Abstract
Five different representatives (I–V) of a new class of bifunctional alkylating agents, the 4-aroyl-1-nitrosohydrazinecarboxamides (“nitrososemicarbazides”), were evaluated for their potential interaction with DNA and for their cytotoxic activity in vitro toO 6-alkylguanine-DNA alkyltransferase-positive (Mer+) and-negative (Mer−) human cell lines. The HeLa MR cell line (Mer−) showed up to 20-fold higher sensitivity at IC50 (dose that inhibits colony formation by 50%) to agents I–V than did the HeLa S3 cell line (Mer+) in a colony-formation assay. These data were compared to those obtained by treatment of the two cell lines with carmustine, a currently used antitumor drug. In Mer+ cells comparable results to those with carmustine were obtained with compounds III, IV and V; in Mer− cells compounds I and II showed nearly the same effects as carmustine. Whether compounds I–V produce DNA strand breaks and/or DNA-protein cross-links was investigated using an alkaline filter elution technique. In this assay all compounds produced DNA single-strand breaks; no correlation could be detected between the strand breakage frequency and cytostatic, mutagenic and antitumor activity.
Key words: Nitrosoureas, Nitrososemicarbazides, Cytotoxicity assay, Alkaline filter elution assay
Abbreviations
- Carmustine
1,2-bis-(2-chloroethyl)-1-nitrosourea
- lomustine
1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea
- IC50
dose that inhibits colony formation by 50%
- PC
polycarbonate
- HVLP
polyvinylidene fluoride
References
- Ali-Osman F, Srivenugopal K, Berger MS, Stein DE (1990) DNA interstrand crosslinking and strand break repair in human glioma cell lines of varying [1, 3-bis(2-chloroethyl)-1-nitrosourea] resistance. Anticancer Res 10:677–682 [PubMed] [Google Scholar]
- Carter SK (ed) (1976) Proceedings of the Seventh New Drug Seminar. Nitrosoureas. Cancer Treat Rep 60:645–811
- Colvin M (1982) The alkylating agents. In: Chabner B (ed): Pharmacologic principles of cancer treatment. Saunders, Toronto, pp 276–308 [Google Scholar]
- Dolan ME, Norbeck L, Clyde C, Hora NK, Erickson LC, Pegg AE (1989) Expression of mammalianO6-alkylguanine-DNA alkyltransferase in a cell line sensitive to alkylating agents. Carcinogenesis 10:1613–1619 [DOI] [PubMed] [Google Scholar]
- Emmanuel NM, Korman DB, Ostrovskja ZA, Gorbatcheva ZB, Dementieva NP (1978) In: Nitrosoalkylureas. New class antitumor drugs. Nauka Moskow [Google Scholar]
- Ewig RAC, Kohn KW (1977a) Protein-dependent and protein-independent DNA crosslinks in mammalian cells treated with alkylating agents. Fed Proc 36:336 [Google Scholar]
- Ewig RAC, Kohn KW (1977b) DNA damage and repair in mouse leukemia L1210 cells treated with nitrogen mustard, 1,3-bis(2-chloroethyl)-1-nitrosourea, and other nitrosoureas. Cancer Res 37:2114–2122 [PubMed] [Google Scholar]
- Golovinsky E, Gugova R, Norpoth K, Mohtashamipur E (1991) Mutagenic activity of some newly synthesized cytostatic 1-(2-chloroethyl)-4-arylacyl-1-nitrososemicarbazides in theSalmonella/mammalian microsome assay. J Cancer Res Clin Oncol 117:1–3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gugova RG, Papageorgion A, Taksirov SI, Topakpashian VV, Margariti E, Boutis, LL, Mourelatos D, Dozi-Vassiliades J, Golovinsky EV, Demirov GD (1992) 4-Aroyl-1-nitrosohydrazinecarboxamides: synthesis, in vivo and in vitro antitumor activity. Eur J Med Chem 27:745–750 [Google Scholar]
- IARC (1987) Genetic and related effects: an updating of selected IARC monographs from volumes 1 to 42. IARC Monogr Eval Carcinog Risks Hum Suppl 6 [PubMed]
- Johnston TP, Montgomery JA (1986) Relationship of structure to anti-cancer activity and toxicity of the nitrosoureas in animal systems. Cancer Treat Rep 70:13–30 [PubMed] [Google Scholar]
- Kohn KW (1977) Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas. Cancer Res 37:1450–1454 [PubMed] [Google Scholar]
- Montgomery JA (1976) Chemistry and structure-activity studies of the nitrosoureas. Cancer Treat Rep 60:651–664 [PubMed] [Google Scholar]
- Muranane JP, Byfield JE (1981) Irreparable DNA cross-links and mammalian cell lethality with bifunctional alkylating agents. Chem Biol Interact 38:75–86 [DOI] [PubMed] [Google Scholar]
- Pegg AE (1990) MammalianO6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129 [PubMed] [Google Scholar]
- Pegg AE, Byers TL (1992) Repair of DNA containingO6-alkylguanine. FASEB J 6:2302–2310 [DOI] [PubMed] [Google Scholar]
- Perstayko AW, Baker KH, Crooke ST, Carter SK, Sohein R (eds) (1981) Nitrosoureas. Current status and new developments. Academic Press, New York [Google Scholar]
- Popp W, Vahrenholz C, Schmieding W, Krewet E, Norpoth K (1991) Investigations of the frequency of DNA strand breakage and cross-linking and of sister chromatid exchange in the lymphocytes of electric welders exposed to chromium- and nickel-containing fumes. Int Arch Occup Environ Health 63:115–120 [DOI] [PubMed] [Google Scholar]
- Popp W, Vahrenholz C, Yaman S, Müller C, Müller G, Schmieding W, Norpoth K, Fahnert R (1992) Investigations of the frequency of DNA strand breakage and cross-linking and of sister chromatid exchange frequency in the lymphocytes of female workers exposed to benzene and toluene. Carcinogenesis 13:57–61 [DOI] [PubMed] [Google Scholar]