ABSTRACT
PURPOSE: This work investigates whether a synergy in cell death induction exists in combining atomic ions irradiation and addition of platinum salts. Such a synergy could be of interest in view of new cancer therapy protocol based on atomic ions--hadrontherapy--with the addition of radiosensitizing agents containing high-Z atoms. The experiment consists in irradiating by fast ions cultured cells previously exposed to dichloroterpyridine Platinum (PtTC) and analyzing cell survival by a colony-forming assay. MATERIALS AND METHODS: Chinese Hamster Ovary (CHO) cells were incubated for six hours in medium containing 350 microM PtTC, and then irradiated by fast ions C(6+) and He(2+), with Linear Energy Transfer (LET) within range 2-70 keV/microm. In some experiments, dimethyl sulfoxide (DMSO) was added to investigate the role of free radicals. The intracellular localization of platinum was determined by Nano Secondary Ion Mass Spectroscopy (Nano-SIMS). RESULTS: For all LET examined, cell death rate is largely enhanced when irradiating in presence of PtTC. At fixed irradiation dose, cell death rate increases with increasing LET, while the platinum relative effect is larger at low LET. CONCLUSION: This finding suggests that hadrontherapy or protontherapy therapeutic index could be improved by combining irradiation procedure with concomitant chemotherapy protocols using platinum salts.
Subject(s)
Carbon , Heavy Ions , Helium , Linear Energy Transfer , Organoplatinum Compounds , Animals , CHO Cells , Cell Survival/physiology , Cell Survival/radiation effects , Colony-Forming Units Assay , Cricetinae , Cricetulus , Dimethyl Sulfoxide/pharmacology , Dose-Response Relationship, Radiation , Female , Free Radicals/metabolism , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/radiation effects , Organoplatinum Compounds/therapeutic use , Radiation Dosage , Radiation Tolerance , Spectrometry, Mass, Secondary Ion , Time FactorsABSTRACT
BACKGROUND: Retinoblastoma is the most common malignant intraocular tumor in children. The current treatment gives a good vital prognostic but there are several drawbacks to the arsenal of "classical antitumoral" therapies. Photodynamic therapy (PDT) could be an exciting non-toxic and non-mutagenic alternative protocol. METHOD: In this paper, we report about the screening of the in vitro photocytotoxicity of hydrophenylporphyrins and chlorins and their glycoconjugated derivatives in a human retinoblastoma cell line (Y79) and for comparison in a colorectal adenocarcinoma cell line (HT29). RESULTS: Despite lower photodynamic activity than that observed for hydroxylated photosensitizers, in particular Foscan(®) glycoconjugated derivatives display phototoxicity (IC50 2.4-0.05µM ±10%) against Y79 cells with examples of significant intrinsic cytotoxicity. Amongst them the triglucosyl porphyrin 10 is highly photocytotoxic (IC50 0.9µM ±10%) but is fully devoid of cytotoxicity (IC50>15µM). The photoactivity is highly modulated by the presence of a diethyleneglycol spacer between the chromophore and the glycoside (compounds 14-17, IC50 0.5, 0.6, 0.05 and 0.35µM ±10%) and by the anomeric configuration of the sugar (compound 15 and 17, IC50 0.6 and 0.05µM ±10% respectively). One of the main problems for the use of Foscan(®) is its poor solubility which might be improved by glycoconjugation. Moreover Foscan has been shown to induce necrosis after PDT leading to a possible ulceration of surrounding tissues unsuitable for a conservative treatment. A preferential mitochondrial subcellular localization which has been previously reported for some glycoconjugated photosensitizers could enhance the contribution of apoptosis process. CONCLUSION: Tri-α-O-galactosyl porphyrin 16 is a better candidate than Foscan(®) for a clinical application of PDT for a conservative therapy of retinoblastoma.
ABSTRACT
The most significant impact of the Chernobyl accident is the increased incidence of thyroid cancers among children. In order to accurately estimate the radiation dose provided by radioiodines, it is important to examine how the distribution of newly incorporated iodine varies with time and if this distribution varies according to the iodine status. The kinetic distribution of intra colloidal newly organified iodine in the rat immature thyroid was recorded and analysed using the ionic nanoprobe NanoSims50. Our observations imply that in case of radioiodine contamination, the energy deposits vary (i) with time, (ii) from one follicle to another, and (iii) from one cell to another inside the same follicle regardless the iodine status. The kinetic heterogeneity of iodine distribution must be take in account in thyroid dose evaluation.
Subject(s)
Iodine Radioisotopes/pharmacokinetics , Spectrometry, Mass, Secondary Ion , Thyroid Gland/metabolism , Animals , Animals, Newborn , Colloids , Disease Models, Animal , Female , Iodine/deficiency , Iodine Radioisotopes/analysis , Radioactive Hazard Release , Rats , Rats, Wistar , Thyroid Gland/growth & development , Thyroid Gland/ultrastructureABSTRACT
Glucoconjugated tri and tetra(meta-hydroxyphenyl)chlorins have been synthesized in order to explore how glucoconjugation of the macrocycle affects the photoactivity of the molecule. Internalization processes, photosensitizing efficacy of TPC(m-O-GluOH)(3) and TPC(m-O-GluOH)(4), in HT29 human adenocarcinoma cells have been compared to those of tetra(meta-hydroxyphenyl) chlorin (m-THPC, Foscan). The tetra glucoconjugated chlorin, TPC(m-O-GluOH)(4), was found to be poorly internalized and weakly photoactive. In contrast, the asymmetric and more amphiphilic compound TPC(m-O-GluOH)(3), exhibited superior phototoxicity compared to m-THPC. Drug concentration, temperature and sodium azide effects indicated that TPC(m-O-GluOH)(3) internalization partly proceeds via an active receptor-mediated endocytosis mechanism. Cellular uptake appeared as a saturable process and remained 30% lower than for mTHPC. However, a maximum phototoxicity in HT29 cells (survival fraction of 2+/-0.6%) were observed for concentration as low as 2 microM. A 4-fold higher concentration of m-THPC was necessary to observe the same level of photoactivity. This higher phototoxicity has been correlated to a greater mitochondrial affinity. On the basis of these results, work is in progress to further evaluate the potential of glycosylated chlorins in photodynamic therapy (PDT).
Subject(s)
Glycoconjugates/chemistry , Glycoconjugates/pharmacology , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/pharmacology , Porphyrins/chemical synthesis , Porphyrins/pharmacology , Cell Survival/drug effects , Cell Survival/radiation effects , Dose-Response Relationship, Drug , Glycoconjugates/pharmacokinetics , HT29 Cells , Humans , Mesoporphyrins/pharmacology , Microscopy, Fluorescence , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacokinetics , Porphyrins/chemistry , Porphyrins/pharmacokinetics , Spectrometry, Fluorescence , Structure-Activity RelationshipABSTRACT
meta-Tetra(hydroxyphenyl)chlorin (mTHPC), a second generation photosensitizer used in photodynamic therapy (PDT), was incorporated into long circulating carriers with the aim of improving the tumor selectivity by limiting the reticuloendothelial system (RES) uptake. Biodistribution of mTHPC (0.06 mg kg(-1) was studied directly in nude mice bearing HT29 human tumor by optical fiber fluorimetry and tissue drug contents were determined by HPLC after extraction. The drug was incorporated in the oily core of nanocapsules surrounded by poly(D,L lactic acid) (PLA NCs), PLA grafted with polyethylene glycol (PLA-PEG) or PLA coated with poloxamer 188 (polox PLA). Compared to PLA NCs, incorporation of mTHPC in surface-modified nanocapsules resulted in strong modifications of the drug biodistribution and tumoral retention with a three-fold increase of drug level as early as 24 h post-administration. A reduced liver uptake was observed at early times post-administration indicating that surface-modified NCs are effective in limiting the RES uptake and could be potential carriers to enhance the therapeutic ratio of lipophilic photosensitizers. Furthermore, in situ fluorescence measurements and concentration data were found in broad agreement showing that optical fiber fluorimetry is a very sensitive method that can be used to follow the biodistribution of fluorescent drugs in real-time.
Subject(s)
Adenocarcinoma/drug therapy , Colonic Neoplasms/drug therapy , Mesoporphyrins/pharmacokinetics , Radiation-Sensitizing Agents/pharmacokinetics , Skin/metabolism , Adenocarcinoma/metabolism , Animals , Colonic Neoplasms/metabolism , Female , Humans , Mesoporphyrins/therapeutic use , Mice , Mice, Nude , Photochemotherapy , Radiation-Sensitizing Agents/therapeutic use , Tissue Distribution , Transplantation, Heterologous , Tumor Cells, CulturedABSTRACT
Three acridine-diaminopurine heterodimers tethered by a linker containing an N,N'-substituted guanidine were prepared. The molecules differ by the site of introduction of the linker on the 2,6-diaminopurine. The interactions of the new heterodimers with abasic site containing oligonucleotide were compared, and their cytotoxicity was measured in the presence or absence of the antitumor alkylating agent BCNU.
Subject(s)
2-Aminopurine/analogs & derivatives , 2-Aminopurine/metabolism , Acridines/metabolism , Intercalating Agents/metabolism , Oligonucleotides/metabolism , 2-Aminopurine/chemistry , 2-Aminopurine/pharmacology , Acridines/chemistry , Acridines/pharmacology , Animals , Base Sequence , Carmustine/pharmacology , Cell Line/cytology , Cell Line/drug effects , DNA Damage , Dimerization , Inhibitory Concentration 50 , Nucleic Acid Denaturation/radiation effects , Oligonucleotides/chemistry , Purines/chemistry , ThermodynamicsABSTRACT
We describe the synthesis, DNA binding measurements and pharmacological properties of a series of new heterodimeric molecules, in which a 2,6-diaminopurine is linked to a 9-aminoacridine chromophore. The linking chain contains a central N,N'-disubstituted guanidine, connected to the two chromophores by polymethylenic units of variable length.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Carmustine/pharmacology , DNA/drug effects , Adenocarcinoma/pathology , Animals , Cattle , Humans , Leukemia L1210/pathology , Lung Neoplasms/pathology , Magnetic Resonance Spectroscopy , Mice , Tumor Cells, CulturedABSTRACT
The synthesis of a series of 35 substituted 3,4-diphenyl quinolines and isoquinolines is described. The majority of these molecules differ from all other triphenylethylene based antiestrogens by a different spatial location of the aminoalkyl side chain. The binding affinity of the most representative molecules (8, 9, 19, 20, 21, 23 and 25), including analogues 8 and 21 without the side chain, for the estrogen receptor alpha (ER) was determined. The ability of these molecules to induce the progesterone receptor was also studied. Antiproliferative activity was evaluated on MCF-7 human breast cancer cells, while intrinsic cytotoxic/cytostatic properties resulting from interaction with other targets than ER were assayed on L1210 murine leukemia cells. Introduction of an aminoalkylamino side chain at carbon 2 confers strong cytotoxic properties to diphenylquinolines 9 and 10 as well as pure antiestrogenic activities. However, cytotoxicity is so high with respect to antiestrogenicity that the latter was clearly observable only in one case (9b). The structure of compound 9b was determined by X-ray crystallography. Molecular modeling of its docking within the hormone-binding domain of the receptor was subsequently undertaken. According to our results, the design of molecules with the side chain bound to the ethylene part of the triphenyl ethylene skeleton might generate compounds of potential pharmacological interest.
Subject(s)
Drug Design , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor Modulators/pharmacology , Isoquinolines/chemical synthesis , Isoquinolines/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Binding, Competitive/drug effects , Cell Division/drug effects , Crystallography, X-Ray , Estrogen Receptor Modulators/chemistry , Estrogen Receptor Modulators/metabolism , Humans , Isoquinolines/chemistry , Isoquinolines/metabolism , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Molecular Conformation , Molecular Structure , Quinolines/chemistry , Quinolines/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Tumor Cells, CulturedABSTRACT
A glucuro-conjugated carbamate derivative of 5-fluorouracil (5-FU), originally designed as a prodrug for antibody-directed enzyme prodrug therapy (ADEPT) application, has been used for direct in vivo observation of in situ 5-FU generation in two human colon tumors heterotransplanted in nude mice. Because of the very fast elimination of glucuro-conjugated drugs, this observation required intratumoral injection. These tumors, when becoming necrotic, are rich enough in beta-glucuronidase to allow (19)F magnetic resonance spectroscopy monitoring, at the tumor level, of both prodrug elimination and 5-FU liberation without preliminary treatment by a specifically targeted enzyme conjugate. Convenient tumors have been selected by magnetic resonance imaging (MRI) on the basis of a correlative study between MRI and conventional histology. This contribution is the first report evidencing such a direct intra-tumoral conversion of a glucuro-conjugated prodrug into the expected active drug. This method, which should allow overall estimation of the beta-glucuronidase content of tumors, might also be helpful for selecting tumors as specific targets for non-toxic glucuro-conjugated prodrugs without prior treatment with a fusion protein.
Subject(s)
Antimetabolites, Antineoplastic/metabolism , Colonic Neoplasms/metabolism , Fluorouracil/metabolism , Magnetic Resonance Spectroscopy , Prodrugs/metabolism , Animals , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/pharmacokinetics , Colonic Neoplasms/pathology , Female , Fluorouracil/administration & dosage , Fluorouracil/pharmacokinetics , Glucuronidase/analysis , Humans , Injections, Intraperitoneal , Injections, Intravenous , Kinetics , Mice , Mice, Nude , Necrosis , Neoplasm TransplantationABSTRACT
Inhibition of abasic site repair in the cell seems an attractive strategy to potentiate the action of antitumor DNA alkylating drugs. Molecules that bind specifically and strongly to the abasic site are possible candidates to achieve such inhibition. We explored this strategy by preparing molecule 4 that incorporates (1) an aminoacridine intercalator for DNA binding, (2) an adenine moiety for abasic site recognition, and (3) a linker containing two guanidinium functions to increase binding to DNA without inducing cleavage at the base-sensitive abasic site. Compound 4 was compared to analogues containing secondary amines, i.e., 1. We report on synthesis of the new heterodimer 4. We show by physicochemical studies-including determination of association constants with calf-thymus DNA, T(m) measurements, and high-field NMR examination of the complexes formed with abasic DNA duplexes-that 4 binds specifically and more strongly to the abasic site than the analogues. Compound 4 does not cleave abasic plasmid DNA. Compound 4 shows apparent synergy with the anticancer bischloroethylnitrosourea (BCNU) in L1210 and A549 cell lines in vitro. It potentiates BCNU in the in vivo tests. The results favor the pertinence of the strategy.
Subject(s)
Antineoplastic Agents, Alkylating/metabolism , DNA, Neoplasm/metabolism , Animals , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/pharmacology , Cattle , DNA, Neoplasm/chemistry , Drug Screening Assays, Antitumor , Female , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Mice, Inbred DBA , Molecular Structure , Nucleic Acid Denaturation , Tumor Cells, CulturedABSTRACT
The synthesis and characterization of amphiphilic glycoconjugated porphyrins, benzochlorin, and azaporphyrins were reported. Among these molecules, several were found to be efficient photosensitizers in an in vitro assay using the human tumoral cell line HT29. Moreover, glycosylated benzochlorin and azaporphyrins, whose absorption bands in the red region of the visible spectrum are substantially increased as compared to porphyrins, display a good photocytotoxicity on tumor cells after irradiation with wavelength above 590 nm. © 1999 Society of Photo-Optical Instrumentation Engineers.
ABSTRACT
In tissue culture conditions, exogeneous active transforming growth factor-beta1 (TGF-beta1) enhances the lethal effect of DNA-damaging agents (UV-C, gamma rays, cisplatin, methotrexate and 5-fluorouracil) toward human A549 cells and mink Mv1Lu cells, as detected by the loss of their capacity to give rise to colonies; both these cell lines harbor a wild-type p53, as determined by immunoprecipitation. Contrastingly, the sole effect of the cytokine used alone is to inhibit reversibly the multiplication of the same cells without further impairing, once withdrawn from their environment, their capacity to divide and give rise to colonies. The lethal synergy between TGF-beta1 and UV-C was studied on mink and human cell lines, and the biomodulation by TGF-beta1 of cell killing by cisplatin, gamma rays, 5-fluorouracil or methotrexate was tested only on human cells. As investigated with UV-C-irradiated human A549 cells, TGF-beta1 appears to enhance apoptosis rather than to disturb the repair of DNA photolesions (mainly pyrimidine dimers) by the nucleotidic excision repair pathway according to results of nucleosomal ladder and comet tests. Our data raise the possibility that, in vivo, TGF-beta1 might affect the curative and/or undesirable secondary side effects of cancer therapy.
Subject(s)
Antineoplastic Agents/pharmacology , DNA Damage/drug effects , Lung Neoplasms/pathology , Transforming Growth Factor beta/pharmacology , Animals , Cell Death/drug effects , Cisplatin/pharmacology , DNA Damage/radiation effects , Drug Synergism , Fluorouracil/pharmacology , Humans , Lung Neoplasms/drug therapy , Methotrexate/pharmacology , Tumor Cells, CulturedABSTRACT
Low light level fluorescence microscopy studies have been carried out on MCF7-P human mammary tumor cells to localize the intracellular distribution of two new anticancer drugs, Pazelliptine and Intoplicine, which are currently under clinical evaluation. These two molecules are thought to act at the nuclear level, through DNA topoisomerase interactions. Because fluorescence of these compounds appears strongly quenched by intercalation in double strand DNA, secondary ion mass spectrometry (SIMS) imaging was used to check the presence of the drugs in the nuclear compartment. In spite of chemical structure similitudes, pazelliptine and intoplicine appear to be distributed in quite different ways within the cells. Incubation for 1 and 24 hours also allowed us to bring to light strong differences in the distribution kinetics. Pazelliptine quickly enters into the nucleoli but is no longer present in the nucleus after 24 hours incubation. Intoplicine was not detected by fluorescence in the nucleus, however SIMS microscopy allowed us to show its accumulation within this cellular compartment as a function of time of exposure. This study shows the complementarity of fluorescence and SIMS microscopies.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Indoles/pharmacokinetics , Isoquinolines/pharmacokinetics , Pyridines/pharmacokinetics , Humans , Mass Spectrometry , Microscopy, Fluorescence , Tumor Cells, CulturedABSTRACT
Two genistein analogues (MD831 and MD833) have been synthesized and analyzed for their biological properties and their mechanism of action im comparison to genistein either in vitro or in intact cells. We showed that, in vitro, one of these compounds (MD831) inhibits the tyrosine kinase activity associated with the epidermal growth factor receptor (EGFR) as efficiently as genistein. However, treatment of A431 cells with these compounds did not result in any significant modification of EGFR tyrosine phosphorylation. Extracellular-signal regulated kinase (ERK) phosphorylation in cells stimulated by EGF was enhanced in the presence of MD831, whereas the other compounds, genistein and MD833, were able to activate the c-jun N-terminal kinase (JNK). This study showed that two structurally related compounds could elicit markedly different pharmacological effects on two signalling pathways, one involved in the mitogenic response and the other in the stress response. Such compounds may be useful to characterize signalling events involved in cell response to physiological stimuli.
Subject(s)
Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Enzyme Inhibitors/pharmacology , ErbB Receptors/drug effects , Isoflavones/pharmacology , Mitogen-Activated Protein Kinases , Signal Transduction/drug effects , Calcium-Calmodulin-Dependent Protein Kinases/drug effects , ErbB Receptors/metabolism , Genistein , In Vitro Techniques , Isoflavones/chemical synthesis , Isoflavones/chemistry , JNK Mitogen-Activated Protein Kinases , Phosphorylation/drug effects , Tumor Cells, CulturedABSTRACT
Inhibition of glycolysis by methionine is a phenomenon previously shown in transformed cells growing in culture. In a recent paper, [Collet V. et al., Q. Magn. Res. Biol. Med. 11, 127-134 (1995)] we investigated this effect in vivo by 13C nuclear magnetic resonance spectroscopy, but the results did not clearly support this hypothesis. In this work, in vivo 13C NMR spectroscopy has been performed on tumors developing in nude mice following the injection of two types of cells established in culture: (1) rat kidney cells transformed by Kirsten murine sarcoma virus, (NRK-K), i.e. the same tumor cell line as that used in the original paper; and (2) a well dedifferentiated human prostate adenocarcinoma cell line (PC3). Furthermore, in vitro experiments were performed with the same tumor cell lines. The effect of methionine on glycolysis was assayed by biochemical monitoring of lactate production in the supernatant of these cells grown in vitro. Lastly, 1H in vitro NMR spectroscopy of the PC3 line performed on perchloric extracts of both supernatants and cells growing in the presence of (1-13C) glucose, allowed simultaneous detection of glucose and lactate as well as estimation of the lactate-specific enrichment. The in vitro experiments confirmed the inhibiting effect of methionine on glycolysis and demonstrated the absence of a significant modification of the pentose phosphate pathway activity by this aminoacid. In contrast, none of the in vivo experimental results were compatible with this phenomenon, which is probably affected by more general physiological events.
Subject(s)
Adenocarcinoma/metabolism , Glycolysis/drug effects , Kidney Neoplasms/metabolism , Methionine/pharmacology , Prostatic Neoplasms/metabolism , Animals , Carbon Isotopes , Cell Transformation, Viral , Glucose/metabolism , Glucose/pharmacology , Humans , Kidney Neoplasms/virology , Kirsten murine sarcoma virus , Magnetic Resonance Spectroscopy/methods , Male , Mice , Mice, Nude , Neoplasm Transplantation , Pentose Phosphate Pathway/drug effects , Protons , Rats , Tumor Cells, Cultured/drug effectsABSTRACT
Different 7,8,9,10-tetrahydrobenzo[c]phenanthridin-6(5H)-ones (10a-e) were prepared by using a one-pot procedure which includes the preparation of various 6- and 7-alkoxy-1-naphthylisocyanates from 1-naphthylamines and triphosgene, followed by addition of 1-N-morpholino-1-cyclohexenes, and cyclization of the resulting amides upon heating in the presence of hydrogen chloride. Subsequent aromatization, chlorination, and substitution with (dimethylamino)alkylamines, followed by a demethylation or a selective desisopropylation, allowed us to synthesize the derivatives 6a-i and 7a-h bearing a [(dimethylamino)alkyl]amino side chain at their 6-position. These compounds, as the other analogs 5a-b, were devised to further study the structure-activity relationships in the benzo[c]phenanthridine family of antitumor alkaloids led by fagaronine (1a) and nitidine (1b). Topoisomerases I and II cleavable complex assay and evaluation of the cytotoxicity and antitumor properties were performed. In vitro cytotoxicity (L1210 and Calc 18) shows a relationship between the cytotoxicity of these compounds and their topoisomerase poisoning properties. However, all these compounds were devoid of significant antitumor effect on the P388 murine leukemia system.
Subject(s)
Alkaloids/chemical synthesis , Antineoplastic Agents/chemical synthesis , Phenanthridines/chemical synthesis , Adenocarcinoma/drug therapy , Alkaloids/pharmacology , Alkaloids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Benzophenanthridines , Breast Neoplasms/drug therapy , Humans , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Mice , Molecular Structure , Phenanthridines/pharmacology , Phenanthridines/therapeutic use , Structure-Activity Relationship , Topoisomerase I Inhibitors , Topoisomerase II Inhibitors , Tumor Cells, CulturedABSTRACT
Multinuclear nuclear magnetic resonance spectroscopy was used to follow the metabolism and kinetics of 5-fluorouracil (5FU) after i.v. administration at a dose of 100 mg/kg on Wistar rats. 31P spectra allow one to determine both the energetic status and the pH of the tissues under investigation, while serial 19F spectra reveal the drug clearance. Analyses of 5FU kinetics show that the half-life of 5FU elimination is about 35 min in tissue with a pH of 7.3. However, this half-life increases 2.5-fold when the local pH decreases below 6.9. Thus, acidification seems to induce a local retention of 5FU, which tends to prove the existence of active transport. This retention of the drug may have significant clinical implications for assessing and improving chemotherapy alone or in combination.
Subject(s)
Fibrosarcoma/metabolism , Fluorouracil/metabolism , Magnetic Resonance Spectroscopy , 9,10-Dimethyl-1,2-benzanthracene , Animals , Fibrosarcoma/chemically induced , Fluorine/metabolism , Fluorouracil/administration & dosage , Hydrogen-Ion Concentration , Phosphorus/metabolism , Rats , Rats, Inbred Strains , Urea/analogs & derivatives , Urea/metabolism , beta-Alanine/analogs & derivatives , beta-Alanine/metabolismABSTRACT
A simple procedure is described for the determination of the photosensitizing potency of drugs, using three leukemic cell lines, two of lymphocytic origin, L1210 and P388 and one of erythroid type, Friend-745. The procedure allows one to investigate several aspects of the photosensitization properties of tested compounds such as cellular localization and direct (trypan blue exclusion) or delayed (clonogenicity) photomediated toxicities. The method was assessed using crude hematoporphyrin derivative (HPD) as well as dihematoporphyrin ether (DHE) or commercially available Photofrin II. Results were compared to those obtained with normal cells, e.g spleen lymphocytes and erythropoietic stem cells (CFU-e), and discussed in the light of the relative response of normal versus transformed cells.
Subject(s)
Hematoporphyrin Photoradiation , Hematoporphyrins/pharmacology , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/radiation effects , Animals , Cell Survival/drug effects , Cell Survival/radiation effects , Cells, Cultured , Colony-Forming Units Assay , Drug Screening Assays, Antitumor/methods , Female , Hematoporphyrin Derivative , Hematoporphyrins/metabolism , Leukemia, Experimental , Mice , Mice, Inbred DBA , Spleen/metabolism , Time Factors , Tumor Cells, Cultured/metabolismABSTRACT
The nucleophilic selectivity (Swain-Scott's constant s) of chloroethylene oxide (CEO), an ultimate carcinogenic metabolite of vinyl chloride, was determined to be 0.71 using the 4-(p-nitrobenzyl)pyridine (NBP) assay (Spears method). The molar extinction coefficient of the adduct formed between NBP and CEO was measured; and the second-order rate constants for the reactions of CEO with NBP and with thiosulfate were estimated at three temperatures. The disappearance of CEO and the formation of chloroacetaldehyde (CAA) and glycolaldehyde (GCA) were followed in D2O or a mixture of D2O/hexadeuterated acetone (acetone-d6), using Fourier transform proton nuclear magnetic resonance spectroscopy (1H-FTNMR). Evidence was obtained that CEO reacts with chloride ions to yield CAA at a rate constant of about 17 M-1 h-1 in D2O/acetone-d6 (1 : 1, v/v) at 280 K. Under the same conditions, the first-order rate constant kr for the thermal rearrangement of CEO into CAA was estimated to be approximately 0.41 h-1. These data suggest that the isomerization of CEO may be a minor reaction in physiological saline. These chemical properties of CEO are discussed in relation to the mechanism of vinyl chloride-induced carcinogenesis.
Subject(s)
Carcinogens , Ethylene Oxide , Magnetic Resonance Spectroscopy , Pyridines , Acetaldehyde/analogs & derivatives , Anions , Chemical Phenomena , Chemistry , Chlorides , Deuterium , Ethylene Oxide/analogs & derivatives , Indicators and Reagents , Kinetics , Temperature , ThiosulfatesABSTRACT
BD40, a new antitumor drug derived from 9-azaellipticine, is thought to have an oxygen-dependent metabolism in vivo. We have investigated the one-electron oxidation of this drug by gamma radiolysis using OH. free radicals as oxidants and the reaction of O2-. with the BD40 oxidized transient(s). The absorption spectrum of the one-electron oxidized free radical was determined by pulse radiolysis using OH. or N.3 as reactant. In the absence of O2 and O2-., the initial yield of disappearance of the drug is equal to 2.5 x 10(-7) mol J-1 independently of the initial concentration of the drug and of the dose rate. When BD40 is oxidized by OH. radicals in the presence of O2 and O2-., the yield is the same. This yield is halved if superoxide dismutase is present during irradiation. Superoxide anions do not react directly with the drug. Thus it is suggested that these radicals oxidize the BD40 free radical produced by oxidation with OH. Biological implications are discussed.