ABSTRACT
We studied cytotoxic activity of a new NO-releasing tetranitrosyl binuclear iron complex with cysteamine (CysAm) for human tumor cells, the relationship between the expression of O6-methylguanine-DNA methyltransferase (MGMT) and cell sensitivity to CysAm, and apoptosis-inducing capacity of this preparation. It was found that histogenetically different cell lines are characterized by different sensitivity to CysAm, and this parameter correlated with the basal level of MGMT. CysAm induced apoptosis via activation of caspases 3 and 7. These data suggest that CysAm can be considered as a potential antitumor agent, but definitive conclusions can be made after preclinical trials.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Cysteamine/chemistry , DNA Modification Methylases/antagonists & inhibitors , DNA Repair Enzymes/antagonists & inhibitors , Iron/chemistry , Nitrogen Oxides/chemistry , Tumor Suppressor Proteins/antagonists & inhibitors , A549 Cells , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , DNA Repair/drug effects , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , Dose-Response Relationship, Drug , Gene Expression , Humans , K562 Cells , Organ Specificity , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolismABSTRACT
Cytestrole acetate (CA), in the structure of which the steroidal antiestrogen component is associated with bis-ß-cloroethylamino group, exhibits a strong cytotoxic activity against hormone-dependent cancer cell lines (CaOV, HeLa, MCF-7). In doxorubicin-resistant MCF-7 cells, CA potentiates the cytotoxic effect of etoposide and doxorubicin, and the IC50 for CA in these cells is 40 times lower than that for tamoxifen (TAM). In transplantable mice breast adenocarcinoma Ca-755, the therapeutic CA dose is 25 mg/kg when administered subcutaneously in oil solution for 5 days. On the DMBA-induced mammary tumors in rats, CA injected subcutaneously led to partial regressions 4 weeks after treatment in 75% of test rats, whereas TAM produced this effect in 43% of rats. Among various drug forms of CA, the most active were oil solution of CA in gelatin capsules for oral use and liposomal emulsion for intravenous administration, since these forms exhibited the highest values of Ca-755 tumor growth inhibition index (TGI = 97 - 98%).
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Hormonal/pharmacology , Breast Neoplasms/drug therapy , Cytostatic Agents/pharmacology , Estrogen Antagonists/pharmacology , Ethinyl Estradiol/analogs & derivatives , Adenocarcinoma/pathology , Animals , Breast Neoplasms/pathology , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Administration Schedule , Drug Synergism , Ethinyl Estradiol/pharmacology , Etoposide/pharmacology , Female , Humans , Inhibitory Concentration 50 , Injections, Subcutaneous , Mice , Rats , Tamoxifen/pharmacology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
The efficiency of photodynamic therapy with photosensitizer Tiosens (Russia) was evaluated in mono- and combined therapy of rats with malignant gliomas (glioblastoma 101/8, oligodendroglioma 14-4-9, and C6 glioma). The efficiency of photodynamic monotherapy was not high: the animals died from brain edema developing in tumor tissue and in the adjacent normal cerebral tissue. Pathomorphological studies of tumor tissue detected necrosis and apoptosis, destruction of vessels with hemorrhages, and vascular thrombosis. Combined therapy for malignant gliomas including Tiosens photodynamic therapy and subsequent temodal or lysomustine chemotherapy, was the most effective. In glioblastoma 101/8, combined therapy with lysomustine or temodal led to prolongation of the lifespan by 127 %; 62.5 and 50 % rats were cured, respectively; in oligodendroglioma 14-4-9, animal lifespan was prolonged by 80 and 60 %, with 43 and 45 % rats cured, respectively. Glioma C6 was least sensitive to therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Oligodendroglioma/drug therapy , Photochemotherapy , Animals , Animals, Outbred Strains , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Drug Screening Assays, Antitumor , Humans , Indoles/administration & dosage , Neoplasm Transplantation , Nitrosourea Compounds/administration & dosage , Organometallic Compounds/administration & dosage , Photosensitizing Agents/administration & dosage , Rats, Wistar , TemozolomideABSTRACT
Esterification of 3-hydroxyl group in 11-acyloxyestra-1,3,5(10)-trienes with p-[bis(2-chloroethyl)amino]phenylacetic acid led to antitumor steroids displaying antiestrogenic and cytotoxic activities. Our substances exhibit their activities on the model of murine mammary adenocarcinoma Ca-755, with inhibition of the tumor growth being 94-99%. A new approach was used for the 11alpha-hydroxylation of estra-1,3,5(10)-trienes.
Subject(s)
Antineoplastic Agents/pharmacology , Estrenes/pharmacology , Estrogen Antagonists/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Drug Screening Assays, Antitumor , Estrenes/chemical synthesis , Estrogen Antagonists/chemical synthesis , Female , Humans , Mammary Neoplasms, Experimental/drug therapy , Mice , Neoplasms, Hormone-Dependent , Ovarian NeoplasmsABSTRACT
The subject of the paper is study of optical absorption of sensitizers in biological tissue. The study shows that absorbance can be used as a tool that allows studying biodistribution of sensitizers and their interaction with tissue in vivo. The article presents a simple technique of determining biological tissue absorption in vivo, and discusses the results of experimental animal studies of some sensitizers.
Subject(s)
Models, Biological , Radiation-Sensitizing Agents/pharmacology , Spectrum Analysis/instrumentation , Tomography, Optical Coherence/methods , Equipment Design , Fluorescence , Humans , Magnetic Resonance Imaging , Radiation-Sensitizing Agents/administration & dosageABSTRACT
We studied the possibility of using liposomal forms of hydroxyaluminium tetra-3-phenylthiophthalocyanine as a near infrared band photosensitizer. Experiments on mice with solid Ehrlich tumor and subcutaneously transplanted P-388 leukemia revealed high selectivity of accumulation of the photosensitizer in tumors in comparison with normal tissues and high photodynamic activity of the preparation. This photosensitizer can be used as the basis for creating an effective preparation for photodynamic therapy and fluorescent diagnosis.
Subject(s)
Carcinoma, Ehrlich Tumor/drug therapy , Indoles/therapeutic use , Leukemia P388/drug therapy , Organometallic Compounds/therapeutic use , Photochemotherapy , Photosensitizing Agents/therapeutic use , Animals , Carcinoma, Ehrlich Tumor/diagnosis , Leukemia P388/diagnosis , Mice , Neoplasm TransplantationABSTRACT
Antitumor activity of a new highly active promising gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one (butagest) was studied in mice with model cervical carcinoma (RShM-5). The reference drug was medroxyprogesteron acetate (MPA, Depo Provera) used in clinics. The new preparation introduced perorally in a dose of 1 mg per mice inhibited the model tumor growth by 73%, which was 18% (p < 0.01) more effective than the action of the reference drug MPA. The effect of the new gestagen was also studied in vitro with respect to human breast carcinoma of the MCF-7 line and human cervical carcinoma HeLa. The viability of the tumor cells was studied during a 6-day incubation with the drug at a concentration of 10(-7)-10(-5) M (MTT test). The reference compounds were progesterone and MPA. These drugs suppressed the growth of both MCF-7 and, in higher concentrations, of HeLa. Butagest inhibited the growth of HeLa in all concentrations. Thus, the new gestagen 17alpha-acetoxy-3beta-butanoyloxy-6-methyl-pregna-4,6-dien-20-one is capable of suppressing the viability of human breast carcinoma and human cervical carcinoma, being comparable or even more effective than the reference drugs.
Subject(s)
17-alpha-Hydroxyprogesterone/analogs & derivatives , 17-alpha-Hydroxyprogesterone/therapeutic use , Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma/drug therapy , Uterine Cervical Neoplasms/drug therapy , 17-alpha-Hydroxyprogesterone/pharmacology , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Female , Humans , Medroxyprogesterone Acetate/pharmacology , Medroxyprogesterone Acetate/therapeutic use , Mice , Mice, Inbred CBA , Progestins/pharmacology , Progestins/therapeutic useABSTRACT
To improve the action and selectivity of new drugs on tumor cells and the use of currently available pharmaceutical technologies to develop the systems of controlled transport of well-known antitumor compounds is one of the ways of enhancing the efficiency of drug therapy for tumors. The tropicity of steroid hormones to definite organs and tissues makes it possible to use them as specific messengers of alkylating groups to target tissues and tumors. Hormone cytostatics synthesized by this principle have a double mechanism of hormonal and cytotoxic actions. The original Russian water-insoluble hormone cytostatistics testifenon, kortifen, and cytestrol acetate demonstrated local tissue irritation together with high antitumor activity. No rational dosage forms make it possible to conduct clinical trials by parenteral administration. The aim of this paper is to summarize the authors' results of designing hydrophobic antitumor hormone cytostatics. The advantages and disadvantages of different approaches to designing traditional dosage forms and to applying colloid liposomal systems for intravenous administration of water-insoluble agents are shown.
Subject(s)
Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/pharmacology , Corticosterone/analogs & derivatives , Corticosterone/administration & dosage , Corticosterone/pharmacology , Liposomes/metabolism , Nitrogen Mustard Compounds/administration & dosage , Nitrogen Mustard Compounds/pharmacology , Prednimustine/administration & dosage , Prednimustine/pharmacology , Biomarkers, Tumor , Female , Humans , Injections, IntravenousABSTRACT
Polysorbate 80-coated poly(butyl cyanoacrylate) nanoparticles (NP) were shown to enable the transport of a number of drugs including the anti-tumour antibiotic doxorubicin (DOX) across the blood-brain barrier (BBB) to the brain after intravenous administration and to considerably reduce the growth of brain tumours in rats. The objective of the present study was to evaluate the acute toxicity of DOX associated with polysorbate 80-coated NP in healthy rats and to establish a therapeutic dose range for this formulation in rats with intracranially implanted 101/8 glioblastoma. Single intravenous administration of empty poly(butyl cyanoacrylate) NP in the dose range 100-400 mg/kg did not cause mortality within the period of observation. NP also did not affect body weight or weight of internal organs. Association of DOX with poly(butyl cyanoacrylate) NP did not produce significant changes of quantitative parameters of acute toxicity of the anti-tumour agent. Likewise, the presence of polysorbate 80 in the formulations was not associated with changes in toxicity compared with free or nanoparticulate drug. Dose regimen of 3x1.5 mg/kg on days 2, 5, 8 after tumour implantation did not cause drug-induced mortality. The results in tumour-bearing rats were similar to those in healthy rats. These results demonstrate that the toxicity of DOX bound to NP was similar or even lower than that of free DOX.
Subject(s)
Antineoplastic Agents/toxicity , Doxorubicin/toxicity , Enbucrilate/toxicity , Maximum Tolerated Dose , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Body Weight/drug effects , Brain Neoplasms/drug therapy , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/therapeutic use , Drug Carriers , Excipients , Glioblastoma/drug therapy , Longevity/drug effects , Nanotechnology , Neoplasm Transplantation , Organ Size/drug effects , Polysorbates , Rats , Rats, Wistar , Tumor Cells, CulturedABSTRACT
The effects of four new synthetic bis-beta-chloroethylamine-containing estrogens and known cytostatic agents chlorophenacyl and estradiol mustard were compared on monolayer cultures of transformed L-929 fibroblasts (from murine skin sarcoma). The drugs within the concentration range of 10(-5)-5 10(-7)M inhibited proliferation of cultured cells by 67%. Chlorophenacyl displayed the least antiproliferative activity (15% inhibition at 10(-5) M). Steroid nucleus introduced into the molecule enhanced antiproliferative activity of test drug in comparison with chlorophenacyl, probably due to accumulation of the hormone-cytostatic molecules in cells. Estradiol had no effect on proliferative activity of L-929 cells, and no specific estrogen-binding sites were found in cultured transformed fibroblasts. The antiproliferative effect of hormone-cytostatics on this culture is not mediated via specific interactions with estrogen receptors.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacology , Estradiol Congeners/pharmacology , Ethylamines/pharmacology , Fibroblasts/drug effects , Animals , Antineoplastic Agents, Hormonal/chemistry , Cell Division/drug effects , Dose-Response Relationship, Drug , Estradiol Congeners/chemistry , Mice , Molecular Structure , Nitrogen Mustard Compounds/pharmacology , Sarcoma , Skin Neoplasms , Tumor Cells, CulturedSubject(s)
Antineoplastic Agents, Alkylating/pharmacology , Antineoplastic Agents, Hormonal/pharmacology , Astrocytoma/drug therapy , Brain Neoplasms/drug therapy , Corticosterone/analogs & derivatives , Glioblastoma/drug therapy , Nitrogen Mustard Compounds/pharmacology , Receptors, Glucocorticoid/metabolism , Animals , Astrocytoma/metabolism , Astrocytoma/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Corticosterone/pharmacology , Glioblastoma/metabolism , Glioblastoma/pathology , Male , Neoplasm Transplantation , RatsABSTRACT
A comparative study was carried out with two alkylating agents IMB-MM and IMB-97 which are di-(2-halogenoethyl) hydrazides of amino acid derivatives. They have been found to exert a high activity towards wide spectrum of experimental tumours. Both agents caused inhibition of incorporation of 3H-thymidine into DNA of melanoma B16, marrow, intestinal mucosa, spleen and liver cells of mice with tumours. A maximal inhibition of DNA synthesis in all tissues was observed 24 h after the single doses of drugs. However 96 h later this effect was removed excluding the tumour cells. The cytofluorimetric study have shown that IMB-MM, like sarcolysine, caused an accumulation of tumour cells in G2/M phase of cell cycle, while IMB-97 increased accumulation of S-phase cells. The difference in phase sensitivity of tumour cells towards IMB-MM and IMB-97 is due to the differences in aminoacid carriers of di-(2-halogenethyl) hydrazide groups.
Subject(s)
Alkylating Agents/pharmacology , Amino Acids/pharmacology , Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , DNA/drug effects , Hydrazines/pharmacology , Melanoma, Experimental/drug therapy , Alkylating Agents/therapeutic use , Amino Acids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , DNA/biosynthesis , DNA, Neoplasm/biosynthesis , Drug Evaluation, Preclinical , Hydrazines/therapeutic use , Melanoma, Experimental/metabolism , Melanoma, Experimental/pathology , Melphalan/pharmacology , Melphalan/therapeutic use , Mice , Neoplasm Transplantation , Time FactorsABSTRACT
A hypothalamic hormone--melanostatin H-L-Pro-L-Leu-NH2- and its 9 analogs were synthesized and their antitumor properties studied. Melanostatin caused a 52-72% inhibition of tumor growth (p less than 0.05) in mice bearing adenocarcinoma of the mammary gland Ca-755, cervical carcinoma CC-5 and melanoma B-16. Non-cytotoxic analogs containing D-leucine or L-lysine showed low activity. Among analogs containing sarcolysine stereomers, chlorphenacyl or chlorambucil, derivatives with L-sarcolysin exerted a high antitumor effect on Ca-755, CC-5, Lewis lung carcinoma, lymphoid leukemia L-1210, sarcoma-37, melanoma B-16 and S-91 (80-99% inhibition of tumor growth, p less than 0.05). L-sarcolysin alone had a higher effect on S-91 only (p less than 0.05). Antitumor effect of melanostatin is due to its amino acid sequences. Melanostatin analogs modified by L-phenylalanine retain their antitumor properties.
Subject(s)
Antineoplastic Agents/chemical synthesis , MSH Release-Inhibiting Hormone/chemical synthesis , Neoplasms, Experimental/drug therapy , Oligopeptides/chemical synthesis , Animals , Antineoplastic Agents/therapeutic use , Female , MSH Release-Inhibiting Hormone/therapeutic use , Male , Mice , Oligopeptides/therapeutic useABSTRACT
Five strains of bacteriophages were isolated for the first time in the USSR from the water of ponds, the paste of methane oxidizing bacteria and the cultural broth of the experimental plant. The strains are specific of the following species: Methylostinus sporium, Methylosinus trichosporium, and Flavobacterium gasotypicum. Bacteriophages lysing Methylocystis impression. Methylomonas agile and Methylococcus capsulatus were not isolated so far. The fine structure of the phages, the shape of negative colonies, the spectrum of lytic activity, and serological properties were studied. The phages can be subdivided into two groups according to the morphology of virions, the shape of negative colonies and serological properties, or into three groups according to the spectrum of lytic activity.