| | 1 | Author
| Mario Suwalsky3, Pedro Hernándeza, Fernando Villenab, CarlosP. Sotomayorc | Requires cookie* | | | Title
| The Anticancer Drug Chlorambucil Interacts with the Human Erythrocyte Membrane and Model Phospholipid Bilayers  | | | | Abstract
| The plasma membrane has gained increasing attention as a possible target of antitumor drugs. It has been reported that they act as growth factor antagonists, growth factor receptor blockers, interfere with mitogenic signal transduction or exert direct cytotoxic effects. Chlor ambucil (4-[p-(bis[2-chloroethyl]amino)phenyl]butyric acid) is an alkylating agent widely used in the treatment of chronic lymphocytic leukaemia. Contradictory reports have been published concerning its interaction with cell membranes. Whereas a decrease in the fluidity of Ehrlich ascite tumor cells has been adduced, no evidences were found that chlorambucil changes membrane lipid fluidity and alkylating agents had effects in these systems even at highly toxic concentrations. Our results showed that chlorambucil at a dose equivalent to its therapeutical concentration in the plasma (3.6 (.im) caused the human erythrocyte membrane to develop cup-shaped forms (stomatocytes). Accordingly to the bilayer couple hypothesis, this means that the drug is inserted into the inner monolayer of the erythrocyte membrane, a conclusion supported by X-ray diffraction performed on multilayers of dimyristoylphospha-tidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the erythrocyte membrane, respectively. It is concluded that the cytotoxic effect of chlorambucil might be due to alter ation of the structure and therefore of the physiological properties of cell membranes such as fluidity, permeability, receptor and channel functions. | | | |
Reference
| Z. Naturforsch. 54c, 1089—1095 (1999); received June 21/July 23 1999 | | | |
Published
| 1999 | | | |
Keywords
| Chlorambucil, Anticancer Drug, Erythrocyte Membrane, Phospholipid Bilayer | | | |
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| | | | | TEI-XML for
| default:Reihe_C/54/ZNC-1999-54c-1089.pdf | | | | Identifier
| ZNC-1999-54c-1089 | | | | Volume
| 54 | |
| 2 | Author
| George Sosnovsky, Jan Lukszo | Requires cookie* | | | Title
| In the Search for New Anticancer Drugs, III+ Phosphorylated Diaziridine Derivatives | | | | Abstract
| Several N-diethoxyphosphoryl derivatives 7 of various diaziridines, and compounds 12, 15a, lob, 18 and 20, structurally related to TEPA (la) and spin labeled Thio-TEPA (lc) were synthesized. 0 Me 0 N-P(0Et) 2 HC=NN-p(<]) o / NR ' • 11 f / 1 ? R-O-P-f N —C—R X R N—R CL N "2 Me Me 7: R 1 . R 3 = alkyl 12 15a: R 1 = R 2 =R 3 =Me R 2 =H, alkyl 15b: R' = H,R 2 R 3 =-|CH2|5-N-0 Me Me In three cases, attempts to synthesize phosphorylated diaziridine derivatives resulted in rearrangements to give the corresponding phosphorylated hydrazone derivatives 11 h, Hi and 12. Me 0 CH = NN — P(0Et)j 11 h: x= H 11 i : x = ci 13 C NMR spectroscopy was shown to be a valuable tool in distinguishing between the structures of diaziridine and hydrazone derivatives. The in vivo testing of five representa-tive compounds (7e, 12, 15a, 16 and 20) against murine lymphocytic leukemia P 388 showed a lack of antitumor activity of compounds 7e, 15 a, 16 and 20, and an activity of compound 12 as evidenced by a T/C value of 194 and a % ILS of 94, at a dose of 32 mg/kg. | | | |
Reference
| Z. Naturforsch. 38b, 884—894 (1983); received August 30/December 24 1982 | | | |
Published
| 1983 | | | |
Keywords
| Phosphorylated Diaziridines, Synthesis, Anticancer Drugs, Leukemia P 388 | | | |
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| | | | | TEI-XML for
| default:Reihe_B/38/ZNB-1983-38b-0884.pdf | | | | Identifier
| ZNB-1983-38b-0884 | | | | Volume
| 38 | |
| 3 | Author
| Maria Konieczny, CarlA. Olson, PeterL. Gutierrez, George Sosnovsky | Requires cookie* | | | Title
| In the Search for New Anticancer Drugs, IV+ Antitumor Activity of Seleno-TEPA | | | | Abstract
| In order to test the effect of selenium on the anticancer activity of alkylating drugs, Seleno-TEPA (4), the selenium analog of the clinically used Thio-TEPA (1) was tested in vivo against the lymphocytic P 388 and lymphoid L1210 murine leukemias. Compound 4 is more active against P 388 leukemia than against L1210, and appears to be active over a narrower concentration range than Thio-TEPA (1). Compound 4 is less active against P 388 leukemia than 1, as evidenced by the T/C values of 164 for 4 and 239 for 1 at a dose of 4.2 mg/kg. The activity of 4 was also evaluated on the HL60 and K 562 human cell lines. Under the conditions of the cell colony assay technique, Seleno-TEPA (4) is less effective than Thio-TEPA (1). | | | |
Reference
| Z. Naturforsch. 38b, 1138—1141 (1983); received August 30 1982/March 14 1983 | | | |
Published
| 1983 | | | |
Keywords
| Thio-TEPA, Selenium, Seleno-TEPA, Anticancer Drugs | | | |
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| default:Reihe_B/38/ZNB-1983-38b-1138.pdf | | | | Identifier
| ZNB-1983-38b-1138 | | | | Volume
| 38 | |
| 4 | Author
| Maria Konieczny, CarlA. Olson, PeterL. Gutierrez, George Sosnovsky | Requires cookie* | | | Title
| In the Search for New Anticancer Drugs, V+ Study of the Binding of Spin-Labeled Thio-TEPA to Cells | | | | Abstract
| The spin labeled analog, SL-O-TT (2), of Thio-TEPA (1) inhibits (£N) 3 PIS) R0P(S)(N3) 2 the incorporation of 3 H-thymidine by 50% (IC50) at a dose of 2.6 X 10~ 4 M in L 1210 and at a dose of 6 X 10~ 4 M in P 388 murine leukemias. On the basis of cell fractionation studies, compound 2 was found to bind about equally to the cell nuclei, microsomes, and mito-chondria. ESR experiments indicate different degrees of immobilization of the label in various fractions. The efficiency of binding of 2 to cells appears to be at least 6 %. | | | |
Reference
| Z. Naturforsch. 38b, 1142—1145 (1983); received August 30/December 24 1982 | | | |
Published
| 1983 | | | |
Keywords
| Anticancer Drugs, Nitroxyl Label, Spin Labeled Thio-TEPA, ESR | | | |
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| default:Reihe_B/38/ZNB-1983-38b-1142.pdf | | | | Identifier
| ZNB-1983-38b-1142 | | | | Volume
| 38 | |
| 5 | Author
| G. Eo Rg, S. Osnovsky, ShuW. En, Li, M. Ahesw, AraR. Ao | Requires cookie* | | | Title
| In the Search for New Anticancer Drugs, XXI. Spin Labeled Nitrosoureas | | | | Abstract
| The spin labeled nitrosoureas 7 a—e and 12 were synthesized and evaluated in vivo for their anticancer activities against the murine lymphocytic leukem ia P388. C om pounds 7 a —c, 7 e and 12 possessed activities ranging from 31 to 542 percent increase in life span (% IL S), w hereas com pound 7 d was marginal (% IL S = 21). All CD2Fj male mice treated with the most active com pounds (7a and 12) at 35 mg/kg for 9 days were alive after 30 days, w hereas all mice treated with the clinical drug CCNU (lc) succumbed. Compounds 7 a —e and 12 were further evalu ated for their antineoplastic activity against lymphoid leukem ia L1210. C om pounds 7a and 12 exhibited, on day 60, a % ILS of 713 and 620, respectively. The lipophilicities of com pounds 7 a —e and 12 were determ ined using the E PR and UV methods. Compounds 7a and 12 which differ from CCNU and M eCCNU by the replacement of the cyclohexyl and methylcyclohexyl groups with six and five m em bered nitroxyl radical moieties were more hydrophilic than the clinical drugs. | | | |
Reference
| Z. Naturforsch. 42c, 921—931 (1987); received August 14 1986 | | | |
Published
| 1987 | | | |
Keywords
| Nitrosoureas, Nitroxyl Radicals, Spin Labeling, Anticancer Drugs, Leukemia P388 and L1210 | | | |
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| default:Reihe_C/42/ZNC-1987-42c-0921.pdf | | | | Identifier
| ZNC-1987-42c-0921 | | | | Volume
| 42 | |
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