residue at position -14 to either cytosine or thymine was found to result in a drastic decrease of transcription, even in the presence of the natural -35 hexamer TTTCCA that differs by only two nucleotides from the consensus sequence TTGACA. It was concluded that the promoter region of pckA contains an extended -10 module, 5'-TG-3', located one base upstream of the -10 hexamer, which is crucial for transcription.

Base Sequence↗

PubMed1999

Cra-dependent transcriptional activation of the icd gene of Escherichia coli.

The icd gene of Escherichia coli, encoding isocitrate dehydrogenase, was shown to be expressed from two different promoters: the previously identified icd P1 and a newly detected second promoter, icd P2, whose expression is positively regulated by the catabolite repressor-activator protein Cra, formerly called FruR. In each case, we determined the mRNA start site by primer extension analysis of in vivo transcripts and examined the interaction of the icd control region with either RNA polymerase or Cra. We observed that (i) the Cra factor binds to and activates transcription from a site centered at position -76.5 within the icd P2 promoter region and (ii) three particular mutations in the C-terminal end of the alpha subunit of RNA polymerase (L262A, R265A, and N268A) considerably diminish transcription initiating from the icd P2 promoter, as shown by in vitro experiments performed in the presence of mutant RNA polymerases carrying Ala substitutions.

Amino Acid Substitution↗

PubMed1998

Inactivation of isocitrate dehydrogenase kinase/phosphatase by 5'-[p-(fluorosulfonyl)benzoyl]adenosine is not due to the labeling of the invariant lysine residue found in the protein kinase family.

The ATPase activity of Escherichia coli isocitrate dehydrogenase kinase/phosphatase was rapidly lost after prior incubation with the ATP analogue 5'-[p-(fluorosulfonyl)benzoyl]adenosine (FSBA). This inactivation was prevented by the presence of either 5 mM ATP or 5 mM ADP plus Mg2+, while it could be fully reversed by subsequent addition of dithiothreitol, thereby indicating the involvement of cysteine residue(s) in this process. About 2 mol [3H]FSBA/mol IDHK/P were bound during the time course of the inactivation. However, this binding was not significantly modified by either prior incubation with ATP or subsequent addition of dithiothreitol. This suggested that FSBA-mediated inactivation of isocitrate dehydrogenase kinase/phosphatase occurred via the formation of a disulfide bond. Accordingly, mass spectral analysis revealed that on addition of FSBA, a disulfide bond was formed between residues Cys356 and Cys523. The mutation Cys356Ser renders the enzyme insensitive to FSBA treatment indicating that Cys356 is the primary target for this analogue. However, the Cys523Ser mutant was still inactivated by FSBA and mass spectral analysis showed that this was due to the formation of a new disulfide bond between Cys356 and Cys480.

Adenosine↗

PubMed1998

FruR-mediated transcriptional activation at the ppsA promoter of Escherichia coli.

The start site of transcription of the ppsA gene, whose expression is controlled by the regulatory protein FruR in Escherichia coli, was determined by primer extension of in vivo transcripts. The interactions of the ppsA promoter with either RNA polymerase or FruR factor were analysed by the base removal method. Our results indicate that: (i) the RNA polymerase binding site has a -10 extended module but lacks its -35 hexamer; (ii) FruR binds to a target DNA region centered around position -45.5 upstream of the ppsA gene. In addition, circular permutation analysis showed that, upon binding to its site, FruR induces a sharp bend of 120 degrees in the DNA helix, which suggests a crucial involvement of FruR-induced bending in ppsA promoter activation. Direct contacts between the upstream activating DNA and RNA polymerase were studied in an in vitro transcription assay by using reconstituted RNA polymerase mutants containing Ala substitutions in C-terminal domain of their alpha subunit. The alpha[L262A], alpha[R265A] and alpha[N268A] substitutions, which caused the most drastic reduction in the FruR-mediated activation of the ppsA promoter, had previously been shown to inhibit the upstream element-mediated activation at the rrnBP1 promoter.

Alanine↗

PubMed1997

DNA flexibility of the UP element is a major determinant for transcriptional activation at the Escherichia coli acetate promoter.

The specific interaction of the upstream element-containing promoter of the Escherichia coli acetate operon with either the RNA polymerase holoenzyme or its alpha subunit has been analyzed by the base removal method. Our results indicate that: (i) direct and specific base contacts can be detected in the acetate promoter-alpha subunit complex; (ii) base elimination in the upstream element of the acetate promoter enhances the binding of RNA polymerase. A similar effect is observed when studying the interactions between RNA polymerase and the rrnB ribosomal operon P1 promoter.

Acetates↗

PubMed1997

Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability.

Milnacipran (Ixel) is a new antidepressant with essentially equal potency for inhibiting the reuptake of both serotonin and noradrenaline, with no affinity for any neurotransmitter receptor studied. A review of the studies comparing milnacipran, placebo and active comparator antidepressants provides clear-cut evidence of its efficacy in both severe and moderate depression in hospitalized and community settings. Meta-analyses of the original data of controlled trials involving 1032 patients, comparing milnacipran with imipramine or selective serotonin reuptake inhibitors (SSRIs), show that milnacipran provides antidepressant efficacy similar to that of imipramine and significantly superior to that of the SSRIs. An analysis of a database of over 3300 patients shows that both the general and cardiovascular tolerability of milnacipran are superior to those of the tricyclic antidepressants (TCAs) with fewer cholinergic side-effects. The tolerability of milnacipran was comparable to that of the SSRIs, with a higher incidence of dysuria with milnacipran, and a higher frequency of nausea and anxiety with the SSRIs. Milnacipran is a new therapeutic option in depression, which offers a clinical efficacy in the range of the TCAs combined with a tolerability equivalent to that of the SSRIs.

Adrenergic Uptake Inhibitors↗

PubMed1996

Preclinical pharmacology of milnacipran.

Milnacipran (Ixel) is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake and its lack of affinity for neurotransmitter receptors. It inhibits virtually equipotently the reuptake of serotonin and noradrenaline both in vitro and in vivo, as demonstrated by the antagonism of centrally acting monoamine displacers. It has no effect on dopamine reuptake. In addition, milnacipran has been shown by intracerebral microdialysis to increase the extracellular levels of both serotonin and noradrenaline after acute administration. Milnacipran is devoid of interactions at any known neurotransmitter receptor or ion channel. In particular, and unlike tricyclic antidepressants, it does not act at noradrenergic, muscarinic or histaminergic receptors. Contrary to tricyclic antidepressants, chronic administration of milnacipran does not modify beta-adrenoceptor binding or second messenger function. Milnacipran is active on various animal models of depression such as the forced swimming test in the mouse, learned helplessness in the rat and the olfactory bulbectomized rat model. This pharmacological profile, associated with an excellent bioavailability in man, was predicted to be that required for a powerful and well-tolerated antidepressant. Subsequent clinical development has shown this prediction to be well founded.

Adrenergic Uptake Inhibitors↗

PubMed1996

Milnacipran and selective serotonin reuptake inhibitors in major depression.

In drug development the move from tricyclic antidepressants (TCAs) to selective serotonin reuptake inhibitors (SSRIs) involved not only the loss of the direct receptor interactions responsible for the adverse side effects of TCAs, but also the ability to inhibit the reuptake of noradrenaline. Selectivity for the single neurotransmitter, serotonin, may explain why SSRIs tend to be less efficacious than the TCAs, especially in more serious forms of depression. The advent of selective serotonin and noradrenaline reuptake inhibitors (SNRIs) has tended to confirm the idea that an action on both monoamine systems is important for maximal antidepressant efficacy. This paper reviews clinical trials comparing the new SNRI milnacipran with the SSRIs fluoxetine and fluvoxamine. A meta-analysis of the principal trials shows greater response rates (the proportion of patients with a decrease in symptom scores of 50% or more) with milnacipran (50 mg twice a day) than with fluoxetine (20 mg once a day), or fluvoxamine (100 mg twice a day) (milnacipran: 64%; SSRIs: 50%). Remission rates (the proportion of patients with Hamilton Depression Rating Scores of 7 or below) were also higher with milnacipran than with SSRIs (39 versus 28%). In one study, in which 100 mg milnacipran was given once a day in the evening, the higher response rate obtained with fluoxetine appears to be largely attributable to an inappropriate milnacipran dosage regimen. Data from a pharmacovigilance database including all patients participating in clinical trials with milnacipran (n = 5732) showed that, compared with the SSRIs, milnacipran produced fewer gastrointestinal side effects, such as nausea, and less anxiety. Milnacipran was, however, associated with a higher incidence of headache, dry mouth and dysuria. The results of these studies suggest that milnacipran is superior in efficacy to SSRIs and is equally well tolerated. Milnacipran, therefore, appears to offer a therapeutic advantage over the SSRIs.

Adrenergic Uptake Inhibitors↗

PubMed1996

Efficacy and tolerability of milnacipran: an overview.

The relative benefits and risks of milnacipran, a novel antidepressant which selectively inhibits the reuptake of serotonin and noradrenaline, have been evaluated in comparative trials against tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). A total of 2462 patients with major depressive disorders have been investigated. At the optimal dose (50 mg twice a day), the efficacy of milnacipran was equivalent to that of the TCAs, with response rates of approximately 65% in both cases. Milnacipran was consistently effective against all of the principal elements of depression (anxiety, cognitive function, sleep and psychomotor retardation), and did not produce sedation or the emergence of suicidal thoughts. The Clinical Global Impression (CGI-3) score, a measure of the overall therapeutic impact of a treatment, was significantly higher with milnacipran than with TCAs (1.98 versus 1.84, p < 0.05). TCAs were associated with a higher frequency of adverse events than milnacipran, particularly with respect to anticholinergic-like effects; dysuria was the only adverse event occurring twice as frequently with milnacipran than with TCAs. Compared with TCAs, milnacipran was also associated with a lower incidence of cardiovascular adverse events. No haematological abnormalities occurred during treatment with milnacipran, and the incidence of abnormal liver function tests tended to be lower with milnacipran than with TCAs. In comparisons with SSRIs, milnacipran produced significantly higher response rates. The CGI-3 scores were significantly higher in milnacipran-treated patients (2.64 versus 2.32, p < 0.05). The adverse event profiles of the two treatments were similar, as was the incidence of abnormal liver function tests. These studies suggest that milnacipran offers clinical advantages over TCAs in terms of tolerability, and over SSRIs in terms of efficacy. In particular, the lack of cardiovascular adverse events appears to offer advantages in cases of deliberate overdose. To date, 15 such overdoses have occurred; none was fatal and each had a favourable outcome. The reproducible pharmacokinetic characteristics of milnacipran present further advantages over both groups of agents, due to lack of drug accumulation and a low risk of drug interactions.

Adrenergic Uptake Inhibitors↗

PubMed1995

In vitro and in vivo pharmacology of S 16474, a novel dual tachykinin NK1 and NK2 receptor antagonist.

Since tachykinins released from lung sensory nerve endings are thought to play a role in inflammatory diseases of airways via NK1 and NK2 receptors, dual tachykinin NK1 and NK2 receptor antagonists may have a great therapeutic potential. In vitro, the cyclopeptide S 16474 (cyclo-[Abo-Asp(D-Trp(Suc0Na)-Phe-N-(Me)Bzl)]) bound to both human tachykinin NK1 and NK2 receptors expressed in two lines of transfected Chinese hamster ovary cells (IC50 values 85 nM and 129 nM, respectively), while showing a poor affinity for the rat tachykinin NK1 receptor. S 16474 inhibited the contractions induced by substance P in isolated rabbit vena cava (pA2 7.0) and by neurokinin A in rabbit pulmonary artery (pA2 5.6). In vivo in anaesthetized guinea-pigs, S 16474 was found to dose dependently inhibit the bronchoconstrictions induced by intravenously administered substance P, neurokinin A and capsaicin. Plasma extravasation evoked in bronchi by endogenously released tachykinins under vagus nerve stimulation was abolished by S 16474 (10 mu mol/kg i.v.). These results demonstrate clearly that S 16474 is a tachykinin receptor antagonist exhibiting, in vitro and in vivo, a dual inhibitory effect on NK1 and NK2 receptors.

Animals↗

PubMed1995

Effects of the bradykinin B2 receptor antagonist S 16118 (p-guanidobenzoyl-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin) in different in vivo animal models of inflammation.

The effects of S 16118 (p-guanidobenzoyl-[Hyp3,Thi5,D-Tic7, Oic8]bradykinin (BK)], a new, potent and long-acting BK B2 antagonist, were tested in some in vivo models of inflammation. In rats, S 16118 (0.1 and 1 mg/kg) given i.v. or s.c. delayed the edema formation induced by intraplantar carrageenan injections up to 4 hr after administration, confirming the involvement of kinins in this inflammatory reaction. In guinea pigs treated with atropine, vagal stimulation induced bronchial microvascular leakage. Aerosolization of S 16118 (5 x 10(-3) M for 20 sec), 4 min before vagus nerve stimulation, induced a 60% decrease in the Evans blue extravasation, demonstrating the modulatory role of BK in neurogenic inflammation. In rats, caerulein infusion (4 nmol/kg/hr) induced hypotension, massive pancreatic edema, hypovolemia due to plasma leakage and an increase in serum lipase and amylase activity. S 16118 (100 nmol/kg s.c.) prevented the hypotension, the pancreatic edema and the hypovolemia and induced a marked increase in the serum lipase and amylase activity. This confirms that BK, acting on BK B2 receptors, is involved in this model of pancreatitis. In rabbits, the injection of lipopolysaccharides (LPS; 600 micrograms/kg i.v.) induced hypotension, metabolic acidosis and leukopenia. S 16118 (1.73 mumol/kg i.v.) did not influence the effects of LPS injection. In mice, i.p. LPS (25 mg/kg) administration induced over 90% mortality in 96 hr. S 16118 (1 mg/kg x 4), given 30 min before LPS injection and 4, 8 and 24 hr after LPS injection, did not influence the mortality rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

S 14297, a novel selective ligand at cloned human dopamine D3 receptors, blocks 7-OH-DPAT-induced hypothermia in rats.

The selective dopamine D3 receptor agonist, 7-OH-DPAT ((+)-7-hydroxy-2-(di-n-propylamino)tetralin) and the novel naphthofurane, S 14297 ((+)-[7-(N,N-dipropylamino)-5,6,7,8-tetrahydro- naphtho(2,3b)dihydro,2,3-furane]), bound with high affinity and selectivity to recombinant, human dopamine D3 versus D2 receptors stably transfected into Chinese hamster ovary cells: Ki values = 2 versus 103 nM for 7-OH-DPAT and 13 versus 297 nM for S 14297. In contrast, the putative dopamine D3 receptor antagonist, AJ 76 (cis-(+)-5-methoxy-1-methyl-2-(n- propylamino)tetralin), displayed low affinity and selectivity for dopamine D3 versus D2 sites (70 versus 154 nM). 7-OH-DPAT (0.01-0.16 mg/kg s.c.) provoked hypothermia in rats, an action abolished by S 14297 (0.04-0.63 mg/kg s.c.) and, less potently, by AJ 76 (0.16-2.5 mg/kg s.c.). S 14297 (20.0 mg/kg s.c.) did not modify prolactin secretion. These data suggest that dopamine D3 receptors mediate hypothermia in the rat and that S 14297 acts as a selective antagonist at these sites.

2-Naphthylamine↗

PubMed1994

Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)-6H-pyrido[4,3-b]carbazole-1-N- [(dialkylamino)alkyl]carboxamides, a new promising series of antitumor olivacine derivatives.

Starting from 2-(2-aminoethyl)-6-methoxy-1-methylcarbazole, ethyl 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-carboxylate was obtained through a three-step sequence. This compound and its 6-methyl derivative react with (dialkylamino)alkylamines to provide various 9-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole-1-(N-substituted carboxamides) whose boron tribromide demethylation afforded corresponding 9-hydroxy-1-(N-substituted carbamoyl)-olivacines. The same pathway but starting from 2-(2-aminoethyl)-6-methoxy-1,4-dimethylcarbazole led to ethyl 9-methoxy-5,11-dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxylate which did not normally react with amines. It provided either the recovered starting material at 120 degrees C or 9-methoxyellipticine resulting from an unexpected decarboethylation in a steel vessel at 180 degrees C. Biological testing of the newly obtained 1-carbamoylolivacine derivatives showed that 9-hydroxylated compounds displayed high cytotoxicity for cultured L1210 and colon 38 cells (IC50 range 5-10 nM) and good antitumor activity in vivo in the P388 leukemia and colon 38 models when administered by the iv route. The most active compound in these series is 9-hydroxy-5,6-dimethyl-1-[N-[2-(dimethylamino)ethyl]carbamoyl]-6H- pyrido[4,3-b]carbazole which was selected for further evaluation on murine solid tumors and for toxicological studies.

Adenocarcinoma↗

PubMed1994

New N alpha-guanidinobenzoyl derivatives of hirudin-54-65 containing stabilized carboxyl or phosphoryl groups on the side chain of phenylalanine-63.

We report on the synthesis and pharmacological properties of a new series of thrombin inhibitors derived from hirudin carboxyl-terminal fragments. Two (arylphosphono)phenylalanines, p-PO3H2-L-Phe1 and m-PO3H2-L-Tyr, and one (carboxymethyl)phenylalanine, p-CH2COOH-L-Phe, were prepared and incorporated into position 63 of the modified hirudin's C-terminal dodecapeptide using the Fmoc solid-phase synthesis strategy. Substitution by any one of the residues led to very active analogs which doubled the thrombin time at low micromolar concentration (Ctt2) in vitro (1 microM < Ctt2 < 3 microM) and potently increased the activated partial thromboplastin time (APTT) ex vivo. These compounds displayed a higher potency in vitro and a longer duration of action in vivo than both the corresponding sulfated or phosphorylated tyrosine counterparts.

Amino Acid Sequence↗

PubMed1994

Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49.

1. S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL-FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes. 2. In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 microM, 3 microM and 10 microM) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 microM, -23.8 +/- 3.9% and -27.9 +/- 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 microM. In these preparations, action potential duration at 50% of total repolarization (APD50) was more affected by UL-FS 49 than S 16257 at any concentration tested (at 3 microM, +8.9 +/- 2.9% and +29.1 +/- 3.7% for S 16257 and UL-FS 49, respectively; P < or = 0.01). 3. To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 microM, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 microM, +6.1 +/- 0.6% and +11.2 +/- 1.3% elevation of APD50, for S 16257 and UL-FS 49, respectively). 4. Application of UL-FS 49 (3 microM) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD50 and APD90 (+149.4 +/- 51.2% and +86.0 +/- 15.4%, respectively). S 16257 (3 MicroM) induced only a weak prolongation of AP (+ 14.1 +/- 5.0% and + 14.8 +/- 3.3% for APD50 and APD90, respectively) significantly smaller than in the case of UL-FS 49.5. These results show that S 16257 slows the rate of spontaneous AP firing in isolated SAN mainly by a reduction of the diastolic depolarization of the cells, which suggests an inhibition of the pace-maker current (If). S 16257 and UL-FS 49 are equipotent in their bradycardic effect but S 16257 is more specific as it induces less increase in myocardial repolarization time.

Action Potentials↗

PubMed1993

[In vitro characterization of S9788, a new modulator of multidrug resistance].

S9788, a new triazinoaminopiperidine derivative, was 250-fold more active than verapamil in sensitizing DC-3F/AD cells to actinomycin D. This multidrug-resistance modulating activity of S9788 was confirmed on DC-3F/AD, P388/ADR-10, P388/VCR-20, KB/A1, K562/R, S1/tMDR, and COLO320DM cells, with respect to actinomycin D, doxorubicin, vincristine, vinblastine and etoposide. S9788 is 2-255-fold more active than verapamil, depending on the cell line and the cytotoxic agent used, potentiating preferentially the cytotoxicity of the vinca-alkaloid derivatives. S9788 only had a slight effect on vincristine accumulation and retention by parental sensitive cells, as well as on their sensitivity to cytotoxic drugs. S9788 fully restored vincristine accumulation and retention by S1/tMDR cells (S1 cells transfected by the mdr 1 gene) to a level similar to that measured in S1 cells, leading to a blockade in the G2 + M phase of the cell cycle. Therefore, S9788 enhances vincristine activity by restoring its cellular accumulation in resistant cells. After a short incubation period of cells with vincristine (4 h), a condition close to the clinical administration of this cytotoxic agent, a post-incubation for 20 hours more with 5 microM S9788, fully restored the sensitivity of S1/tMDR cells to vincristine. After an exposure of 4 hours at equal concentrations, the accumulation of S9788 was 13-fold that of verapamil in S1/tMDR cells, and 20 hours after the removal of the modulators, S9788 was retained at a concentration 20-fold that of verapamil. S9788 is therefore a powerful new modifier of the P-gp-mediated multidrug-resistance, which by its pharmacological properties (cellular kinetics and activity), might be used in combination with existing chemotherapy against tumors displaying the MDR phenotype.

Animals↗

PubMed1992

New triazine derivatives as potent modulators of multidrug resistance.

A series of 70 triazine derivatives have been synthesized and tested for their capacity to modulate multidrug resistance (MDR) in DC-3F/AD and KB-A1 tumor cells in vitro, in comparison with verapamil (VRP), a calcium channel antagonist currently used in therapy as an antihypertensive drug, which also shows MDR modulating activity. Among the 12 selected compounds, 16 (S9788) showed high MDR reversing properties in vitro (300- and 6-fold VRP at 5 microM in DC-3F/AD and KB-A1 cells, respectively) and induced a strong accumulation of adriamycin. The relationship between the increase of ADR accumulation and the fold reversal induced by these compounds and their lack of effects on the sensitive DC-3F cells suggest that they act mainly by inhibiting the P-glycoprotein (Pgp) catalyzed efflux of cytotoxic agents, as already described for a majority of MDR modulators. In vivo, in association with the antitumor drug vincristine (0.25 mg/kg), 16 (100 mg/kg) increased the T/C by 39% in mice bearing the resistant tumor cell line P388/VCR. According to these interesting properties, 16 was selected for a clinical development because it was more bioavailable than 34, even though it was less active.

ATP Binding Cassette Transporter, Subfamily B, Mem↗