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The effects of boron containing peptides on L1210 lymphoid leukemia metabolism

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The purpose of this study was to establish the efficacy and mode of action of peptide boron derivatives as antineoplastic agents and to evaluate their safety in vivo. Boron-containing phenylalanine and tyrosine methyl esters were found to be potent cytotoxic agents in a number of murine and human cancer cell lines. DNA, RNA and protein syntheses were inhibited by selected agents, e.g. [(trimethylamine boryl)carbonyl]-phenylalanine-acetyl ester (9) andN-acetyl-p-boron-phenyl-alanyl-phenlalanine-methyl ester (10), in L1210 lymphoid leukemia cells. IMP dehydrogenase, OMP decarboxylase, m-RNA, t-RNA, r-RNA polymerase and ribonucleoside reductase activities were inhibited. d(CTP) levels were reduced. DNA strand scission occurred after 24 hr incubation. Acute toxicity studies in mice demonstrated that the key derivative was safe at therapeutic levels with no effects on histology of major organs, hematopoietic parameters and clinical values.

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References

  • Aaronson SA, Todaro GJ, Freeman AE (1970) Human sarcoma cells in culture. Exp Cell Res 61: 1

    Google Scholar 

  • Anderson KM, Mendelson IS, and Guzik G (1975) Solubilized DNA-dependent nuclear RNA polymerases from the mammary glands of late-pregnant rats. Biochem Biophys Acta 383: 56

    Google Scholar 

  • Appel SH (1968) Purification and kinetic properties of brain orotidine 5′-phosphate decarboxylase. J Biol Chem 243: 3924

    Google Scholar 

  • Archibald RM (1944) Determination of citrulline and allontoin and demonstration of citrulline in blood plasma. J. Biol Chem 156: 121

    Google Scholar 

  • Bagnara AS, Finch LR (1972) Quantitative extraction and estimation of intracellular nucleoside-triphosphate inEscherichia coli. Anal Biochem 45: 24

    Google Scholar 

  • Becker J, Lohr G (1979) Inosine-5′-phosphate dehydrogenase activity in normal and leukemic blood cells. Klin Wochenschr 57: 1109

    Google Scholar 

  • Brown BA (1984) Hematology: principals and procedures, 4th ed. Lea & Febiger, Philadelphia, p 29

    Google Scholar 

  • Cadman E, Heimer R, Benz C (1981) The influence of methotrexate pretreatment on S-flaxorouracil metabolism in L1210 cells. J Biol Chem 256: 1695

    Google Scholar 

  • Christopherson RI, Yu ML, and Jones ME (1981) An overall radioassay for the first three reactions of de novo pyrimidine synthesis. Anal Biochem 111: 240

    Google Scholar 

  • Eagle H (1955) Propagation in a fluid medium of a human epidermoid carcinoma strain KB. Proc Soc Exp Biol 89: 362–364

    Google Scholar 

  • Eichler DC, Fisher PA, Korn D (1977) Effect of calcium on the recovery distribution of DNA polymerase a from cultured human cells. J Biol Chem 252: 4011

    Google Scholar 

  • Geran RJ, Greenberg NM, MacDonald MM, Schumacher AM, Abbott BJ (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemo Rep 3: 9–24

    Google Scholar 

  • Hall IH, Carlson GL, Abernathy G, Piantadosi C (1974) Cycloalkanones IV. Antifertility agents. J Med Chem 17: 1253

    Google Scholar 

  • Hall IH, Spielvogel BF, Sood A (1990) The antineoplastic activity of trimethylamine carboxyboranes and related esters and amides in murine and human tumor cell lines. Anticancer Drugs 1: 133

    Google Scholar 

  • Hall IH, Morse KW, Spielvogel BF, Sood A (1991) DNA interaction with metal complexes and salts of substituted boranes and hydroborates in murine and human tumor cell lines. Anticancer Drugs 2: 389

    Google Scholar 

  • Harder HC, Rosenberg B (1970) Inhibitory effects of antitumor platinum compounds on DNA, RNA, and protein synthesis in mammalian cells. Int J Cancer 6: 207

    Google Scholar 

  • Ho YK, Hakala T, Zakrzewski SF (1971) 5-(1-Adamantyl) pyrimidines as inhibitors of folate metabolism. Cancer Res 32: 1023

    Google Scholar 

  • Howle JA, Gale GR (1970) Cis-dichlorodiammine plantinum (II): Persistent and selective inhibition of deoxyribonuclease acid synthesis in vivo. Biochem Pharmacol 19: 2757

    Google Scholar 

  • Hunting D, Henderson J (1982) Determination of deoxyribonucleoside triphosphates using DNA polymerase a: a critical evaluation. Can J Biochem 59: 723

    Google Scholar 

  • Kalman SM, Duffield PH, Brzozwki TJ (1966) Purification and properties of a bacterial carbamyl phosphate synthetase. J Biol Chem 241: 1871

    Google Scholar 

  • Kampf A, Barfknecht R, Schaffer P, Osaki S, Mertes M (1976) Synthetic inhibitors ofEscherichia coli calf thymus and Ehrlich ascites tumor thymidylate synthetase. J Med Chem 19: 903

    Google Scholar 

  • Koritz S, Gohen P (1968) Colorimetric determination of carbamyl amino acid and related compounds. J Biol Chem 243: 3924

    Google Scholar 

  • Leibovitz AL, Stinson JC, McComb III WB, McCoy CE, Mazur KC, Mabry ND (1976) Classification of human colorectal adenocarcinoma cell lines. Cancer Res 36: 4562

    Google Scholar 

  • Liao LL, Kupchan SM, Horwitz SB (1976) Mode of action of the antitumor compound bruceatin, an inhibitor of protein synthesis. Mol Pharmacol 12: 167–176

    Google Scholar 

  • Liu L, Davis J (1981) Novel topologically knotted DNA from bacteriophage P4 capsids: Studies with DNA topoisomerases. Nucleic Acids Res 9: 3979

    Google Scholar 

  • Lowry OH, Rosebrough J, Farr AL, Randall R (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193: 265

    Google Scholar 

  • Maley F, Ochoa S (1958) Enzymatic phosphorylation of deoxycytidylic acid. J Biol Chem 233: 1538

    Google Scholar 

  • Mamaril FP, Dobrjasky A, Green S (1970) A rapid method for isolation of nuclei of Ehrlich ascites tumor cells. Cancer Res 30: 352

    Google Scholar 

  • Miller KG, Lie LF, England PT (1981) A homogenous Type II DNA topoisomerase from HeLa cell nuclei. J Biol Chem 256: 9334

    Google Scholar 

  • Minowada J, Ohnuma T, and Moore GE (1972) Rosette-forming human lymphoid cell lines. 1. Establishment and evidence for origin of thymus-derived lymphocytes. J Natl Cancer Inst 49: 891

    Google Scholar 

  • Moore EC, Hurlbert RB (1966) Regulation of mammalian deoxyribonucleotide biosynthesis by nucleotide or activators and inhibitors. J Biol Chem 241: 4802

    Google Scholar 

  • Nelson-Rees WA, Flandermeyer RR, Hawthorne PK (1975) Distinctive banded marker chromosomes of human tumor cell lines. Int J Cancer 16: 74

    Google Scholar 

  • Ness AT, Pastewka JV, Peacock AC (1984) Evaluation of a recently reported stable Liebermann-Burchard reagent and its use for direct determination of serum total cholesterol. Clin Chem Acta 73: 812

    Google Scholar 

  • Oswald CB, Chaney SG, Hall IH (1990) Inhibition of nucleic acid synthesis in P388 lympocytic leukema cells in culture by cis-platinum derivatives. Biomed Biochim Acta 49: 579

    Google Scholar 

  • Pera JF Jr, Rawlings CJ, Shackleton J, Roberts JJ (1981) Quantitative aspects of the formation and loss of DNA interestrand crosslinks in Chinese hamster cell following treatment with cis-diaminodichloro-platinum (II) (cisplatin). II. Comparison and results from alkaline elution, DNA renaturation and DNA sedimentation studies. Biochem Biophys Acta 655: 152

    Google Scholar 

  • Puck TT, Marcus PI, Cieciura SJ (1956) Clonal growth of mammalian cells in vitro-growth characteristics of colonies from single HeLa cells with and without a ‘feeder’ layer. J Exp Med 103: 273

    Google Scholar 

  • Sawada H, Tatsumi K, Sadada M, Shirakawa S, Nakamura T, Wakisaka G (1974) Effects of neocarzinostatin on DNA synthesis in L1210 cells. Cancer Res 34: 3341

    Google Scholar 

  • Smith HS, Owens RB, Hiller, AJ, et al. (1976) The biology of human cells in tissue culture 1. Characterization of cells derived from osteogenic sarcoma. Int J Cancer 17: 219

    Google Scholar 

  • Snyder HR, Reedy AJ, Lennarz WJ (1958) Synthesis of aromatic boronic acids. Aldehydoboronic acids and boronic acid analogues of tyrosine. J Am Chem Soc 80: 835

    Google Scholar 

  • Sood A, Sood CK, Spielvogel BF, Hall IH (1990) Boron analogues of amino acids VI. Synthesis and characterization of di- and tripeptide analogues of antineoplastic, antiinflammatory and hypolipidemic agents. Eur J Med Chem 25: 301

    Google Scholar 

  • Sood CK, Sood A, Spielvogel BF, Yousef JA, Burnham B, Hall IH (1991) Synthesis and antineoplastic activity of some cyano-, carboxy-, carbo-methoxy-, and carbamoylborane adducts of heterocyclic amines. J Pharm Sci 80: 1133

    Google Scholar 

  • Spassova MK, Russev GC, Goovinsky EV (1976) Some pyrazoles as inhibitors of purine biosynthesis de novo. Biochem Pharmacol 25: 923

    Google Scholar 

  • Spielvogel BF, Sood A, Shaw BK, Hall IH (1991) From boron analoques of amino acids to boronated DNA: Potential new pharmaceutical and neutron capture agents. IME Boron VII, Poland, August 1990. Pure Appl Chem 63: 415

    Google Scholar 

  • Suzuki H, Nishimura T, Muto SK, Tanaka N (1978) Mechanism of action of macromomycin: DNA strand scission, inhibition of DNA synthesis and mytosis. J Antibact 32: 875

    Google Scholar 

  • Tietz NW (1976) Fundamentals of clinical chemistry. Saunders, Philadelphia, p 249

    Google Scholar 

  • Woynarowski JW, Beerman TA, Konopa J (1981) Induction of deoxyribonucleic acid damage in HeLa S3 cells by cytotoxic and antitumor sesquiterpine lactones. Biochem Pharmacol 30: 3005

    Google Scholar 

  • Zhao Y, Hall IH, Oswald CB, Yokoi T, Lee KH (1987) Antimalarial agents III. Mechanism of action of artesunate againstPlasmodium berghi infection. Chem Pharm Bull 35: 2052

    Google Scholar 

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Hall, I.H., Hall, E.S., Miller, M.C. et al. The effects of boron containing peptides on L1210 lymphoid leukemia metabolism. Amino Acids 4, 287–302 (1993). https://doi.org/10.1007/BF00805829

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