Identification of novel antitubulin agents by using a virtual screening approach
based on a 7-point pharmacophore model of the tubulin colchi-site.
Massarotti A, Theeramunkong S, Mesenzani O, Caldarelli A, Genazzani AA, Tron GC. Chem Biol Drug Des. 2011 Dec;78(6):913-22. doi: 10.1111/j.1747-0285.2011.01245.x.
Epub 2011 Oct 31.
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Tubulin inhibition represents an established target in the field of anticancer
research, and over the last 20 years, an intensive search for new antimicrotubule
agents has occurred. Indeed, in silico models have been presented that might aid
the discovery of novel agents. Among these, a 7-point pharmacophore model has
been recently proposed. As a formal proof of this model, we carried out a
ligand-based virtual screening on the colchicine-binding site. In vitro testing
demonstrated that two compounds displayed a cytotoxic profile on neuroblastoma
cancer cells (SH-SY5H) and one had an antitubulinic profile.
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The interactions of age, sex, body mass index, genetics, and steroid weight-based
doses on tacrolimus dosing requirement after adult kidney transplantation.
Stratta P, Quaglia M, Cena T, Antoniotti R, Fenoglio R, Menegotto A, Ferrante D,
Genazzani A, Terrazzino S, Magnani C. Eur J Clin Pharmacol. 2011 Nov 20.
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PURPOSE: The aim of this study was to evaluate the effect of different clinical
covariates on tacrolimus dose requirements in adult kidney transplant patients
with a specific focus on drug interactions. PATIENTS: Tacrolimus dosing
requirement, normalized by drug levels and expressed as the concentration/dose
(C/D) ratio as a surrogate index of tacrolimus bioavailability, was employed to
identify four categories of tacrolimus dosing requirement, namely, very high,
high, small, and very-small, in very fast, fast, slow, and very slow
metabolizers, respectively. Steroid weight-based doses were analyzed instead of
fixed doses, and genetic analysis of cytochrome P450 (CYP) 3A5*1/*3 and
multi-drug resistance 1 (MDR1) C3435T and C1236T polymorphisms were performed
RESULTS: Multivariate analysis on 450 adult transplant patients identified six
risk factors for being slow metabolizers and therefore requiring small tacrolimus
doses: male sex (OR 1.615, p = 0.020); age >60 years (OR 2.456, p = 0.0005);
body mass index ≥25 (OR 1.546, p = 0.046), hepatitis C virus positivity
(OR 2.800, p = 0.0004); low steroid dose <0.06 mg/kg (OR 3.101, p < 0.0001).
Patients with a small tacrolimus requirement were at increased risk for multiple
infections (OR 1.533, p = 0.0008) and higher systolic blood pressure (OR 1.385,
p = 0.022) and showed a significant association with the CYP3A5*3/*3 genotype
adjusted by MDR1 polymorphisms C3435T and C1236T (OR 8.104, p = 0.0001).
CONCLUSIONS: Our results demonstrate the importance of the interaction among
genetic and clinical factors in conditioning tacrolimus disposition, with
corticosteroid weight-based dose being the only modifiable risk factor for
tacrolimus requirement. As the tacrolimus dosing requirement increases with
increasing tacrolimus clearance through concomitant steroid use, undesirable
changes in tacrolimus levels may occur when steroid doses are tapered,
predominantly in slow metabolizers. This often neglected drug interaction has to
be monitored to optimize tacrolimus exposure in kidney transplant patients.
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Common Variants of GSTP1, GSTA1, and TGFβ1 are Associated with the Risk of
Radiation-Induced Fibrosis in Breast Cancer Patients.
Terrazzino S, La Mattina P, Gambaro G, Masini L, Franco P, Canonico PL, Genazzani
AA, Krengli M. Int J Radiat Oncol Biol Phys. 2011 Nov 11.
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PURPOSE: To provide new insights into the genetic basis of normal tissue
radiosensitivity, we evaluated the association between eight polymorphic variants
located in six genes related to DNA repair mechanisms, oxidative stress, and
fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1
Ile105Val, GSTA1 C-69T, eNOS G894T, TGFβ1 C-509T, and TGFβ1 T869C) and the risk
of subcutaneous fibrosis in a retrospective series of patients who received
radiotherapy after breast-conserving surgery. METHODS AND MATERIALS: Subcutaneous
fibrosis was scored according to the Late Effects of Normal Tissue-Subjective
Objective Management Analytical scale in 257 breast cancer patients who underwent
surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain
reaction-restriction fragment length polymorphism analysis on genomic DNA
extracted from peripheral blood. The association between genetic variants and the
risk of moderate to severe fibrosis was evaluated by binary logistic regression
analysis. RESULTS: Two hundred thirty-seven patients were available for the
analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis
(Grade 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions
(Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio
[OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI,
1.176-8.826; p = 0.022), and TGFβ1 T869C (OR 0.295; 95% CI, 0.090-0.964; p =
0.043) polymorphisms were found to be significantly associated with the risk of
Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three
risk genotypes were found to be at higher odds for the development of Grade 2-3
fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI,
1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI,
2.671-27.447; p = 0.0003). CONCLUSIONS: These results suggest that functional
variations in genes involved in oxidative stress response and fibroblast
proliferation may modulate the development of radiation-induced fibrosis in
breast cancer patients. The results of the combined analysis support the notion
that approaches based on the combination of different genetic markers have the
potential to predict normal tissue responses.
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Regioselective suzuki coupling of dihaloheteroaromatic compounds as a rapid
strategy to synthesize potent rigid combretastatin analogues.
Theeramunkong S, Caldarelli A, Massarotti A, Aprile S, Caprioglio D, Zaninetti R,
Teruggi A, Pirali T, Grosa G, Tron GC, Genazzani AA. J Med Chem. 2011 Jul 28;54(14):4977-86. Epub 2011 Jun 30.
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Combretastatin A-4 (CA-4) is a potent tubulin depolymerizing agent able to
inhibit tumor growth and with antivascular effects. Although it is in clinical
trials, the search for novel analogues that may display better/different features
is still ongoing. In this manuscript we describe the synthesis of novel
constrained analogues of CA-4 obtained in only two synthetic steps exploiting a
regioselective Suzuki coupling of dihalogenated heteroaromatic and alicyclic
compounds. All the compounds synthesized have been evaluated for cytotoxicity and
for their ability to inhibit tubulin assembly. One of them, 38, displayed low
nanomolar cytotoxicity and proved to have a pharmacodynamic profile similar to
that of CA-4 and a better pharmacokinetic profile, but most important of all,
this synthetic strategy may pave the way for the easy and rapid generation of
novel rigid analogues of combretastatins.
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Reciprocal potentiation of the antitumoral activities of FK866, an inhibitor of
nicotinamide phosphoribosyltransferase, and etoposide or cisplatin in
neuroblastoma cells.
Travelli C, Drago V, Maldi E, Kaludercic N, Galli U, Boldorini R, Di Lisa F, Tron
GC, Canonico PL, Genazzani AA. J Pharmacol Exp Ther. 2011 Jun 17.
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Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme involved in
numerous metabolic pathways. Its principal role is in redox reactions, and as
such it is not heavily "consumed" by cells. Yet a number of signaling pathways
that bring about its consumption have emerged recently. This has brought about
the hypothesis that the enzymes that lead to its biosynthesis may be targets for
anticancer therapy. In particular, inhibition of the enzyme nicotinamide
phosphoribosyl transferase (NAMPT) has been shown to be an effective treatment in
a number of preclinical studies, and two lead molecules (FK866 and CHS828) have
now entered preclinical trials. Yet, the full potential of these drugs is still
unclear. In the present study we have investigated the role of FK866 in
neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells
induces autophagy and its effects are potentiated by chloroquine and antagonized
by 3-methyladenine or by down-regulating ATG7. Autophagy, in this model, appears
to be crucial for FK866-induced cell death. On the other hand, a striking
potentiation of the effects of cisplatin and etoposide is given by co-treatment
of cells with ineffective concentrations of FK866 (1nM). The effect of etoposide
on DNA damage is potentiated by FK866 treatment while the effect of FK866 on
cytosolic NAD depletion is potentiated by etoposide. Even more strikingly,
co-treatment with etoposide/cisplatin and FK866 unmasks an effect on
mitochondrial NAD depletion.
