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

Some new methyl-8-methoxypsoralens: synthesis, photobinding to DNA, photobiological properties and molecular modelling.

The tricyclic structure of known natural photochemotherapeutic drugs as 8-methoxypsoralen and 5-methoxypsoralen is often taken as a model in the search of new sensitizer agents with less phototoxic and mutagenic effects. This paper describes the synthesis, characterization, photobinding to DNA, photobiological properties and computational chemistry of some 8-methoxypsoralen derivatives bearing two or three methyl groups at the key positions of the two photoactive double bonds. Results showed that photoreactivity and photobiological behavoiur depend on thr pattern of methyl sustitutions. Antiproliferative activity in cell lines shows good correlation with DNA interaction data

Methyl derivatives of tetracyclic psoralen analogues: antiproliferative activity and interaction with DNA

A number of new tetracyclic psoralen derivatives were studied. The fourth ring is constituted by cyclopentane (4, 7 and 9), cyclohexane (11, 15 and 18) or benzene (12, 16 and 20) fused to either 4',5' or 3,4 photoreactive double bond of tricyclic furocoumarin moiety. The photoantiproliferative activity of all compounds, tested on two human tumor cell lines (HeLa and HL-60), appeared from 8 to 22 times higher than that of the well-known photochemotherapeutic drug 8-methoxypsoralen (8-MOP) in HeLa, slightly higher in HL-60. Interestingly, the evaluation of skin phototoxicity on guinea pigs evidenced a decrease in erythema induction for all compounds with respect to the drug. As regards the molecular mechanism of action, the ability to photoadd to DNA is demonstrated by isolation and characterization of the photoadducts and by the ability to give rise to interstrand cross-links for the difunctional derivativesS

Photoaddition of thienocoumarin derivatives to DNA: stoichiometry and kinetics of binding

Photoreaction of the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II) to DNA was studied. The quantitative evaluation of the photo- bound molecules was performed by means of inductively coupled plasma atomic emission spectrometry (ICP-AES), exploiting the presence of the sulphur atom inside the tricyclic chromophore. The concurrent estimation of the phosphorus atom, present exclusively in the macromolecule, allowed possible intercalation sites to be identi\ufb01ed and their involvement in the photoaddition reaction to be determined. The development of a kinetic model made it possible to discriminate and evaluate the single kinetic events that constitute the overall photoaddition process of I and II to DNA

Methyl derivatives of tetracyclic psoralen analogues: antiproliferative activity and interaction with DNA

A number of new tetracyclic psoralen derivatives were studied. The fourth ring is constituted by cyclopentane (4, 7 and 9), cyclohexane (11, 15 and 18) or benzene (12, 16 and 20) fused to either 4',5' or 3,4 photoreactive double bond of tricyclic furopcoumarin moiety. The photoantiproliferative activity of all compounds, tested on two human tumor cell lines (HeLa and HL60), appeared from 8 to 22 times higher than that of the well-known photochemotherapeutic drug 8-methoxypsoralen (8-MOP) in HeLa, slightly higher in HL60. Interestingly, the evaluation of skin phototoxicity on guinea pigs evidenced a decrease in erythema induction for all compounds with respect to the drug. As regards the molecular mechanism of action, the ability to photoadd to DNA is demonstrated by isolation and characterization of the photoadducts and by the ability to give rise to interstrand cross-links for the difunctional derivatives

Synthesis and biological activity of linear and angular 4-methoxymethylthienocoumarins and 4-acetoxymethylthienocoumarins.

This paper reports the synthesis of 4-methoxymethyl and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one as well as 4-methoxymethyl- and 4-acetoxymethyl-6,9-dimethyl-2H-thieno[2,3-h]-1-benzopyran-2-one. The synthesized derivatives were tested on human cells in UVA irradiation conditions. Skin phototoxicity and cross-link formation in DNA were also studied. Results indicate that the new thienocoumarins have good antiproliferative activity, greater than that of the well-known photochemotherapeutic drug 8-methoxypsoralen, but they are practically devoid of skin photosensitization effects

New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction and antiproliferative activity.

The synthesis of new tetrahydrobenzo- and benzopsoralen derivatives carrying at position 5 or 8 of the furocoumarin moiety a methoxy, hydroxy, or dimethylaminopropoxy side chain is reported. The study of their photoantiproliferative activity and ability to induce erythema on guinea pig skin allows us to state that the derivatives carrying the dimethylaminopropoxy side chain exhibit a very interesting photobiological pattern. Indeed, if compared with the lead compounds 5-MOP and 8-MOP, they exert a higher cytotoxic activity devoid of significant skin phototoxicity. Between them, the more interesting appears to be 16, a nonphototoxic compound whose antiproliferative activity on HeLa cells is 2 orders of magnitude higher than that of the reference drug 8-MOP. Photoreaction experiments have revealed that, like classic furocoumarins, A-T is the preferred nucleic base pair in its photobinding. Moreover, the extent of covalent photoaddition to DNA correlates well with the photobiological activity. For this compound a certain effect was also observed in the dark. Evaluation of the ability to induce DNA cleavage in the presence of human topoisomerase II has suggested that this enzyme is probably the target accountable for this effect

Thienocoumarin derivatives: interaction with nucleic acids and synthetic polydeoxyribonucleotides

This paper reports the photobiological properties of two new thienocoumarins, 4,6,9-trimethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound I) and the 6,9-dimethyl-4-methoxymethyl-2H-thieno[3,2-g]-1-benzopyran-2-one (compound II). Cell growth inhibition studies have revealed significant antiproliferative potency on human tumor cell lines. The photoaddition process of these tritium-labeled derivatives was investigated using various nucleic acid structures (calf thymus DNA, bacterial DNA, and synthetic polydeoxyribonucleotides). The results obtained show that both compounds photobind to DNA to a higher extent than 8-MOP, taken as the reference drug. The capacity to form interstrand crosslinks into DNA helix was also evaluated. Interestingly, notwithstanding the lack of cutaneous phototoxicity, II revealed a good ability to induce diadduct formation