[Abstract unavailable

The development of photoactivatable prodrugs of platinum-based antitumor agents is aimed at increasing the selectivity and hence lowering toxicity of this important class of antitumor drugs. These drugs could find use in treating localized tumors accessible to laser-based fiber-optic devices. Pt(IV) complexes appeared attractive because these octahedral complexes are usually substitution inert and require reduction to the Pt(II) species to become cytotoxic. Based on the knowledge of Pt(IV) photochemistry, Pt(IV) analogs of cisplatin, [Pt(en)Cl(2)] and transplatin were designed, synthesized and investigated for their ability to be photoreduced to cytotoxic Pt(II) species. Two classes of photoactivatable Pt complexes have been looked at thus far: diiodo-Pt(IV) and diazido-Pt(IV) diam(m)ine complexes. The first generation, diiodo-Pt(IV) complexes, represented by cis, trans-[Pt(en)(I)(2)(OAc)(2)], react to visible light by binding irreversibly to DNA and forming adducts with 5'-GMP in the same manner as [Pt(en)Cl(2)]. Furthermore, the photolysis products are cytotoxic to human cancer cells in vitro. However, these complexes are too reactive towards biological thiols (i.e., glutathione), which rapidly reduced them to cytotoxic Pt(II) species, thus making them unsuitable as drugs. The second generation, diazido-Pt(IV) complexes, represented by cis, trans, cis-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] and cis, trans-[Pt(en)(N(3))(2)(OH)(2)], are also photosensitive, binding irreversibly to DNA and forming similar products with DNA and 5'-GMP in the presence of light as the respective Pt(II) complexes. However, they are stable to glutathione and thus show very low dark cytotoxicity. Light of lambda(irr) = 366 nm activates both complexes to cytotoxic species that effectively kill cancer cells by destroying their nuclei, leaving behind shrunken cell ghosts. Interestingly, the all-trans analog, trans, trans, trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] is non-toxic to HaCaT keratinocytes in the dark, but as active as cisplatin in the light. These studies show that photoactivatable Pt(IV) antitumor agents represent a promising area for new drug development.

A possible way to avoid dose-limiting side effects of platinum anticancer drugs is to employ light to cause photochemical changes in nontoxic platinum prodrugs that release active antitumor agents. This strategy could be used in the treatment of localized cancers accessible to irradiation (e.g., bladder, lung, esophagus, and skin). We report here that nontoxic photolabile diam(m)ino platinum(IV) diazido complexes inhibit the growth of human bladder cancer cells upon irradiation with light, and are non-crossresistant to cisplatin. Their rate of photolysis closely parallels that of DNA platination, indicating that the photolysis products interact directly, and rapidly, with DNA. Photoactivation results in a dramatic shrinking of the cancer cells, loss of adhesion, packing of nuclear material, and eventual disintegration of their nuclei, indicating a different mechanism of action from cisplatin.

BackgroundRecent years have witnessed that there is a revival of interest in drug discovery from medicinal plants for the maintenance of health in all parts of the world. The aim of this work was to investigate 26 plants belonging to 17 families collected from a unique place in Yemen (Soqotra Island) for their in vitro anticancer, antimicrobial and antioxidant activities.MethodsThe 26 plants were extracted with methanol and hot water to yield 52 extracts. Evaluation for in vitro anticancer activity was done against three human cancer cell lines (A-427, 5637 and MCF-7) by using an established microtiter plate assay based on cellular staining with crystal violet. Antimicrobial activity was tested against three Gram-positive bacteria, two Gram-negative bacteria, one yeast species and three multiresistant Staphylococcus strains by using an agar diffusion method and the determination of MIC against three Gram-positive bacteria with the broth micro-dilution assay. Antioxidant activity was investigated by measuring the scavenging activity of the DPPH radical. Moreover, a phytochemical screening of the methanolic extracts was done.ResultsNotable cancer cell growth inhibition was observed for extracts from Ballochia atro-virgata, Eureiandra balfourii and Hypoestes pubescens, with IC50 values ranging between 0.8 and 8.2 μg/ml. The methanol extracts of Acanthospermum hispidum, Boswellia dioscorides, Boswellia socotrana, Commiphora ornifolia and Euphorbia socotrana also showed noticeable antiproliferative potency with IC50 values < 50 μg/ml. The greatest antimicrobial activity was exhibited by extracts from Acacia pennivenia, Boswellia dioscorides, Boswellia socotrana, Commiphora ornifolia, Euclea divinorum, Euphorbia socotrana, Leucas samhaensis, Leucas virgata, Rhus thyrsiflora, and Teucrium sokotranum with inhibition zones > 15 mm and MIC values ≤ 250 μg/ml. In addition, the methanolic extracts of Acacia pennivenia, Boswellia dioscorides, Boswellia socotrana and Commiphora ornifolia showed good antioxidant potential at low concentrations (more than 80% at 50 μg/ml).ConclusionOur results show once again that medicinal plants can be promising sources of natural products with potential anticancer, antimicrobial and antioxidative activity. The results will guide the selection of some plant species for further pharmacological and phytochemical investigations.

The aim of this work was 2-fold: (i) to identify correlations between the activities of pairs of 19 anti-tumor agents in a mini-panel of 14 human cancer cell lines of diverse origins with the goal of validating the panel, and (ii) to look for correlations between the activities of 19 standard anti-tumor agents and the intracellular concentrations of glutathione (GSH). Validation with analogous data from the National Cancer Institute (NCI) Developmental Therapeutics Program was made. The cell growth inhibition potencies of the anti-tumor agents [cisplatin, carboplatin, oxaliplatin, DACH-Pt, melphalan, chlorambucil, thiotepa, busulfan, doxorubicin, etoposide, camptothecin, vinblastine, podophyllotoxin, colchicine, taxol, hydroxyurea, methotrexate, 5-azacytidine and 5-fluorouracil (5-FU)] were estimated in 14 cancer cell lines by their GI50 values. An enzymatic assay based on the method of Tietze was employed to measure intracellular total GSH concentrations. The Delta method was used to compare pairs of anti-tumor agents; similarities and differences in activity profiles (mean graphs) were evaluated by regression analysis. Most, but not all, of the correlations could be explained based on similarities in the mechanisms of action and many correlations/non-correlations were also observed in the NCI data. Some correlations were unexpected however, and not seen in the NCI data. For example, strong positive correlations (P < 0.01) were found between the GI50 values of melphalan/chlorambucil and the anti-mitotic agents. Similarly unexpected, a strong positive correlation was observed between methotrexate and cisplatin (P < 0.01). Interestingly, moderate to strong negative correlations (P < 0.01-0.05) were found between the GI50 values of 5-FU and the anti-mitotic agents/melphalan/chlorambucil. Significant positive correlations between intracellular GSH concentrations and GI50 values were found only for thiotepa (P < 0.05) and doxorubicin (P < 0.01). Data from a NCI panel of 34 cancer cell lines showed no correlations between GSH levels and the GI50 values of the same 19 compounds. In conclusion, a panel of 14 human cancer cell lines of diverse origin was used to identify similarities and differences in the activities of standard anti-tumor agents. The level of significance was stronger with the 34 cell lines of the NCI, however. Our results indicate that GSH intracellular concentrations correlate with resistance only with doxorubicin and thiotepa in these cell lines.