Inhibition of rat hepatic CYP2E1 by quinacrine: molecular modeling investigation and effects on 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutagenicity.

Increased activity of CYP2E1 has been associated with increased risk of chemically-mediated cancers, through enhanced activation of a variety of procarcinogens. In this context, inhibition of CYP2E1 is potentially of significance in xenobiotic toxicity. The aim of the present study was to test the hypothesis that quinacrine inhibits hepatic CYP2E1. For this purpose, disulfiram (75 mg/kg i.p) as an inhibitor and isoniazid (100 mg/kg i.p) as an inducer of CYP2E1, as well as quinacrine (50 mg/kg i.p) were administered to Wistar rats and the hepatic activity of CYP2E1 was measured. The expression of CYP2E1 was further assessed by Western blot analysis. As expected, disulfiram inhibited, while isoniazid induced the activity and expression of the enzyme. Interestingly, treatment with quinacrine resulted in a significant decrease of CYP2E1 activity and expression. To investigate any similarities in the inhibition of CYP2E1 by quinacrine and disulfiram, molecular modeling techniques were adopted and revealed that quinacrine molecule anchors inside the same binding pocket of the protein where disulfiram is also attached. Finally, as assessed by the sister chromatid exchanges (SCE) assay, quinacrine was demonstrated to reduce the mutagenic effects of the tobacco-specific N-nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is known to be converted to active mutagen in the liver principally through CYP2E1. We suggest that these antimutagenic effects of quinacrine could be possibly attributed, at least in part, to its ability to block the bioactivation of NNK, mainly by the inhibition of CYP2E1. Our results, even preliminary, indicate that quinacrine as an inhibitor of CYP2E1 might be protective against chemically-induced toxicities such as NNK-induced mutagenicity.

Mononuclear copper(II) complexes with 2-thiophene carboxylate and N-N donors; DNA interaction, antioxidant/anti-inflammatory and antitumor activity.

Redox-active compounds such as copper-phenanthroline are known as artificial/chemical nucleases with a great impact and potential for their applications as metallotherapeutics. In that vein, the mononuclear copper(II) complexes [Cu(L)2(bipy)] (1), [Cu(L)2(bipy)(H2O)] (2) and [Cu(L)2(phen)(H2O)] (3), where L = 2-thiophene carboxylate, bipy = 2,2΄-bipyridine and phen = 1,10-phenanthroline, have been prepared and pharmacochemically studied, while the crystal structure of 1 is also reported. All the tested complexes preferably bind to CT-DNA via minor groove as resulted from UV spectroscopy studies, luminescent titration, EB competition assays and viscosity measurements. Complexes 2 and 3 in aqua behave like a "light switch" for DNA. The intensity enhancement, with the increase of DNA concentration, reached about 3-fold for 2 and 10-fold for 3. In vitro antioxidant activity of compounds 1-3, was evaluated using two different antioxidant assays: a) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical and b) inhibition of lipid peroxidation. Moreover, their inhibitory activity on soybean lipoxygenase (LOX) was evaluated for their anti-inflammatory potency. The tested complexes showed good activity on both lipid peroxidation and soybean LOX inhibition while complex 2 exhibited the best antioxidant/anti-inflammatory activity. A computational analysis over the LOX protein structure 1JNQ was performed, in an effort to support their possible mode of action. The cytotoxicity of the complexes was determined and their efficacy against several human cancer cell lines (ovarian, OAW-42; lung, A549; colon, HT29; breast, MDA-MB-231; kidney, Caki-2; and cervical, Hela) and human non-tumor cell lines (lung, MRC-5; and breast, MTSV1-7) were evaluated. The best cytotoxic activity was appeared for complex 3. In silico, computational methods support antiestrogen activity of the administered complexes on normal breast cells.

Synthesis, structure elucidation and biological evaluation of triple bridged dinuclear copper(II) complexes as anticancer and antioxidant/anti-inflammatory agents.

Seeking for copper based metallo-therapeutics, three triple bridged dinuclear copper(II) complexes [Cu2(µ2-L2)(bipy)2(µ2-OH)(µ2-H2O)](NO3)2·H2O (1·H2O), [Cu2(µ2-L2)(bipy)2(µ2-OH)(µ2-NO3)](NO3)·0.6MeOH·0.4H2O (2·0.6MeOH·0.4H2O) and [Cu2(µ2-L1)(bipy)2(µ2-OH)(µ2-NO3)(H2O)](NO3)·2H2O (3·2H2O) where L2=2-thiophene acetato, L1=2-thiophene carboxylato and bipy=2,2'-bipyridine were synthesized and structurally characterized. The complexes were subjected in vitro to a pharmacochemical evaluation for their antioxidant/anti-inflammatory activity, cytotoxicity and efficacy against human ovarian, lung, colon, breast, kidney and cervical cancer cell lines along with non tumor human lung and breast cell lines. The biological results support the structure related cytotoxic activity of the compounds. Complex 3 presented a combination of best anticancer and anti-inflammatory activities. A computational analysis over the LOX-3 protein structure 1JNQ was performed to support the possible mode of action.

Combinational effect of topotecan and octreotide on murine leukemia cells in vivo and in vitro.

PURPOSE: The activity of topotecan (TPT) against a number of hematological malignancies is now notably increased. TPT is a drug which inhibits the DNA enzyme topoisomerase I (topo I), thereby leading to the induction of tumor cell apoptosis. On the other hand, octreotide (OCT) is a synthetic analogue of somatostatin, which can induce apoptosis and antiproliferative effects on various human tumor cell lines, human xenografts and animal tumors, as well as on lymphoproliferative neoplasms. Hereby, we studied the effects of TPT and OCT, and their combination in the treatment of the rodent P388 lymphocytic leukemia, in vitro and in vivo. MATERIALS AND METHODS: Cell cultures of P388 lymphocytic leukemia cells, as well as BDF1 male and female mice implanted with the P388 leukemia cells, were used for the in vitro and in vivo evaluation of the antineoplastic activity of OCT and TPT. RESULTS: A significant increase of antileukemic activity of the combined treatment with both TPT and OCT was demonstrated. These results suggest that OCT enhances the effectiveness of TPT in the treatment of leukemia. CONCLUSION: Our results indicate that the combination of OCT with TPT in the treatment of hematological neoplasias is effective, and represents an interesting addition to the future therapeutic options, because os its mechanism of action and its toxicity profile.

Synergistic interaction between a mixed ligand copper (II) chelate complex and two anticancer agents in T47D human breast cancer cells in vitro.

PURPOSE: We have developed a copper(II) chelate complex with a tridentate ONN-Schiff ligand and the anion of salicylate, showing a potent cytotoxic activity against a panel of human and murine cancer cell lines. In this experiment we have explored the combination effect between Cu(SalNEt(2))salicylate (Cu-Sal) complex and two widely used drugs in cancer chemotherapy, bleomycin (BLM) and 5-fluorouracil (5-FU), against T47D human breast cancer cells. Previous theoretical quantum-chemical studies of this complex and ass adducts with biological molecules elucidated the underlying mechanism of action of this complex. MATERIALS AND METHODS: Cells grown in adherence in 96-well microplates were exposed simultaneously to both agents for 48 h. During cytotoxicity was assessed via the XTT colorimetric assay. The combined drug interaction was assessed with the median-effect analysis and the combination index (CI). RESULTS: Concurrent treatment of cells with Cu-Sal complex and the chemotherapeutic drugs BLM and 5-FU and the antioxidant agent ascorbic acid (AsA) resulted mainly in synergistic interaction for most concentration ratios. CONCLUSION: Cu-Sal complex interacts synergistically with the chemotherapeutic drugs for most schedules of administration. These findings call for prompting to search for possible interaction of this complex with other cellular elements of fundamental importance in cell proliferation.

Synergistic interaction between a novel mixed ligand copper(II) chelate complex and a panel of anticancer agents in T47D human breast cancer cells in vitro.

PURPOSE: We have developed a novel copper(II) chelate complex with a tridentate ONN-Schiff base ligand and the anion of salicylate, which presented a potent cytotoxic activity against a panel of human and murine cancer cell lines. In this experiment we explored the combined effect between Cu(SalNEt(2))salicylate (Cu-Sal) complex and the widely used anticancer drugs carboplatin (CBDCA), cyclophosphamide (CTX) and paclitaxel (TXL) against T47D human breast cancer cells. Theoretical (quantum-chemical) study of this complex and its adducts with biological molecules were carried out, aiming at the elucidation of the underlying mechanism of action. MATERIALS AND METHODS: Cells grown in adherence in 96-well microplates were exposed simultaneously to both agents for 48 h. Drug cytotoxicity was assessed via the XTT colorimetric assay. The combined drug interaction was assessed with the median-effect analysis and the combination index (CI). RESULTS: Copper(II) salicylate complex was proved active against T47D human breast cancer cells. Concurrent treatment of cells with Cu-Sal complex and the chemotherapeutic drugs CBDCA, CTX and TXL, mainly showed a synergistic interaction in most concentration ratios. CONCLUSION: Cu-Sal complex interacts synergistically with tested chemotherapeutic drugs for most schedules of administration, and only occasionally an additive or antagonistic effect was apparent. With the aid of quantum-chemical calculations it was demonstrated that the mechanism of action of this complex involves binding to DNA and RNA. These findings prompt to search for possible interaction of this complex with other cellular elements of fundamental importance in cell proliferation.

A preclinical survey on the efficacy of lactandrate in the treatment of colon carcinoma.

PURPOSE: There has been a recent and dramatic increase in the pace of drug development for colorectal cancer which holds promise to further improve curative therapy. We tested lactandrate, an alkylating ester of D-lactam androsterone, for antineoplastic activity against colon adenocarcinoma in vitro and in vivo. MATERIALS AND METHODS: The cytostatic and cytotoxic activity of lactandrate were evaluated in vitro against 9 human colon adenocarcinoma cell lines. The in vitro testing was performed with the sulforhodamine B (SRB) colorimetric assay and the mean concentrations of each drug that generated 50% (GI50) or total (100%) growth inhibition (TGI), as well as the drug concentrations that produced cytotoxicity against 50% of the cultured cells (IC50) were calculated. The in vivo antitumour effect was determined against two rodent colon carcinomas, the Colon 26 and the relatively chemoresistant Colon 38 carcinoma, as well as against the human xenograft CX-1 colon carcinoma. RESULTS: Lactandrate displayed a satisfactory activity against the 9 human colon cancer cell lines, inducing significant growth inhibition and cytotoxicity. Lactandrate induced antiproliferative activity against colon cancer cell lines linearly correlated with the carcinoembryonic antigen (CEA) production. There was a non-linear polynomial correlation between CEA production and the cytotoxic effect of lactandrate. The more differentiated cell lines DLD-1 and HCC2998 appeared more resistant to the cytostatic effect of lactandrate. In vivo, the compound produced a significant antitumour activity against Colon 26 and Colon 38, as well as a moderate antitumour effect against CX-1 colon carcinoma. CONCLUSION: Preclinical research supports the high in vitro and in vivo antitumour potential of lactandrate against colon carcinoma. Therefore, lactandrate represents an important candidate drug for further clinical development.

Optimization of the sulforhodamine B colorimetric assay.

Sulforhodamine B (SRB) protein staining has been widely used for cell proliferation and chemosensitivity testing, substituting for tetrazolium-based assays. However, the cell fixation step in the original assay is subject to error. We tested whether aspiration of medium with an automatic microplate multiwash device prior to fixation improves the method for adherent cells. A panel of adherent cell lines was used. Signal-to-noise ratios were significantly increased in the new assay. Coefficients of variation (CV) between replicate wells were significantly lower especially at lower cell densities. The linearity of the method improved, with absolute linearity over the whole range of cell densities. The aspiration procedure dislodged only negligible numbers of cells. Cytotoxicity testing using the cytotoxic agent paclitaxel showed no IC50 (50% inhibitory concentration) differences between the new and original methods but a better CV was associated with the optimized protocol. We conclude that aspiration of the growth medium prior to fixing comprises a safe and reliable practice which improves CV, linearity and the signal-to-noise ratio of the SRB assay.

CDK-inhibitor olomoucine inhibits cell death after exposure of cell lines to cytosine-arabinoside.

Signal transduction for apoptosis or programmed cell death, after DNA damage in mammalian cells, is believed to involve activation of cyclin-dependent kinases (CDKs), especially CDK-1 (cdc2) and CDK-2. We used CDK-inhibitor olomoucine, a purine analogue to evaluate the role CDK inhibition on cytosine-arabinoside (Ara-C)-induced cell death. The two drugs showed an antagonistic effect, suggesting that apoptosis after exposure to Ara-C is inhibited by olomoucine. DNA-electrophoresis showed a clear inhibition of the apoptotic pattern when olomoucine was added to Ara-C. We conclude that CDK-inhibitor olomoucine inhibits cell death induced by Ara-C.

Protein tyrosine kinase inhibitor, genistein, enhances apoptosis and cell cycle arrest in K562 cells treated with gamma-irradiation.

Genistein, is a natural isoflavone compound with a potent activity against protein tyrosine kinases. The leukemic cell line, K562, is a bcr/abl (Philadelphia chromosome) positive cell line that is resistant to DNA-damaging agents, including gamma-irradiation. Treatment with genistein increased apoptosis and promoted G2-phase arrest in the non-apoptotic population of the gamma-irradiated K562 cells. Irradiated cells that survived 72 h after the irradiation had a normal distribution in cell cycle, whilst genistein treatment kept cells arrested in the G2-phase, decreased the S-phase fraction and suppressed DNA-synthesis. Taken together, our results show that genistein augments apoptotic cell death after gamma-irradiation in K562 cells and this result cannot be attributed to abrogation of the G2/M checkpoint.

In vitro combined effect of a new series of copper (II) complexes with cisplatin or epirubicin on human breast and cervical cancer cell lines.

The in vitro cytotoxic effects of some recently synthesized copper (II) complexes were investigated in combination with two clinically important anticancer agents, cisplatin (CDDP) and epirubicin (EPR), on three human breast cancer cell lines (BT20, MCF7 and T47D), a human cervical carcinoma cell line (HeLa) and two non-tumour cell lines (BHK-21 and L929). The in vitro antiproliferative effects were measured by means of XTT assay and drug potency was expressed in terms of IC50 values. Synergistic effects were observed for EPR in combination with a Cu(II) malonate derivative in BT20, MCF7 and HeLa cells. Antagonistic effects were apparent when CDDP combined with a pivalate derivative in HeLa cells. For other drug combinations, synergism, adjuvance or antagonism was demonstrable depending on the cell line applied or the varied administration schedules. The results suggest that these novel complexes may enhance the cytotoxic activity of CDDP or EPR against human tumour cell lines when administered in combination with them.

Cytotoxic effects of a mixed ligand copper(II) chelate complex against a panel of human and murine cancer cells in vitro. Theoretical study of the mechanism of biologic action through molecular modelling.

PURPOSE: In an effort to discover new compounds with anticancer activity, we have developed a novel copper (II) [Cu(II)] chelate complex with a tridentate ONNSchiff base ligand and the anion of salicylate and we evaluated the in vitro chemosensitivity of various human and murine tumor cell lines by measuring cell growth inhibition. The ultimate goal was to evaluate the existence of a potential antitumor activity of this complex. Beyond the cytotoxic activity assessment of the complex, we aimed at the elucidation of the underlying mechanism of action of this complex and its interactions with biological molecules, carrying out theoretical (quantum-chemical) calculations. MATERIALS AND METHODS: Cells grown in adherence or in suspension in 96-well microplates were exposed to Cu(II) complex for 24, 48 or 72 h. In vitro drug cytotoxicity was assessed by SRB and XTT colorimetric assays. Molecular modelling tools were used applying semiempirical and ab initio calculations. RESULTS: A series of experiments was carried out, showing a potent cytotoxic activity against most of the tested cancer cell lines. Quantum-chemical calculations demonstrate that the mechanism of the cellular damage can be explained, at least in part, by the ability of the nucleobases and nucleotides to be subject to nucleophilic attack on copper. CONCLUSION: Profound growth inhibitory effects were observed for the tested Cu(II) complex. It was also verified the hypothesis that the mechanism of action of this complex involves binding to DNA and RNA. These findings prompt to search for possible interaction of this complex with other cellular elements of fundamental importance for cell proliferation.

A novel silver iodide metalo-drug: experimental and computational modelling assessment of its interaction with intracellular DNA, lipoxygenase and glutathione.

The new mixed ligand silver(I) complex of formula [AgI(TPP)2(MBZT)] (1) was obtained by reacting 2-mercapto-benzothiazole (MBZT) with triphenylphosphine (TPP). The complex was characterized by m.p., vibrational spectroscopy (FT-IR), (1)H NMR, UV-vis, ESI-MS spectroscopic techniques and its structure was confirmed by X-ray crystallography. Mixed ligand complexes of silver(I) iodide with thiones and phosphines are very rare in the literature and to the best of our knowledge compound 1 is the first of this kind exhibiting significant biological effects. Complex 1 was evaluated for its in vitro cytotoxic activity (cell viability) under irradiation with UV light and without irradiation against human cancer cell lines: MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), Caki-1 (renal), A549 (lung), OAW-42 (ovarian), HeLa (cervical) and additionally against the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line (MTSV17) with SRB assay. The results showed that 1 mediates a strong cytotoxic response to the tested normal and cancer cell lines. It exhibits equal activity against MDA-MB-231 cells where estrogen receptors (ERs) are devoid with the one against MCF-7 where ERs are present. Molecular docking studies have shown that 1 is docked in the different pocket than that of the ERs modulators. The binding affinity of 1 towards the intracellular molecules DNA and lipoxygenase (LOX) was studied for the evaluation of the mechanism of its cytostasis. The binding constant (Kb) of 1 towards CT-DNA was calculated by UV-Vis and fluorescent spectra suggesting intercalation or electrostatic interactions of 1 into DNA. Docking studies on DNA-complex interactions confirm the binding of 1. Moreover, the influence of complex 1 on the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied. In addition, since the deactivation of cisplatin caused by glutathione, seems to be an important determinant of its cytotoxic effects, the reaction of 1 with glutathione (GSH) was investigated by UV-absorption spectroscopy.

Dexamethasone plus octreotide regimen increases anticancer effects of docetaxel on TRAMP-C1 prostate cancer model.

AIM: The aim of this study was to evaluate whether the neoadjuvant use of the dexamethasone (DEX) plus octreotide (OCT) regimen can improve the direct anticancer effects of docetaxel (DOC) in the TRAMP-C1 prostate cancer model. MATERIALS AND METHODS: TRAMP-C1 cells were first characterized for the expression of SSTR1-5 and then were inoculated onto the femur of C57Bl mice. Investigation protocols employed TRAMP-C1 cell proliferation and invasion assays, analysis of radiographic images of the bone lesions and overall survival of the diseased animals. RESULTS: The triple combination treatment scheme showed significant anticancer effects, in both proliferation and invasion assays, compared to any single agent treatment scheme. DOC treatment following the neoadjuvant administration of DEX plus OCT regimen improved significantly the anticancer effects both on the grading of the bone lesions and on the overall survival of the diseased animals. CONCLUSION: Our data suggest that the neoadjuvant administration of DEX plus OCT regimen can improve the anticancer effects of DOC on the TRAMP-C1 model.

Preparation and pharmacochemical evaluation of mixed ligand copper(II) complexes with triethanolamine and thiophenyl-2 saturated carboxylic acids.

The dinuclear complex [Cu(2)(L(1))(2)(H(2)tea)(2)] (1) as well as the linear trinuclear complexes [Cu(3)(L(1))(4)(H(2)tea)(2)] (2), [Cu(3)(L(2))(4)(H(2)tea)(2)] (3) and [Cu(3)(L(1))(2)(H(2)tea)(2)(NO(3))(2)] (4) where L(1) = 2-thiophene carboxylato, L(2) = 2-thiophene acetato and H(2)tea = the single deprotonated form of triethanolamine have been prepared and pharmacochemically studied. The crystal structure of 1 is also reported. In vitro antioxidant activity of free ligands and their respective copper complexes includes: a) interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical, b) the ΗΟ˙ mediated oxidation of DMSO, c) scavenging of superoxide anion radicals, d) inhibition of lipid peroxidation and e) soybean lipoxygenase inhibition. The results indicate selectivity of the complexes to different free radicals as a consequence of their physichochemical features. The majority of the complexes 1, 2, 3, 4 effectively inhibit lipid peroxidation. The trinuclear complex 3 is by far the most active with IC(50)=10 µM, within the set, followed by complexes 1 and 2. The complexes were evaluated for their efficacy as anticancer agents against different cancer and normal human cell lines. Results showed that, these compounds mediate a moderate cytotoxic response to normal and cancer cell lines tested and induce cell cycle arrest in G2/M phase of the cell cycle. Flow cytometric analysis suggested that the tested compounds can induce apoptosis.

Synthesis, structural characterization and biological studies of the triphenyltin(IV) complex with 2-thiobarbituric acid.

The reaction between 2-thiobarbituric acid (H(2)TBA), which was treated with an equimolar amount of potassium hydroxide, in a water with triphenytin chloride in methanol, results in the formation of the {[Ph(3)Sn(O-HTBA)]}(n) (1) complex. Crystals of the hydrated 1 with formula {[Ph(3)Sn(O-HTBA)]·0.7(H(2)O)}(n) were growth from methanol/acetonitrile solution, of the white precipitation, filtered off, from the reaction. The crystal structure of complex 1 has been determined by X-ray diffraction at 120 K. Complex 1 is polymeric. The geometry around the tin(IV) ions is trigonal bi-pyramidal with coordination to three C atoms from phenyl groups and one O atom from a de-protonated HTBA ligand. Complex 1 and the already known [(n-Bu)(3)Sn(O-HTBA)·H(2)O] (2) were evaluated for their in vitro cytotoxic activity (cell viability) against human cancer cell lines: HeLa (cervical), OAW-42 (ovarian), MCF-7 (breast, ER positive), MDA-MB-231 (breast, ER negative), A549 (lung), Caki-1 (renal) and additionally, the normal human lung cell line MRC-5 (normal human fetal lung fibroblast cells) and normal immortalized human mammary gland epithelial cell line MTSV17 with a Trypan Blue assay. Moreover complex 1 was evaluated for its in vitro cell growth proliferation activity against leiomyosarcoma cells (LMS), MCF-7 and MRC-5 cells with a Thiazolyl Blue Tetrazolium Bromide (MTT) assay. The type of cell death caused by complexes 1 and 2 was also evaluated by use of flow cytometry assay. The results showed that these compounds mediate a strong cytotoxic response to normal and cancer cell lines tested through apoptosis and induce cell cycle arrest in S phase of the cell cycle, suggesting DNA intercalation (direct or indirect) with the complexes. Finally, the influence of these complexes 1 and 2 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically and theoretically studied.

Antitumor activity of L-asparaginase from Thermus thermophilus.

L-asparaginase (EC 3.5.1.1) was purified to homogeneity from Thermus thermophilus. The apparent molecular mass of L-asparaginase was found to be 33 kDa by SDS-PAGE, whereas by Sephacryl S-300 superfine column it was found to be 200 kDa, indicating that the enzyme in the native stage acts as hexamer. It is a thermostable enzyme and keeps all of its activity at 80 degrees C for 10 min. The antiproliferative activity of the purified L-asparaginase from T. thermiphilus was tested against the following human cell lines: K-562 (chronic myelogenous leukemia), Raji (Burkitt's lymphoma), SK-N-MC (primitive neuroectodermal tumor), HeLa (cervical cancer), BT20 and MCF7 (breast cancers), HT-29 (human colon cancer), and OAW-42 (ovarian cancer). The antiproliferative activity of T. thermophilus enzyme was compared with Erwinase, the commercially available L-asparaginase from Erwinia corotovora. The potency difference between the two L-asparaginases was greater in HeLa and SK-N-MC than in other cell lines. The fact that L-asparaginase from T. thermophilus does not hydrolyse L-glutamine makes it advantageous for future clinical trials.

Cytotoxicity of three resin-based root canal sealers: an in vitro evaluation.

The cytotoxicity of three resin-based root canal sealers (AH26, AH-Plus, Topseal) was evaluated in vitro. The experiments included two cell lines, L929 mouse skin fibroblasts and RPC-C2A rat pulp cells. The cytotoxicity was assessed by sulforodamine B (SRB) colorimetric assay and hemocytometer viable cell counting after 24- and 48-h exposure. AH26 had a severe cytotoxic effect whilst Topseal and AH-Plus showed a markedly lower toxic influence on the cells during the experimental period.

In vitro synergistic effects of some novel Cu(II) complexes in combination with epirubicin and mitomycin C against HeLa-S3 cervical cancer cell line.

The in vitro predictive chemosensitivity of a HeLa-S3 human cervical cancer cell line to a new series of Cu(II) complexes as well as their combination with several chemotherapeutic drugs was determined. Antiproliferative activity was evaluated by the XTT assay. Among all tested drugs, HeLa-S3 cells were especially sensitive to epirubicin (EPR) or mitomycin C (MMC) antitumor agents. The combination of EPR or MMC with the complexes resulted in a pronounced synergistic amplification of their antiproliferative effect. This marked synergism was observed in all drug combinations.

A comparative study on cytogenetic and antineoplastic effects induced by two modified steroidal alkylating agents.

We investigated the effects of two newly synthesized steroidal derivatives of nitrogen mustard on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The compound 33-hydroxy-5alpha,22alpha-spirostan- 12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(1) was, on a molar basis, less effective in inducing sister chromatid exchange and suppressing cell proliferation rate indices than compound 3beta-hydroxy-12alpha-aza-C-homo-5alpha,22alpha-spirostan-12-one-p-(N,N-bis(2-chloroethyl)amino)phenylacetate(2). A correlation was observed between the magnitude of the sister chromatid exchange response and the depression of cell proliferation index. We also studied the effects of the aforementioned compounds on Lewis lung carcinoma. The order of the percent inhibition of tumor growth achieved by the compounds coincides with the order of the cytogenetic effects they induce.