Lisa Dalla Via

Photochemotherapy in the Treatment of Cancer

The development of therapies which are selective for tumor tissues is one of the most important goals in anticancer research. Within this framework photochemotherapy can be considered a very promising approach. Its therapeutic effectiveness depends on two connected factors: drug and light. The drug (photosensitizer) is able to exert an antiproliferative effect only after interaction with suitable light. Both the photosensitizing drug and light alone are ineffective at doses used for these treatments. Nowadays, photochemotherapy is used in the treatment of cutaneous T-cell lymphoma and cavitary tumors. In the first case the photosensitizer is a psoralen derivative (P) and long-wavelength ultraviolet radiation (UVA) is used (PUVA therapy). In the second case, the treatment with porphyrins, porphyrin-based and non porphyrin-based photosensitizers is followed by irradiation with 600-1000 nm light (photodynamic therapy, PDT). This review is concerned with PUVA and PDT treatments of cancer. The molecular mechanisms considered accountable for the photochemotherapeutic effects are discussed, the development of new chemical structures aimed at improving the effectiveness and/or overcoming some undesired side effects will also be reported. Moreover, some clinical applications will be described.

Epithelial–mesenchymal transition in malignant mesothelioma

Epithelial–mesenchymal transition is a physiopathological process by which epithelial cells acquire mesenchymal shape and properties. Malignant mesothelioma is histologically characterized by the concomitant presence of epithelioid and sarcomatoid features, the latter being associated to worse prognosis, thus suggesting a role of epithelial–mesenchymal transition in this dual phenotype. We studied 109 malignant mesotheliomas (58 epithelioid, 26 sarcomatoid, and 25 biphasic) by immunohistochemistry and qRT–PCR analysis, and demonstrated a substantial switch from epithelial markers (E-cadherin, β-catenin, and cytokeratins 5/6) to mesenchymal markers (N-cadherin, vimentin, α-smooth muscle actin, Snail, Slug, Twist, ZEB1, ZEB2, S100A4, MMP2, and MMP9) through epithelioid to biphasic and sarcomatoid histotypes. In agreement with these findings, the ectopic expression of miR-205 (a repressor of ZEB1 and ZEB2 expression) in MeT-5A (mesothelial cell line), H2452 (an epithelioid malignant mesothelioma cell line) and MSTO-211H (a biphasic malignant mesothelioma cell line) not only induced a significant reduction of ZEB1 and ZEB2 and a consequent up-regulation of E-cadherin gene expression, but also inhibited migration and invasion. Moreover, miR-205 was significantly down-regulated in biphasic and sarcomatoid histotypes (qRT–PCR and in situ hybridization analyses). Collectively, our findings indicate that epithelial–mesenchymal transition has a significant part in the morphological features of malignant mesothelioma. In particular, miR-205 down-regulation correlated significantly with both a mesenchymal phenotype and a more aggressive behavior.

Synthesis, in vitro antiproliferative activity and DNA-interaction of benzimidazoquinazoline derivatives as potential anti-tumor agents

The synthesis of benzimidazoquinazoline derivatives bearing different alkylamino side chains is reported. All new compounds tested by means of an in vitro assay exhibit antiproliferative activity toward human tumor cell lines. The cytotoxic effect depends on the type of side chain inserted in the planar nucleus and in some cases it is comparable to that of the well-known drug ellipticine. In order to understand the mechanism of action of these compounds, the interaction with DNA has been investigated. Linear flow dichroism measurements allowed us to verify the formation of a molecular complex with DNA and the corresponding geometry of interaction. Intrinsic binding constants have also been evaluated by performing fluorimetric titrations.

Synthesis, DNA binding and in vitro antiproliferative activity of purinoquinazoline, pyridopyrimidopurine and pyridopyrimidobenzimidazole derivatives as potential antitumor agents

Abstract In the search for new antitumor agents, 8,10-dimethylpurino[7,8-a]quinazoline-5,9, 11(6H,8H,10H)-triones 1 , 8,10-dimethylpyrido [2′,3′:4,5]pyrimido[1,2-f]purine-5,9,11 (6H,8H, 10H)-triones 2 , and 5,7-dihydro-5-oxopyrido[3′,2′:5,6]pyrimido[1,2-a]benzimidazoles 3 , a series of new planar heteropolycyclic compounds, were synthesized. The approach to understanding their structure-activity relationship involved a physico-chemical investigation of the binding process of these molecules to DNA, considered to be an important target for drug action, and an examination of their biological activity. Thermodynamic parameters of the DNA binding process, intrinsic binding constant and exclusion parameter were determined. The mode of interaction was additionally investigated by means of linear flow dichroism studies. Evaluation of the biological activity included cell growth inhibition in human tumoral cell lines and the ability to induce DNA cleavage in the presence of eukaryotic topoisomerase II. Only compounds of the purinoquinazoline series 1 , which are able to form a complex with DNA and to inhibit the topoisomerase II, show antiproliferative activity.

Targeting the ubiquitin–proteasome pathway with inorganic compounds to fight cancer: a challenge for the future

Proteasomes are large multicatalytic complexes endowed with proteinase activity, located both in the cytosol and in the nucleus of eukaryotic cells. The ubiquitin-proteasome system is responsible for selective degradation of most intracellular proteins and therefore plays an essential regulatory role in many critical cellular processes. The proteasomal activity can also contribute to the pathological states of many diseases, including inflammation, neurodegeneration and cancer, through a disregulation in the level of regulatory proteins. These diseases may be targeted by modulating components of the ubiquitin-proteasome pathway, using small molecules as inhibitors. Bortezomib (Velcade(®)), used for the treatment of relapsed multiple myeloma, is the first and, up to now, the only proteasome inhibitor approved by the US FDA. Nowadays, the discovery that some metal-based complexes exert their antiproliferative action by affecting proteasomal activities provides the possibility of developing new opportunities in cancer therapy.

Spermine binding to liver mitochondria.

Non-equilibrium binding of spermine to mitochondrial membranes is studied in rat liver mitochondria by applying a new thermodynamic treatment of ligand-receptor interactions (Di Noto, V., Dalla Via, L., Toninello, A. and Vidali, M. (1996) Macromol. Theory Simul. 5, 165-181). The presence on mitochondrial membranes of two spermine binding sites, both with monocoordination, is demonstrated. The calculated binding energy is characteristic for weak interactions. The treatment allows also to evaluate the variations of the molar fraction ratio of spermine bound to sites 1 and 2 as function of total bound spermine. The possible role of the two sites is discussed.

Synthesis and biological evaluation of new camptothecin derivatives obtained by modification of position 20

The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC(50) values ranging from 0.03 to 12.2 μM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.

DNA binding ellipticine analogues: synthesis, biological evaluation, and structure-activity relationships.

Novel angular and branched ellipticine‐correlated anticancer agents were developed. In particular, compound 24, with two basic side chains on opposite sides of the molecule, exhibits cytotoxicity in the nanomolar range, acting as a DNA intercalator and topoisomerase II inhibitor. SAR studies with pyridocarbazole derivatives in comparison with corresponding smaller pyrroloquinolines are discussed.

A new benzoangelicin with strong photobiological activity.

Benzoangelicins 4-6 were synthesized in good yields from 7-hydroxy-5-methoxy-4-methylcoumarin (1). In the absence of UVA radiation, compounds 5 and 6 were only weakly active against HL60 and HeLa tumour cells; in its presence, compound 6 was 10 times more active than the reference compound 8-methoxypsoralen. None of 4-6 exhibited cutaneous phototoxicity.

Dialkylaminoalkylindolonaphthyridines as potential antitumour agents: Synthesis, cytotoxicity and DNA binding properties

The synthesis of new planar derivatives characterised by the presence of an indolonaphthyridine nucleus, carrying a dimethylaminoethyl or a dimethylaminopropyl side chain is reported. The antiproliferative activity of the new products was tested by means of an in vitro assay on human tumour cell lines (HL-60 and HeLa). A number of compounds (1a-d, 1h) showed IC(50) values comparable to that obtained with the well-known drug ellipticine on the HL-60 cell line. The interaction with DNA was also investigated. Linear flow dichroism measurements allowed us to understand the interaction geometry. The thermodynamic parameters of the binding process, i.e. intrinsic binding constant and exclusion parameter, were determined by fluorimetric titration.