Tested Tumor Cell Research Articles

Design, Synthesis and Biological Evaluation of Caudatin and its Ester Derivatives as Novel Antitumor Agents

A series of caudatin ester derivatives were synthesized and tested for their activities against human lung cancer A549, human prostate cancer PC3, human liver cancer BEL-7402 and human gastric cancer SGC-7901 cell lines. All the compounds showed noticeable activities against the tested tumor cell lines, and the IC50s are all lower than that of caudatin. Among them, 5e and 5h are the most potent compounds. SAR study implies that introducing either a halogenated acyl group or amino aryl group to the C3β position of caudatin is beneficial to their anti-viability activities, and the lipophilicity affects the anti-viability activity of caudatin derivatives.

Recombinant expression and purification of a MAP30-cell penetrating peptide fusion protein with higher anti-tumor bioactivity

MAP30 (Momordica Antiviral Protein 30 Kd), a single-stranded type-I ribosome inactivating protein, possesses versatile biological activities including anti-tumor abilities. However, the low efficiency penetrating into tumor cells hampers the tumoricidal effect of MAP30. This paper describes MAP30 fused with a human-derived cell penetrating peptide HBD which overcome the low uptake efficiency by tumor cells and exhibits higher anti-tumor bioactivity. MAP30 gene was cloned from the genomic DNA of Momordica charantia and the recombinant plasmid pET28b-MAP30-HBD was established and transferred into Escherichia coli BL21 (DE3). The recombinant MAP30-HBD protein (rMAP30-HBD) was expressed in a soluble form after being induced by 0.5mM IPTG for 14h at 15°C. The recombinant protein was purified to greater than 95% purity with Ni–NTA affinity chromatography. The rMAP30-HBD protein not only has topological inactivation and protein translation inhibition activity but also showed significant improvements in cytotoxic activity compared to that of the rMAP30 protein without HBD in the tested tumor cell lines, and induced higher apoptosis rates in HeLa cells analyzed by Annexin V-FITC with FACS. This paper demonstrated a new method for improving MAP30 protein anti-tumor activity and might have potential applications in cancer therapy area.

Three spirostanol saponins and a flavane-O-glucoside from the fresh rhizomes of Tupistra chinensis

Four new compounds, including three new spirostanol saponins [tupistroside G-I (1–3)] and a new flavane-O-glucoside [tupichiside A (4)], together with ten known compounds, were isolated from the fresh rhizomes of Tupistra chinensis. The structures of the new compounds were elucidated by spectroscopic analysis and chemical evidence. All compounds were tested in vitro for their cytotoxic activities against the Human LoVo and BGC-823 cell lines, and six of them were found to possess potent cytotoxicity. Compounds 2, 8 and 9 showed significant cytotoxicity against the tested tumor cell lines with IC50 values ranging from 0.2 to 0.9μM.

Amaryllidaceae alkaloids from the bulbs of Lycoris radiata with cytotoxic and anti-inflammatory activities

Four new Amaryllidaceae alkaloids, (+)-1-hydroxy-ungeremine (1), (+)-6β-acetyl-8-hydroxy-9-methoxy-crinamine (2), (+)-2-hydroxy-8-demethyl-homolycorine-α-N-oxide (3), (+)-N-methoxylcarbonyl-2-demethyl-isocorydione (4), together with two known compounds, (+)-6β-acetyl-crinamine (5) and 8-demethyl-homolycorine-α-N-oxide (6) were isolated from the ethanol extract of the bulbs of Lycoris radiata. Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (1H–1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. All the isolated alkaloids were in vitro evaluated for their cytotoxic activities against eight tumor cell lines (BEN-MEN-1, CCF-STTG1, CHG-5, SHG-44, U251, BGC-823, HepG2 and SK-OV-3) and anti-inflammatory activities against Cox-1 and Cox-2. As a result, alkaloids 1 and 4 exhibited significant cytotoxic activities against all tested tumor cell lines except against BEN-MEN-1. Additionally, alkaloids 1 and 4 possessed selective inhibition of Cox-2 comparable with the standard drug NS-398 (>90%).

Antimicrobial and cytotoxic isopimarane diterpenoid glycosides from Microlepia pilosissima Ching

A phytochemical investigation of the EtOH extract of the dry fronds of Microlepia pilosissima Ching afforded four new isopimarane diterpene glycosides, 3α-O-α-L-rhamnopyranosyl-7β-O-β-D-fucopyranosyl-ent-iospimara-8(14),15-diene (1), 3α-O-[2-O-acetyl-α-L-rhamnopyranosyl]-7β-O-β-D-fucopyranosyl-ent-iospimara-8(14),15-diene (2), 3α-O-[β-D-glucopyranosyl-(1→2)-α-L-rhamnopyranosyl]-7β-O-β-D-fucopyranosyl-ent-iospimara-8(14),15-diene (3) and 3α-O-[β-D-fucopyranosyl-(1→2)-α-L-rhamnopyranosyl]-7β-O-β-D-fucopyranosyl-ent-iospimara-8(14),15-diene (4) as well as their aglycone, 3α,7β-dihydroxy-ent-iospimara-8(14),15-diene (5). Their structures were characterized by spectroscopic methods, including 1D-NMR, 2D-NMR, and HR-ESI-MS. The isolated compounds were evaluated in vitro for antimicrobial properties against three pathogen fungi and two oral pathogens and cytotoxicities against eight tumor cell lines. As a result, compounds 1–4 appeared to be promising antimicrobial potential and possessed moderate cytotoxic activities against the tested tumor cell lines.

Antiproliferative activity of synthetic fatty acid amides from renewable resources

In the work, the in vitro antiproliferative activity of a series of synthetic fatty acid amides were investigated in seven cancer cell lines. The study revealed that most of the compounds showed antiproliferative activity against tested tumor cell lines, mainly on human glioma cells (U251) and human ovarian cancer cells with a multiple drug-resistant phenotype (NCI-ADR/RES). In addition, the fatty methyl benzylamide derived from ricinoleic acid (with the fatty acid obtained from castor oil, a renewable resource) showed a high selectivity with potent growth inhibition and cell death for the glioma cell line—the most aggressive CNS cancer.

Cytotoxic, anti-inflammatory and hemostatic spirostane-steroidal saponins from the ethanol extract of the roots of Bletilla striata

Four new spirostane steroidal saponins, (1α,3α)-1-O-[(β-d-xylopyranosyl-(1→2)-α-l-rhamnopyranosyl)]-3-O-d-glucopyranosyl-5α-spirostan (1), (1α,3α)-1-O-[(β-d-xylopyranosyl-(1→2)-α-l-rhamnopyranosyl)oxy]-3-O-d-glucopyranosyl-25(27)-ene-5α-spirostan (2), (1α,3α)-1-O-[(β-d-xylopyranosyl-(1→2)-α-l-rhamnopyranosyl)oxy]-epiruscogenin (3), and (1α,3α)-1-O-[(β-d-xylopyranosyl-(1→2)-α-l-rhamnopyranosyl)oxy]-epineoruscogenin (4) together with two known compounds, bletilnoside A (5) and 3-O-β-d-glucopyranosyl-3-epi-neoruscogenin (6), were isolated from the ethanol extract of the roots of Bletilla striata (Thunb.) Reichb. f. The structures of the isolated compounds were established based on 1D and 2D (1H–1H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. The isolated compounds were tested in vitro for cytotoxicities against seven tumor cell lines, anti-inflammatory activities against Cox-1 and Cox-2, and hemostatic activities. As a result, compounds 1–4 and 6 exhibited significant cytotoxicities against all the tested tumor cell lines with IC50 value less than 30μM and selective inhibition of Cox-2 comparable with the standard drug NS-398 (>90%). Additionally, compounds 1–6 showed potent hemostatic activities.

EGFR mutation testing in pulmonary adenocarcinoma: Evaluation of tumor cell number and tumor percent in paraffin sections of 120 small biopsies

ObjectivesSuccessful evaluation of EGFR mutational status in small biopsies may be hampered by the number of tumor cells present in the tissue section. The aim of the present study was to determine the minimal number of tumor cells necessary for a reliable EGFR mutation testing in lung adenocarcinoma. Materials and methodsThe minimal number of tumor cells was determined experimentally in surgical specimens of 12 EGFR-mutated cases. DNA was extracted from progressively smaller tumor areas obtained with laser capture microdissection and was tested using a real-time PCR technique. The results were then validated in tissue sections of 120 small biopsies, where total number of tumor cells and percent tumor cells were determined in H&E digitalized slides. ResultsThe laser capture microdissection study revealed that a tumor area of 0.12mm2, containing 140±34 tumor cells, was large enough to allow detection of EGFR mutations in 11 of 12 cases. Moreover, it was also demonstrated that EGFR gene amplification and/or chromosomal polysomy could cause a 2–4-fold increase in the sensitivity of the assay. The reliability of these findings was tested in 120 small biopsies containing 26 EGFR-mutated cases. It was found that only a single case had <200 tumor cells, that the EGFR-mutated case with the lowest tumor content had 364 tumor cells occupying a tumor area of 0.12mm2, and that 11 of the 26 EGFR-mutated cases (42%) had <20% tumor cells. Finally, the incidence of EGFR-mutated cases in 145 small biopsies (21.4%) was similar to that detected in 132 surgical specimens (20.5%). ConclusionsOur findings suggest that when a small biopsy contains enough tumor cells to allow a histological diagnosis of adenocarcinoma it probably contains also an adequate number of tumor cells for a successful EGFR mutation testing if a real-time PCR technique is used.

Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity.

Five dimeric oleanolic acids linked at C-28 by 1,6-hexanediamine, or built around the carbon chains of varying lengths between two carboxyl groups were synthesized, to investigate the effect of internal spacer length and species upon the stereochemical features and anti-tumor activity of the resultant bis-oleanolic acids. The IC50 values of these dimeric compounds for cytotoxicity evaluation in vitro against Hep-G2, A549, BGC-823, MCF-7 and PC-3 tumor cell lines, were mainly under 10.0 μM. This result was much better than the inhibition of proliferation against tested tumor cell lines of the monomer oleanolic acid and the commercial anticancer drug 5-fluorouracil. The cytotoxicity selectivity detection revealed that dimer 11c exhibited low cytotoxicity towards normal human liver cell HL-7702. A combination of fluorescence staining observation and flow cytometric analysis indicated that 11c could induce Hep-G2 cell apoptosis. Molecular mechanism studies suggested that 11c induced apoptosis is mediated through the intrinsic apoptotic pathway with changes in mitochondrial membrane potential by finally activating effector caspase-3/9 to trigger cell apoptosis. Further studies revealed that 11c caused cell cycle arrest at G1 phase in Hep-G2 cells. Taken together, these results suggest that 11c may be a potential candidate for further cancer research.

Abstract 4551: Emerging effects of Chinese herbal medicines on human cancer cells proliferation

Abstract Chinese herbal medicine is a major aspect of traditional Chinese medicine, which focuses on restoring a balance of energy, body, andspirit to maintain health rather than treating a particular disease or medical condition. Some of Chinese herbs have shown therapeutic effects in cancer patients. Yunnan Baiyao (White Medicine from Yunnan, YNBY) and Snow daisy are popular Chinese herbs for routine clinical usage. YNBY is a Chinese herbal medicinal powder used to stop bleeding, reduce swelling and improve circulation in traumatic injuries. While Snow daisy has effects on maintaining blood pressure and reducing coronary heart diseases and inflammation when consumed in form of tea. Although it has been hypothesized that both YNBY and Snow daisy flower tea (SDFT) may help to prevent tumor proliferation and even reduce tumor growth, yet no systematic study and analysis have been carried out. Therefore, in this study the effects of YNBY and SDFT on tumor cell proliferation were evaluated and the signal transduction pathways mediating the effects were also determined. We tested tumor cells (lung, breast and oral cancer cell lines) and normal human fibroblast cells with different YNBY and SDFT dilution in cultured medium. Then the proliferation ability of these treated cells was tested by MTT assay and visualized via Dil (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindocarbocyanine Perchlorate) staining. Subsequently, several apoptosis factors (Fas pathway related, i.e., Fas/CD95, Fas Ligand, Caspase-8) which may be secreted by YNBY and SDFT treated tumor cells were tested using ELISA and Western Blot. The results showed that YNBY and SDFT can significantly inhibit lung tumor cells proliferation when its concentration was above 0.4mg/mL and 2mg/mL, respectively (P&amp;lt;0.01). The data indicated that YNBY could induce lung tumor cells apoptosis through Fas related pathway. The expression of Fas/CD95 and caspase-8 in treated lung tumor cells was much higher than which in control groups (P&amp;lt;0.01) suggesting that YNBY and SDFT may provoke tumor cells death by inducing cell apoptosis through Fas pathway. YNBY and SDFT may constitute potential therapeutic effects for lung cancer patients. Citation Format: Xufei Zhang, Hao Li, Herschel Angela Espiritu, Anita Kim, Li Zhong. Emerging effects of Chinese herbal medicines on human cancer cells proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4551. doi:10.1158/1538-7445.AM2014-4551

Abstract 3355: Inhibiting glyoxylase 1 as a strategy to target highly glycolytic cancer cells

Abstract Cancer cells typically display altered glucose metabolism characterized by a preference of aerobic glycolysis (Warburg effect) resulting in higher levels of glycolytic waste including methylglyoxal (MG). GLO1 (Glyoxalase 1) functions in the detoxification of MG: MG reacts with glutathione to form hemithioacetal, which is converted into S-D-Lactoylglutathione by GLO1 and further metabolised into D-lactate by GLO2. When not detoxified, MG acts as a cytotoxic reagent by forming DNA- and protein-adducts (advanced glycation end products = AGEs) that subsequently lead to cell death. Therefore, GLO1 has been discussed as a potential anti-tumor target for highly glycolytic cancers. We confirmed previous reports that GLO1 expression is elevated in several tumor entities as compared to normal tissue. Tumor cells with high GLO1 expression levels are proposed to be highly dependent on GLO1 for removal of toxic MG. Therefore sensitivity to GLO1 inhibition was probed in a panel of cell lines covering lung, colon, breast, prostate and skin cancer with varying GLO1 amplification and expression levels. siRNA-mediated knock down of GLO1 did neither cause significant reduction of cellular proliferation nor significant induction of apoptosis in any of the tested tumor cells. Furthermore, treatment of these cells with a potent GLO1 inhibitor (Chiba et al. Bioorg Med Chem Lett. 2012, IC50=11 nM) did not affect proliferation or induce apoptosis at sub-µM concentrations. In addition, no increase in AGEs upon GLO1 inhibition could be detected by western blot. Activity of the GLO1 inhibitor was further tested under conditions expected to increase endogenous MG levels such as hypoxia and elevated glucotriose (via GAPDH inhibition). Furthermore, a spheroid assay was developed to test the GLO1 inhibitor in a 3D assay system, better reflecting in vivo tumor growth. Even under hypoxic or spheroidal assay conditions, proliferation of cancer cells could not be reduced upon GLO1 inhibition. We could demonstrate however that GLO1 inhibition in A375 melanoma and SW620 colon adenocarcinoma cells sensitized the cells to exogenous MG. Taken together we could not confirm earlier published data that GLO1 inhibition leads to reduced proliferation and induction of apoptosis in cancer cells that have elevated GLO1 expression levels. Being aware that cellular systems may not reflect the situation in vivo, we speculate that GLO1 function alone may be redundant in detoxifying MG. Other possible enzymes which have been linked to MG removal include aldose reductase. Simultaneous inhibition of both enzymes might be a strategy to target highly glycolytic cancers in the future. Citation Format: Sylvia Gruenewald, Michael Steckel, Andreas Timmermann, Hartmut Rehwinkel, Patrick Steigemann, Sylvia Zacharias, Alexander Walter, Marcus Bauser, Andrea Haegebarth. Inhibiting glyoxylase 1 as a strategy to target highly glycolytic cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3355. doi:10.1158/1538-7445.AM2014-3355

Novel phenyl and pyridyl substituted derivatives of isoindolines: Synthesis, antitumor activity and DNA binding features

Novel phenyl-substituted (3a-3d, 4a, 5, 8a, 8b and 9a) and pyridyl-substituted (3e-3i, 4b, 8c-8e, 9b and 9c) isoindolines were prepared in the reaction of o-phthalaldehyde and corresponding substituted aromatic and heteroaromatic amines by modification of reaction conditions from low to high temperature and from neutral to acidic environment.The antiproliferative activity of chosen substituted isoindolines was assessed on a panel of tumour cell lines and normal human fibroblasts. The majority of tested compounds was active at the highest tested concentrations phenyl-substituted isoindolines 3a and 3b and pyridyl-substituted isoindoline 3g showed a selective effect at micromolar concentrations on HepG2 cell line in comparison with other tested tumour cell lines and normal human fibroblasts. The strongest yet non-selective effect was observed for the pyridyl-substituted isoindoline 8c. These isoindoline derivatives showed diverse mechanism of action on tumour cell death induction as compounds 3a and 8c probably induced mitotic catastrophe while compound 3b induced apoptosis. Indeed, DNA binding properties evidenced that compounds 8a, 8c and 8d bind to DNA as highly potent DNA intercalators. By contrast, compounds 3b, 3e, 3i, 4a and 5 did not target the DNA. At last, the phenyl-substituted compound 8b proved to be a strong DNA binding compound with sequence selective binding and without DNA intercalation profile.

Design and synthesis of novel spin-labeled camptothecin derivatives as potent cytotoxic agents

In our continuing search for natural product-based spin-labeled antitumor drugs, 20 novel spin-labeled camptothecin derivatives were synthesized via a Cu-catalyzed one pot reaction and evaluated for cytotoxicity against four human tumor cell lines (A-549, MDA-MB-231, KB, and KBvin). Eighteen of the target compounds (9a, 9b, 9d–9k, 9m–9t) exhibited significant in vitro antiproliferative activity against these four tested tumor cell lines. Compounds 9e and 9j (IC50 0.057 and 0.072μM, respectively) displayed the greatest cytotoxicity against the multidrug-resistant (MDR) KBvin cell line and merit further development into preclinical and clinical drug candidates for treating cancer including MDR phenotype.

Biological evaluation of the activity of some benzimidazole-4,7-dione derivatives.

The study presented here is a follow up of the authors’ interest in the approach to selective and cytotoxic bioreductive anticancer prodrugs. The current work is devoted to explore both the biological activity of some previously obtained compounds and the search for an explanation of their target(s) in hypoxic pathways. In this work the biological activity of some benzimidazole-4,7-diones was evaluated. These compounds were examined as potential bioreductive agents specific for the hypoxic environment found in tumor cells. The main aim was concerned with establishing their cytotoxic properties by using proliferation, apoptosis and DNA destruction tests on selected tumor cells. Their cytotoxic effects on two tumor cell lines (human lung adenocarcinoma A549 cells line and human malignant melanoma WM115) was compared by means of a WST-1 test. Next, the mode of cytotoxicity behind the selected tumor cells’ death was determined by the caspase 3/7 test. The last point referred to the DNA destruction of A549 and WM115 cells and the in situ DNA Assay Kit test was applied. The cytotoxic tests confirmed their activity against the tumor cells and target hypoxia (compounds 2b, 2a, 2d). The screening test of the caspase-dependent apoptosis proved that the exposure of the tested tumor cells in hypoxia to these benzimidazole-4,7-diones promoted the apoptotic cell death. Additionally, the DNA damage test established that benzimidazole-4,7-diones can be potential hypoxia-selective agents for tumor cells, especially compound 2b. All results classify the tested benzimidazole-4,7-diones as promising, lead molecules and provide a rationale for further molecular studies to explain their usefulness as potential inhibitors of the hypoxia-inducible factor 1 (HIF1).

CS1 is a novel topoisomerase IIα inhibitor with favorable drug resistance profiles

DNA topoisomerase II (Topo II) is an essential nuclear enzyme and a validated target for anticancer agent screening. CS1, a novel 2-phenylnaphthalene, had potent cytotoxicity against nine tested tumor cell lines and showed 6–10-fold less toxicity against normal cell lines compared with etoposide. In addition, CS1 showed potential anti-multidrug resistance capabilities. kDNA decatenation, DNA relaxation and cleavage complex assays indicated that CS1 acted as a nonintercalating topoisomerase IIα (Topo IIα) inhibitor by stabilizing the DNA-Topo IIα cleavage complex. CS1 also induced DNA breaks in MDA-MB-231 cells evidenced by comet tails and the accumulation of γH2AX foci. The ability of CS1 in inducing DNA breaks mediated by Topo II resulted in G2/M phase arrest and apoptosis. Moreover, CS1 exhibited dramatic in vivo antitumor activity and lower toxicity compared with etoposide. This work supports the development of CS1 as a promising candidate for the treatment of cancer by targeting Topo IIα.

SAR analysis and biological studies of synthesized podophyllum derivates obtained by N linkage modification at C-4 position

A series of C4-N-substituted podophyllum derivatives were synthesized and tested for cytotoxicity in HeLa, BGC-823, A549, Huh7 and MCF-7 cells by MTT assay. Pharmacologically, most derivatives displayed potent cytotoxicity against at least one of the tested tumor cell lines. Structure activity relationship (SAR) analysis suggests that compounds with imidogen exposed on the pyridine, rather than pyrimidine, exhibited significantly elevated potency. Moreover, the presence of a chlorine atom in the heterocyclic ring enhanced cytotoxicity, with the order 3-position>4-position>5-position>6-position. Specifically, two compounds, 3g and 3h, with 2-amino-3-chloropyridine substituted into the podophyllotoxin (PPT) and 4′-O-demethylepipodophyllotoxin (DMEP) scaffolds were shown to have the most potent HeLa cells cytotoxicity compared to other synthesized derivatives or reference compounds PPT, DMEP and etoposide (VP-16). The compound 3g was shown to inhibit microtubule polymerization and compound 3h affected topoisomerase II catalytic activity. Both compounds resulted in G2/M phase arrest and apoptosis, purportedly by increasing the expression of P53, followed by Bax up-regulation, Bcl-2 down-regulation, and caspase-3 activation. As a result of this work, we conclude that compounds 3g and 3h are more potent anticancer agents than VP-16, and that they work by different antitumor mechanisms.

Co(ii), Ni(ii) and Cu(ii) complexes with phenylthiazole and thiosemicarbazone-derived ligands: synthesis, structure and cytotoxic effects

Complexes of Co(II), Ni(II) and Cu(II) with 2-(3,5-dimethyl-1H-pyrazole-1-yl)-4-phenyl-1,3-thiazole (a) and 3,5-dimethyl-1H-pyrazole-1-carbothioamide (b) ligands were synthesized. The crystal and molecular structures of four of them were determined by the X-ray diffraction method. In the complexes with ligand a the metal atom was bound via two nitrogen atoms, whereas ligand b interacted through the nitrogen and sulfur atoms. Comparing the coordination modes observed for both studied ligands, the thiocarbamoyl sulfur atom can participate in metal binding and in bridge formation, whereas the thiazole (aromatic) sulfur atom is not involved in the coordination. This effect seems to enhance (at least partially) conformational flexibility. Hydrogen bonds played a principal role in the crystal network formation of the analyzed compounds. The cytotoxic activity of the complexes against HL-60 and NALM-6 leukemia cells and the WM-115 melanoma cell line was also measured. The copper(II) complex with the thiosemicarbazone ligand (7b) exhibited relatively high cytotoxicity towards all tested tumor cells. The cytotoxicity of copper(II) complexes 7b and 9b against the melanoma WM-115 cells was over three times higher than that of cisplatin.

CTCs could guide cancer therapy.

Using a microchip device, scientists were able to capture and culture circulating tumor cells for genetic analysis and drug testing, which identified new tumor mutations that were susceptible to targeted agents.

Antitumor activity and DNA binding studies on rare earth metal complexes with all-trans retinoic acid andl-glutamic acid

Four new complexes have been synthesized by the reaction of rare earth (III) nitrate with all-trans retinoic acid as the first ligand and L-glutamic acid as the second ligand in an alcoholic solution (pH = 6.5–7.0) with the aim to develop new antitumor drugs. The composition of the complexes has been characterized by elemental analysis, molar conductivity, IR spectroscopy, 1H NMR spectroscopy, thermogravimetric analysis and UV-vis methods. The general molecular formula of the complexes was determined to be REL2L′ (RE = Nd, Eu, La, Sc, L = all-trans retinoic acid, L′ = L-glutamic acid). The antitumor activities of complexes and corresponding ligands were tested by MTT methods. The results indicate that the four rare earth complexes possess different degrees of inhibiting effects on HepG2, A549 and HeLa cells. The suppression ratio of the complexes against the tested tumour cells is superior for the two ligands and RE(III) ions. Especially, the EuL2L′ showed the most obvious antitumor activity on HepG2 and HeLa cells. To investigate the mechanism of inhibition of the complexes, EuL2L′ reacting with DNA was studied by fluorescence spectra, viscosity, UV and CD spectra, and the results showed that the mode of interaction was mainly by intercalation, which may be the one of the important reasons for the highest antitumor activity of the EuL2L′ complex. The results obtained in this study provide certain ideas and an experimental basis for the development of highly efficient and rare earth antitumor drugs that have low toxicity.

Diesterified derivatives of 5-iodo-2'-deoxyuridine as cerebral tumor tracers.

With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2′-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3′,5′-di-O-acetyl-2′-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3′,5′-di-O-pivaloyl-2′-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31–47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability.