RESUMO
Some photobiological properties of 1'-thieno-4,6,4'-trimethylangelicin (TTMA), a new isoster of 4,6,4'-trimethylangelicin (TMA) were studied in comparison with the parent compound. The TTMA absorbs UVA light and photobinds in vitro to DNA more efficiently than TMA; however, in Ehrlich cells in vivo TTMA linked to DNA to a lesser extent than the parent compound. In general, the formation of damage into DNA is in line with this last result: In fact, TTMA and TMA form equivalent amounts of interstrand cross-links (ISC) both in vitro in linearized PM2 DNA and in vivo in HeLa cells. In this system TTMA induces DNA-protein cross-links (DPC) more efficiently than TMA; on the contrary, no significant amounts of single-strand breaks were detected with both compounds. The antiproliferative activity of TTMA is consistent with these results, being only slightly more pronounced than that of TMA. Experiments carried out using double irradiation demonstrated that these drugs are capable of inducing antiproliferative effects by biphotonic reactions, including the formation of both ISC and DPC. Thus, replacement of the oxygen atom by a sulfur increases the UV absorption of the drug and its capacity to photobind to DNA in vitro but does not yield a comparable enhancement of its photosensitizing properties in vivo; this might be due to various reasons, for instance to an increase in the lipophilic character that could modify the behavior in vivo.
Assuntos
Furocumarinas/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Carcinoma de Ehrlich/tratamento farmacológico , Divisão Celular/efeitos dos fármacos , Dano ao DNA , Células HeLa , Humanos , Camundongos , Fotoquimioterapia , Células Tumorais CultivadasRESUMO
The mechanism of action of two tetrahydrobenzopsoralenquinones: 4-methyl-tetrahydrobenzopsoralenquinone (compound 3) and 4-hydroxymethyltetrahydrobenzopsoralenquinone (compound 4) was studied in mammalian cells. These agents differ structurally from earlier benzo and tetrahydrobenzopsoralen derivatives 4-hydroxymethylbenzopsoralen (compound 1) and 4-hydroxymethyltetrahydrobenzopsoralen (compound 2) by the replacement of the benzopyranone with a quinonepyranone. In this study, we evaluated the antiproliferative activity of such derivatives in normal human lymphocytes and CHO cells cultivated in vitro. Compound 4 showed a noticeable antiproliferative activity. Studying the induction of chromosomal aberrations and of SCEs, we demonstrated that compound 4 has a clastogenic effect on mammalian cells. By means of DNA filter elution and protein precipitation techniques we evaluated the DNA damage produced by the tested compounds. Some experiments performed in presence of a DNA synthesis inhibitor showed that ongoing DNA synthesis is involved in cell killing by derivative 4. All data obtained suggest that compound 4 can interfere with the activity of topoisomerase II. Catalytic studies carried out with purified topoisomerase II and bacteriophage DNA confirmed this hypothesis.