Abstract
Adozelesin and carzelesin are synthetic analogues of the extremely potent antitumor antibiotic CC-1065, which alkylates N3 of adenine in a consensus sequence 5′-(A/T)(A/T)A* (A* is the site of alkylation). We have investigated the DNA sequence selectivity of adozelesin and carzelesin by thermally induced DNA strand cleavage assay using radiolabeled restriction DNA fragments. An analysis of alkylation patterns shows that the consensus sequences for carzelesin and adozelesin have been found to be 5′-(A/T)(A/T)A* and 5′-(A/T)(G/C)(A/T)A*. A new consensus sequence, 5′-(A/T)(A/T)CA*, has been observed to display an additional alkylation site for adozelesin but not for carzelesin. These results indicate that the pattern of sequence selectivity induced by carzelesin is similar but not identical to those induced by adozelesin.
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References Cited
Awada, A., Punt, C. J. A., Gil, T., Kwakkelstein, M. O., Van Tellingen, O., Wagener, D. J. T. and Piccart, M. J. Phase I clinical and pharmacokinetic study of carzelesin (U-80244) administered on a 4-weekly iv bolus schedule.Proc. Am. Assoc. Cancer Res., 36, 237 (1995).
Boger, D. L., Johnson, D. S., Yun, W. and Tarby, C. M. Molecular basis for sequence selective DNA alkylation by (+)- and ent-(−)-CC-1065 and related agents: alkylation site models that accomodate the offset AT-rich adenine N3 alkylation selectivity.Bioorg. Med. Chem., 2, 115–135 (1994).
Boger, D. L. and Johnson, D. S. CC-1065 and the duocarmycins: Unraveling the keys to a new class of naturally derived DNA alkylating agents.Proc. Natl. Acad. Sci. U.S.A., 92, 3642–3649 (1995).
Boger, D. L. and Johnson, D. S. CC-1065 and the duocarmycin-understanding their biological function through mechanistic studies.Angew. Chem., 35, 1438–1474 (1996).
Fleming, G. F., Ratain, M. J., O'Brien, S. M., Schilsky, R.L., Hoffman, P. C., Richards, J. M., Vogelzang, N. J., Kasunic, D. A. and Earhart, R. H. Phase I study of adozelesin administered by 24-h continuous intravenous infusion.J. Natl. Cancer Inst., 86, 368–372 (1994).
Hurley, L. H., Lee, C.-S., McGovren, J. P., Mitchell, M. A., Warpehoski, M., Kelly, R. C., Aristoff, P. A. Molecular basis for the sequence specific DNA alkylation by CC-1065.Biochemistry, 27, 3886–3892 (1988).
Hurley, L. H., Reynolds, V. L., Swenson, D. H., Petzold, G. L. and Scahill, T. A. Reaction of the antitumor antibiotic CC-1065 with DNA. Structure of a DNA adduct with DNA sequence specificity.Science, 226, 843–844 (1984).
Hurley, L. H., Warpehoski, M. A., Lee, C.-S., McGovren, J. P., Scahill, T. A., Kelly, R. C., Mitchell, M. A., Wicnienski, N. A., Gebhard, I., Johnson, P. D. and Bradford, V. S. Sequence specificity of DNA alkylation by the unnatural enantiomer of CC-1065 and its synthetic analogues.J. Am. Chem. Soc., 112, 4633–4649 (1990).
Lee, C.-S. and Gibson, N. W. DNA damage and differential cytotoxicity produced in human carcinoma cells by CC-1065 analogues, U-73,975 and U-77, 779.Cancer Res., 51, 6586–6591 (1991).
Lee, C.-S., Pfeifer, G. P. and Gibson, N. W. Mapping of DNA alkylation sites induced by adozelesin and bizelesin in human cells by ligation-mediated polymerase chain reaction.Biochemistry, 33, 6024–6030 (1994).
Li, L. H., DeKoning, T. F., Kelly, R. C., Krueger, W. C., McGovren, J. P., Padbury, G. E., Petzold, G. L., Wallace, T. L., Ouding, R. J., Prairie, M. D. and Gebhard, I. Cytotoxic and antitumor activity of carzelesin, a prodrug cyclopropylpyrroloindole analogue.Cancer Res., 52, 4904–4913 (1992).
Li, L. H., Kelly, R. C., Warpehoski, M. A., McGovren, J. P., Gebhard, I. and DeKoning, T. F. Adozelesin, a selected lead among cyclopropylpyrroloindole analogs of the DNA-binding antibiotic, CC-1065.Invest. New Drug, 9, 137–148 (1991).
Maxam, A. and Gilbert, W. Sequencing end-labeled DNA with base-specific chemical cleavage.Methods Enzymol., 65, 499–560 (1980).
McGovren, J. P., Clarke, G. L., Pratt, E. A. and DeKoning, T. F. Preliminary toxicity studies with the DNA-binding antibiotic CC-1065.J. Antibiot., 37, 63–70 (1984).
Reynolds, V. L., Molineux, I. J., Kaplan, D. H. and Hurley, L. H. Reaction of the antitumor antibiotic CC-1065 with DNA. Location of the site of thermally induced strand breakage and analysis of DNA sequence specificity.Biochemistry, 24, 6228–6237 (1985).
Weiland, K. L. and Dooley, T. P.In vivo andin vitro DNA bonding by the CC-1065 analogue U-73, 975.Biochemistry, 30, 7559–7565 (1991).
Zsido, T. J., Beerman, T. A., Meegan, R. L., Woynarowski, J. M. and Baker, R. M. Resistance of CHO cells expressing P-glycoprotein to cyclopropylpyrroloindole (CPI) alkylating agents.Biochem. Pharmacol., 43, 1817–1822 (1992).
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Yoon, JH., Lee, CS. Sequence selectivity of DNA alkylation by adozelesin and carzelesin. Arch. Pharm. Res. 21, 385–390 (1998). https://doi.org/10.1007/BF02974631
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DOI: https://doi.org/10.1007/BF02974631