D. Mourelatos

Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects.

The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2].H2O and [Pd(AcTsc)2] while the rest, i.e. (HAcTsc), [Pt(AcTsc)Cl], [Pt(HAcTsc)2]Cl2.2H2O, [Pd(AcTsc)Cl] and [Pd(HAcTsc)2]Cl2, displayed marginal cytogenetic and antitumor effects.

Frequencies of chromosomal aberrations in pesticide sprayers working in plastic green houses

The frequency of chromosome aberrations was studied in peripheral blood lymphocytes of 29 workers occupationally exposed to a mixture of pesticides and in 14 age- and sex-matched healthy controls. There was a significant increase in chromosome aberrations in sprayers when compared to unexposed persons (2.39% compared to 0.54%). No positive correlation between the frequency of chromosome aberrations and the duration of exposure was observed. No significant difference between smokers and non-smokers was found.

Chlorpromazine-induced damage on nucleic acids: a combined cytogenetic and biochemical study.

Chlorpromazine is now emerging as an adjuvant chemotherapeutic agent for the treatment of neoplasia. This was further supported in the present study by the following lines of evidence: it was shown that chlorpromazine causes damage in a series of native nucleic acids, though at somewhat high concentrations. Furthermore, chlorpromazine and caffeine were shown to act synergistically to potentiate the cytogenetic effect of adriamycin on human lymphocytes in vitro and on Ehrlich ascites tumour (EAT) cells in vivo. It is suggested that chlorpromazine alone or in combination with caffeine may exert its cytotoxic effect on normal and neoplastic cells not only indirectly, i.e. by facilitating the intracellular retention of adriamycin, but also directly by intercalating into nucleic acids.

Antineoplastic and Cytogenetic Effects of Platinum(II) and Palladium(II) Complexes with Pyridine-2-Carboxyaldehyde-Thiosemicarbazone

The effect of six novel complexes of Pt(II) and Pd(II) with pyridine-2-carboxyaldehyde thiosemicarbazone (HPyTsc) on sister chromatid exchange rate and human lymphocyte proliferation kinetic was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing cytogenetic and antineoplastic effects are the complexes [Pd(PyTsc)2] and [Pt(PyTsc)2]. Next in order of magnitude in inducing antineoplastic and cytogenetic effects is the compound [Pt(HPyTsc)2]Cl2 while the rest, i.e. [Pd(PyTsc)Cl], HPyTsc, [Pd(HPyTsc)2]Cl2, and [Pt(PyTsc)Cl], show marginal cytogenetic and antineoplastic effects.

Sister chromatid exchanges in lymphocytes of psoriatics after treatment with 8-methoxypsoralen and long wave ultraviolet radiation.

Sister chromatid exchange rates in cultured cells from the blood of patients receiving photochemotherapy have been examined as an indicator of possible genetic hazards of the treatment to patients with psoriasis. Lymphocytes of untreated patients with psoriasis appear to have sister chromatid exchange rates after 72 h of culture indistinguishable from normal subjects and there is no evidence from these studies that sister chromatid exchanges are significantly increased in the lymphocytes of patients receiving photochemotherapy. Cells from blood taken from patients who had been given 8-methoxypsoralen orally 2 h before and then irradiated with UV-A in vitro were found to have an increased exchange rate which could be related to the presence of the drug in the peripheral circulation.

Genotoxic and cytotoxic effects of different types of dental cement on normal cultured human lymphocytes

In this study we have investigated the genotoxic and cytotoxic effects of eluates derived from different types of commercially available dental cements, including glass ionomer cements (GICs) (Ketac Cem/3M ESPE and GC Fuji I/GC Corp), resin-modified glass ionomer cements (RM-GICs) (RelyX Luting/3M ESPE and Vitrebond/3M ESPE) and dual-cure resin cements (RCs) (Variolink II/ Ivoclar-Vivadent and Panavia F 2.0/Kuraray) on normal cultured human lymphocytes. Lymphocyte primary cultures obtained from blood samples of three healthy donors were exposed to serial dilutions of eluates derived from specimens of each material tested. Metaphases were induced with phytohaemagglutinin, collected after 72h treatment by use of colchicine and stained according to the fluorescence plus giemsa (FPG) procedure. Preparations were scored for sister chromatid exchange (SCE) and chromosomal aberrations (CAs), while the proliferation rate index (PRI) was also calculated. Our results show that eluates derived from the RM-GICs and RCs caused severe genotoxic effects by significantly increasing the frequencies of SCEs and CAs in cultures of peripheral blood lymphocytes and by decreasing the relevant PRI values in a dose-dependent manner, whereas the two GICs caused only minor cytogenetic effects. Eluates of the two RM-GICs (Vitrebond and RelyX) were also very cytotoxic, as the first serial dilutions of both materials caused a complete mitotic arrest in lymphocyte cultures. Overall, the degree of genotoxicity and cytotoxicity caused by dental cements decreased as follows: Viterbond>Rely X>Panavia F 2.0>Variolink II>Ketac Cem=GC Fuji I. These results indicate that different types of dental cement differ extensively in their genotoxic and cytotoxic potential and their ability to affect chromosomal integrity, cell-cycle progression, DNA replication and repair. Although these results cannot be directly extrapolated to the clinical situation, the potential occurrence of adverse effects caused by the RM-GICs and RCs tested in this study should be considered when making a clinical decision about dental cements.

Cytogenetic study for possible mutagenic activity induced by ice-nucleation bacteria or their metabolic products in human lymphocytes in vitro

A means for eliminating ice-nucleation-active (INA) bacteria, the microorganisms responsible for frost damage to plants at mild freezing temperatures, is the use as competitors of other naturally occurring, non-nucleating strains. Inactive mutants (INA-) of INA bacteria have been produced by genetic or chemical methods and proposed for biological control of INA populations. Since, however, the application of these INA- mutants in the field may create health hazards to animals, we have studied the possible mutagenic activity of the INA- mutants by examining chromosome aberrations, sister-chromatid exchange (SCE) frequencies, and proliferation kinetics of human lymphocyte cultures. These cultures were treated with: (a) a naturally occurring INA- bacterium (p 767), (b) 2 parental strains (cit 7 and cit 13) of INA bacteria isolated from Citrus orchards, and (c) 2 INA- mutant strains (cit 7 del 1b and cit 13-12), produced, respectively, by chemical modification and by deletion of the corresponding parental strains. Neither whole bacteria nor infiltrates of bacterial growth media, in which toxic metabolic bacterial products might have been released, induced elevation of either chromosome aberrations and SCEs or a cell-division delay. Negative results were also obtained when sonicated bacteria were tested for possible intracellular mutagenic components.

Enhancement of cytogenetic damage by chloropromazine in human lymphocytes treated with alkylating antineoplastics and caffeine

In cultured human lymphocytes chlorpromazine (CPZ) was found to induce cell division delays and to have no effect on sister-chromatid exchanges (SCEs) or on mitotic indices (MIs). CPZ induces cytotoxic effects in combination with caffeine (CAF) and alkylating agents. In combination with CAF it induced cell division delays and suppression of MIs. In combination with melphalan (MEL) and CAF, CPZ synergistically induced SCEs, caused cell division delay and suppressed MIs. In combination with chlorambucil (CBC) and CAF, CPZ produced synergism on induction of SCEs, enhanced cell division delays and reduced MIs.

The allylic 7-ketone at the steroidal skeleton is crucial for the antileukemic potency of chlorambucil's active metabolite steroidal esters

We have investigated the role of the allylic 7-ketone in oxidized &Dgr;5-steroids on antileukemic activity. We synthesized and studied a series of oxidized and non-oxidized steroidal esters of p-N,N-bis(2-chloroethyl)aminophenylacetic acid (PHE), chlorambucils active metabolite. In a comparative study of these 7-keto derivatives, on a molecular basis, regarding their ability to induce sister chromatid exchanges (SCEs) and to inhibit cell proliferation in normal human lymphocytes in vitro, the results with these 7-keto derivatives, on a molecular basis, correlated well with their antileukemic potency against leukemia P388- and L1210-bearing mice, which proved to be significantly increased compared to that of the non-oxidized derivatives. Our results indicate that the role of the steroidal skeleton it is not only for the transportation of the alkylating agent into the cell, but also contributes directly to the mechanism of antileukemic action, by an as-yet unknown way. The main conclusion from this study is that the existence of the allylic 7-keto group in the skeleton of the &Dgr;5-steroidal esters impressively enhances their antileukemic activity, while the toxicity remains at clinically acceptable levels, suggesting that this structural modification should be further investigated.

A new approach for evaluating in vivo anti-leukemic activity using the SCE assay: An application on three newly synthesised anti-tumour steroidal esters

Three newly synthesised steroidal esteric derivatives of nitrogen mustard (compounds 1-3) were comparatively studied on a molar basis regarding their ability to induce sister chromatid exchanges (SCEs) in normal human lymphocytes in vitro and therapeutic effects on leukemia P388 bearing mice. Compounds 1 and 3 are modified steroidal esters of p-methyl-m-N,N-bis(2-chloroethyl)amino benzoic acid, and compound 2 is a modified steroidal ester of chlorambucil. All compounds induced statistically significant increases in SCEs and decreases in proliferation rate indices (PRIs) of cultured human lymphocytes and significantly increased the life span of P388 bearing mice. In this study, the doses applied for therapeutic purposes upon leukemia P388 bearing mice in vivo were derived from cytogenetic observations in normal human lymphocytes in vitro. A substantially better therapeutic effect was obtained compared to the effect achieved after the use of quite higher doses related with LD(10) values. We have demonstrated that the order of anti-tumour effectiveness of the treatment schedules of the three newly synthesised compounds tested (at doses derived from cytogenetic observations) coincides with the order of the cytogenetic effects they induce. The SCE assay appears to have an application in the clinical prediction of tumour sensitivity to potential chemotherapeutics.