Biomedical subjects

A Albini

Publications and source records attributed to A Albini.

At least 19 recordsLinked to original sources

PubMed2006

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells.

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

Animals↗

PubMed2006

Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins.

Artemisinin (ARS) and its derivatives are used for the second-line therapy of malaria infections with Plasmodium falciparum and P. vivax. ARSs also reveal profound antitumor activity in vitro and in vivo. In the present investigation, we correlated the mRNA expression data of 89 angiogenesis-related genes obtained by microarray hybridization from the database of the US National Cancer Institute with the 50% growth inhibition concentration values for eight ARSs (ARS, arteether (ARE), artesunate (ART), artemisetene, arteanuine B, dihydroartemisinylester stereoisomers 1 and 2). The constitutive expression of 30 genes correlated significantly with the cellular response to ARSs. By means of hierarchical cluster analysis and cluster image mapping expression, profiles were identified that determined significantly the cellular response to ART, ARE, artemether and dihydroartemisinylester stereoisomer 1. We have exemplarily validated the microarray data of six out of these 30 genes by real-time RT-PCR in seven cell lines. The fact that sensitivity and resistance of tumor cells could be predicted by the mRNA expression of angiogenesis-related genes indicate that ARSs reveal their antitumor effects at least in part by inhibition of tumor angiogenesis. As many chemopreventive drugs exert antiangiogenic features, ARSs might also be chemopreventive in addition to their cytotoxic effects.

Angiogenic Proteins↗

PubMed2006

Growth factors and chemokines: a comparative functional approach between invertebrates and vertebrates.

Growth factors and cytokines control and coordinate a broad spectrum of fundamental cellular functions, and are evolutionarily conserved both in vertebrates and invertebrates. In this review, we focus our attention on the functional phylogenetic aspects of growth factors/cytokines like the Transforming Growth Factor-beta (TGF-beta), the Connective Tissue Growth Factor (CTGF), and the Vascular Endothelial Growth Factor (VEGF). We will also delve into the activites of two chemokine families, interleukin (IL)-8 (or CXCL8) and CC chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2). These molecules have been selected for their involvement in immune responses and wound healing processes, where they mediate and finely regulate various regeneration processes like angiogenesis or fibroplasia, not only in vertebrates, but also in invertebrates.

Animals↗

PubMed2006

Cytokines and chemokines as regulators of angiogenesis in health and disease.

The intricate interplay between the endothelium and immune cells has been well recognized in the context of immune responses. However, the fact that this inter-relation extends well beyond immune regulation is becoming increasingly recognized, with particular regards to the influence of the immune system on the essential endothelial process of angiogenesis, where the contribution of cytokines drives the angiogenic process. As angiogenesis is an important component of numerous pathological states, among these chronic inflammatory conditions and cancer, understanding the role of cytokines and chemokines in guiding new vessel formation provides key insight into novel therapeutic modalities. Here we review the actions of principal cytokines and chemokines on the angiogenic process and discuss how both can be considered potential pharmaceutical targets or pharmaceuticals themselves for modulation of angiogenesis in chronic inflammation associated with cancer, rheumatoid arthritis and other inflammatory diseases.

Angiogenesis Inducing Agents↗

PubMed2005

WT1 expression in angiogenic tumours of the skin.

AIMS: To determine the expression of WT1 in endothelial proliferations and tumours. Endothelial cells are derived from angioblasts which differentiate into bone marrow stem cells (BMSC). BMSC are characterized by the constitutive expression of the WT1 gene and we have postulated that its expression may be maintained during the differentiation of angioblasts to endothelial cells. METHODS AND RESULTS: The expression of WT1 was studied in human umbilical vein-derived (HUVEC) and brain microvascular endothelial cells (HBME) as well as in a Kaposi sarcoma (KS) cell line in vitro. Forty-two human skin biopsy samples of endothelial proliferations and tumours were analysed for the protein expression of WT1 using the monoclonal antibodies for wt-WT1 (6F-H2) and its 17AA+ variant (2C12). WT1 expression was detectable in HUVEC and KS cells and all WT1 splice variants examined (17AA+/- KTS+/-) were detectable in KS cells, while the 17AA+/- and KTS- variants were present in HUVEC. Immunohistochemical analysis of the 42 human skin biopsy samples revealed cytoplasmic WT1 expression using wild-type specific antibody (6FH2) in microvessels, which is maintained during neoangiogenesis (inflammation, haemorrhage, peritumoral angiogenesis). Around one-third of haemangiomas (3/10) and non-HIV-Kaposi sarcomas (7/18) expressed the WT1 protein in the cytoplasm of tumour cells compared with its frequent expression in angiosarcomas (7/8) using the same antibody (6FH2). The nuclear 17AA+ isoform of WT1 was detectable at protein level in a small proportion of KS cases exclusively (3/7). CONCLUSION: Our data suggest that WT1 protein expression is maintained during angiogenesis and malignant transformation of endothelial cells and can be considered as a new endothelial marker.

Antigens, CD34↗

PubMed2004

Expression of CD44v3 protein in human endothelial cells in vitro and in tumoral microvessels in vivo.

The most universal angiogenic cytokines (VEGF, bFGF, HGF) are all heparin-binding proteins, the function of which is dependent on cell surface heparan sulfate proteoglycans (HSPG). Several proteoglycans have been demonstrated in endothelial cells, but only glypican-1 from the cell surface HSPG subfamily was documented at protein level. Here, we show that CD44v3 is expressed in human immortalized endothelial cells [anchorage-dependent human umbilical vein endothelial cells (HUVEC) and anchorage-independent Kaposi sarcoma (KS-Imm)] at mRNA and protein level, but is absent from the primary culture of human brain microvascular endothelial cells. We have shown that CD44v3 has a large cytoplasmic pool in endothelial cells, but a limited surface expression, mainly at filopodia, colocalized with MMP-2. Angiogenic factors like VEGF or bFGF did not affect surface detection of CD44v3 suggesting a constitutive expression. The putative functional role for endothelial cell surface CD44v3 was identified in chemotaxis assay when anti-CD44v3 antibody pretreatment proved to be inhibitory for HUVEC. Furthermore, we provided evidence for the CD44v3 protein expression in human endothelial cells in vivo in peritumoral microvessels of both human melanoma and glottic cancers, suggesting a role for this part-time heparan sulfate proteoglycan in tumor induced angiogenesis.

Base Sequence↗

PubMed2004

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy.

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-gamma and angiostatic CXCR3 chemokine ligands. Naked DNA intramuscular injection of an expression vector plasmid producing IL-12 resulted in significant, well-tolerated elevation of serum IL-12 levels. Injection of the IL-12 plasmid at least 2 days, and up to 20 days, before subcutaneous injection of matrigel with angiogenic factors resulted in strong prevention of angiogenesis in both C57/bl and nude mice. A single injection of the IL-12 plasmid contemporarily with the matrigel or 2 days after resulted in partial, statistically not significant, inhibition. Control plasmid injection did not affect either angiogenesis or angiogenesis inhibition by IL-12 protein in vivo. Angiogenesis inhibition was observed in NK cell-depleted C57/bl and nude mice as well as in IFN-gamma(-/-) and CXCR3(-/-) knockout mice, indicating that NK- and/or T-cell-initiated IFN-gamma-chemokine cascades were not involved in the angiogenesis inhibition observed in vivo. Finally, IL-12 plasmid DNA gene transfer significantly prevented the growth and vascularization of highly angiogenic KS-Imm Kaposi's sarcoma and TS/A murine mammary carcinoma tumors in nude and/or syngeneic mice. These data suggest that a preventive gene therapy approach using antiangiogenic cytokines can effectively inhibit tumor angiogenesis and KS, representing an example of angioimmunoprevention.

Animals↗

PubMed2003

Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives.

The recognition that angiogenesis is a key early event in tumor progression and metastasis has led to the development of new strategies for cancer therapy. The generation of a new blood vessel network under physiological conditions is regulated by the concerted action of activators and inhibitors. Perturbation of this balance, as it occurs in solid tumor growth and metastasis, appears to be a critical point in tumorigenesis. This has led to the "angiogenic switch" hypothesis: the point at which a tumor acquires the potential to induce angiogenesis is a critical step towards malignancy. Based on experimental evidence, prevention of blood vessel development appears to be the mechanism of action of many successful chemopreventive drugs of natural or synthetic origin: a novel concept that we termed "angioprevention". The hypothesis that anti-angiogenesis is at the basis of tumor prevention also suggests that many anti-angiogenic drugs could be used for chemoprevention in higher risk populations or in early intervention. There is a growing body of experimental evidence that anti-angiogenic strategies will contribute to the future therapy of cancer, several compounds with anti-angiogenic properties are now under clinical investigation including anti-inflammatory compounds, as inflammation may play a key role in angiogenesis. We must persevere in the development of novel, powerful and safer angiogenesis inhibitors and in the use of anti-angiogenic drugs in combination with other natural or synthetic anti-cancer agents in a biological therapy strategy.

Angiogenesis Inhibitors↗

PubMed2003

Photostability of extended-release matrix formulations.

The photostability of drugs has been widely studied while less attention is devoted to the possible modifications that UV light may induce on the excipients of a dosage form, in particular, on the functional polymers used to modulate drug delivery. In this work we have evaluated the effect of UV light on the release characteristics of extended-release matrix tablets containing hydroxypropylmethylcellulose (HPMC) or polyethylene oxide (PEO) as retarding polymers. Two different model drugs have been used: nifedipine (insoluble and photolabile drug) and diltiazem (soluble and photostable drug). Photodecomposition of nifedipine was evaluated and the formation of the photoproducts was followed during the dissolution process. Regarding the dissolution stability, the matrix tablets containing HPMC exposed to UV light have not shown significant differences in drug release profiles compared to the same non-irradiated formulation, while the matrix tablets containing PEO and exposed to the same conditions of UV light have shown a remarkable increase of drug release rate within the first minutes of the dissolution test (burst effect) which is particularly critical because it can cause the loss of the desired therapeutic control.

Chemistry, Pharmaceutical↗

PubMed2003

Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities.

Somatostatin was reported to inhibit Kaposi's sarcoma (KS) cell (KS-Imm) xenografts through an antiangiogenic activity. Here, we show that somatostatin blocks growth of established KS-Imm tumors with the same efficacy as adriamycin, a clinically effective cytotoxic drug. Whereas KS-Imm cells do not express somatostatin receptors (SSTRs), endothelial cells express several SSTRs, in particular SSTR3. We investigated the molecular mechanisms and receptor specificity of somatostatin inhibition of angiogenesis. Somatostatin significantly inhibited angiogenesis in vivo in the matrigel sponge assay; this inhibition was mimicked by the SSTR3 agonist L-796778 and reversed by the SSTR3 antagonist BN81658, demonstrating involvement of SSTR3. In vitro experiments showed that somatostatin directly affected different endothelial cell line proliferation through a block of growth-factor-stimulated MAPK and endothelial nitric oxide (NO) synthase (eNOS) activities. BN81658 reversed somatostatin inhibition of cell proliferation, NO production, and MAPK activity, indicating that SSTR3 activation is required for the effects of somatostatin in vitro. Finally in vivo angiogenesis assays demonstrated that eNOS inhibition was a prerequisite for the antiangiogenic effects of somatostatin, because high concentrations of sodium nitroprusside, an NO donor, abolished the somatostatin effects. In conclusion, we demonstrate that somatostatin is a powerful antitumor agent in vivo that inhibits tumor angiogenesis through SSTR3-mediated inhibition of both eNOS and MAPK activities.

Amides↗

PubMed2002

Differential effects of angiostatin, endostatin and interferon-alpha(1) gene transfer on in vivo growth of human breast cancer cells.

The administration of different angiogenesis inhibitors by gene transfer has been shown to result in inhibition of tumor growth in animal tumor models, but the potency of these genes has been only partially evaluated in comparative studies to date. To identify the most effective anti-angiogenic molecule for delivery by retroviral vectors, we investigated the effects of angiostatin, endostatin and interferon(IFN)-alpha(1) gene transfer in in vivo models of breast cancer induced neovascularization and tumor growth. Moloney leukemia virus-based retroviral vectors for expression of murine angiostatin, endostatin and IFN-alpha(1) were generated, characterized, and used to transduce human breast cancer cell lines (MCF7 and MDA-MB435). Secretion of the recombinant proteins was confirmed by biological and Western blotting assays. Their production did not impair in vitro growth of these breast cancer cells nor their viability, and did not interfere with the expression of angiogenic factors. However, primary endothelial cell proliferation and migration in vitro were inhibited by supernatants of the transduced cells containing angiostatin, endostatin, and IFN-alpha(1). Stable gene transfer of the IFN-alpha(1) cDNA by retroviral vectors in both MCF7 and MDA-MB435 cells resulted in a marked and long-lasting inhibition of tumor growth in nude mice that was associated with reduced vascularization. Endostatin reduced the in vivo growth of MDA-MB435, but not MCF7 cells, despite similar levels of in vivo production, and angiostatin did not impair the in vivo growth of either cell line. These findings indicate heterogeneity in the therapeutic efficacy of angiostatic molecules delivered by viral vectors and suggest that gene therapy with IFN-alpha(1) and endostatin might be useful for treatment of breast cancer.

Angiogenesis Inhibitors↗

PubMed2001

Noncommunicating photoreaction paths in some pregna-1,4-diene-3,20-diones.

The photochemistry of three pregna-1,4-diene-3,20-diones bearing a hydroxy or alkoxy group at C(17) (4-6) has been examined. Irradiation at 254 or 366 nm, where absorption by the cross-conjugated ketone moiety in ring A is predominant or exclusive, causes the 'lumiketone' rearrangement of this chromophore in low to medium quantum yield (Phi(r) 0.05 to 0.31). On the contrary, irradiation at 310 nm, where the isolated ketone at C(20) absorbs a large portion of light causes Norrish-I fragmentation of that chromophore with a higher Phi(r) (0.11-0.83). This leads to end-products arising from the conversion of the C(17) alkyl radical, in a way depending on the structure and the medium (reduction by hydrogen donating solvent, addition of oxygen when present). No intramolecular T-T energy transfer between the separated chromophores occurs. The 'lumiketone' rearrangement occurs independently from the irradiation wavelength (Phi(r) 0.06-0.18) with the strictly related androsta-1,4-dien-3-one 8 lacking the C(20) ketone function.

Androstadienes↗

PubMed2001

Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine.

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi's sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.

Acetylcysteine↗

PubMed2001

Hydrocarbon activation. Synthesis of beta-cycloalkyl (di)nitriles through photosensitized conjugate radical addition.

Photoinduced hydrogen abstraction from aliphatic cyclic hydrocarbons (C(5) to C(7), C(12), as well as adamantane) by triplet aromatic ketones in the presence of alpha,beta-unsaturated (di)nitriles offers a straightforward entry to the corresponding alkylated (di)nitriles via the alkyl radicals. Yields are moderate to good depending on the olefins structure (substitution in beta slows down the addition to mononitriles, but with alpha,alpha-dinitriles electronic activation allows efficient alkylation also of beta,beta-disubstituted substrates). A tandem alkylation-cyclization process has been obtained with (1-methylpent-4-enylidene)malononitrile.

Journal Article↗

PubMed2001

HIV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons.

We investigated the role of the HIV-1 protein Tat in AIDS-associated dementia, by studying its toxicity on rat cortical and hippocampal neurons in vitro. We evaluated the involvement of astroglial cells and of caspase transduction pathway in determining Tat toxicity. Here we report that synthetic Tat(1-86) induced apoptotic death on cultured rat neurons in a time-dependent manner that was not influenced by glial coculture, and that was abolished by blocking caspase transduction pathway. A microfluorimetric analysis on the Tat excitatory properties on neurons, and its effect on intracellular calcium concentrations, revealed that Tat(1-86) induced increase in cytoplasmic free calcium concentrations in rat hippocampal and cortical neurons. This effect required extracellular calcium and was differently reduced by voltage dependent calcium channel blockers and both NMDA and non-NMDA glutamate receptors antagonists. Furthermore, we observed that Tat(1-86)-treated neurons showed increased sensitivity to the glutamate excitotoxicity. Thus, the Tat-induced neuronal injury seems to occur through a direct interaction of the protein with neurons, requires activation of caspases, and is likely to derive from Tat(1-86)-induced calcium loads and disruption of glutamatergic transmission.

Animals↗

PubMed2001

Generation and reactivity of the 4-aminophenyl cation by photolysis of 4-chloroaniline.

4-Chloroaniline and its N,N-dimethyl derivative are photostable in cyclohexane but undergo efficient photoheterolysis in polar media via the triplet state and give the corresponding triplet phenyl cations. CASSCF and UB3LYP calculations show that the 4-aminophenyl triplet cation has a planar geometry and is stabilized by >10 kcal mol(-1) with respect to the slightly bent singlet. The triplet has a mixed carbene-diradical character at the divalent carbon. This species either adds to the starting substrate forming 5-chloro-2,4'-diaminodiphenyls (via an intermediate cyclohexadienyl cation) or is reduced to the aniline (via the aniline radical cation) in a ratio depending on the hydrogen-donating properties of the solvent. Transients attributable to the triplet aminophenyl cation as well as to the ensuing intermediates are detected. Chemical evidence for the generation of the phenyl cation is given by trapping via electrophilic substitution with benzene, mesitylene, and hexamethylbenzene (in the last case the main product is a 6-aryl-3-methylene-1,4-cyclohexadiene). Relative rates of electrophilic attack to benzene and to some alkenes and five-membered heterocycles are measured and span over a factor of 15 or 30 for the two cations. The triplet cation formed under these conditions is trapped by iodide more efficiently than by the best pi nucleophiles. However, in contrast to the singlet cation, it does not form ethers with alcohols, by which it is rather reduced.

Journal Article↗

PubMed2001

Photoinduced, ionic Meerwein arylation of olefins.

Irradiation of 4-chloroaniline or of its N,N-dimethyl derivative in polar solvents generates the corresponding triplet phenyl cations. These are trapped by alkenes yielding arylated products in medium to good yields. B3LYP calculations show that the triplet cation slides with negligible activation energy to a bonded adduct with ethylene, whereas it forms only a marginally stabilized CT complex with water (chosen as a representative sigma nucleophile). The structure of the final products depends on the preferred path from the adduct cation with the alkene. In the case of aryl olefins, this deprotonates to stilbene derivatives, while, from 2,3-dimethyl-2-butene and allytrimethylsilane, allylanilines are obtained by elimination of an electrofugal group in gamma. In the case of mono- and disubstituted alkenes the cation adds chloride rather than eliminating and beta-chloroalkylanilines are obtained. The regio- and sterochemistry of the addition across the alkene are best understood with a phenonium ion structure for the adduct. The nucleophile entering in beta can be varied under conditions in which the adduct cation is trapped more efficiently than the starting phenyl cation. Thus, beta-methoxyalkylanilines are formed when the irradiation is carried out in methanol. beta-Iodoalkylanilines are obtained in acetonitrile containing iodide and unsubstituted alkylanilines in the presence of sodium borohydride. A case of intramolecular nucleophilic trapping is found with 4-pentenoic acid. The reaction is a wide-scope ionic analogue of the radicalic Meerwin arylation of olefins.

Journal Article↗

PubMed2001

Multiple points of intervention in the prevention of cancer and other mutation-related diseases.

Multiple points of intervention are the target for dietary and pharmacological interventions aimed at preventing cancer and other diseases in which mutations in somatic cells play a pathogenetic role. For instance, our studies showed that DNA adducts can be consistently detected in arterial smooth muscle cells from human atherosclerotic lesions. Their levels were significantly correlated with the occurrence of atherogenic risk factors known from traditional epidemiology and were strikingly enhanced in atherosclerotic patients lacking the GSTM1 genotype. Cancer chemoprevention has a dual goal, i.e. prevention of occurrence of the disease (primary prevention) and early detection and reversion of tumors at a premalignant stage (secondary prevention). At a later stage, attempts can be made to prevent local recurrences as well as invasion and metastasis of malignant cells (tertiary prevention). For a rational use of chemopreventive agents it is essential not only to evaluate their efficacy and safety but also to understand the mechanisms involved. Sometimes it is difficult to discriminate whether modulation of a given end-point is actually a specific mechanism or rather the epiphenomenon of other events. For instance, we recently found that apoptosis is considerably stimulated in the respiratory tract of smoke-exposed rats; whereas certain chemopreventive agents work by further enhancing smoke-related apoptosis, other agents appear to downregulate apoptosis simply because they inhibit the genotoxic events signaling this process. We propose here a detailed, updated classification of the points of intervention exploitable in the prevention of mutation and cancer. The general outline includes a variety of extracellular and cellular mechanisms modulating the genotoxic response and tumor initiation as well as tumor promotion, progression, angiogenesis, invasion, and metastasis. This classification is not intended to provide a rigid scheme, since several intervention points are reiterated several times over different phases of the process. Moreover, some mechanisms are strictly interconnected or partially overlapping. Interestingly, a number of chemopreventive agents work through multiple mechanisms, which warrants a higher efficacy and a broader spectrum of action. It is also convenient to combine chemopreventive agents working through complementary mechanisms. In recent preclinical studies, we observed that combination of N-acetylcysteine with either oltipraz or ascorbic acid produces additive or more than additive protective effects towards early biomarkers and/or experimentally-induced tumors.

Animals↗