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Cyclic Nucleotide Modulation of in Vitro Morphological Transformation of Syrian Hamster Cells¹

Department of Pathology, University of South Carolina School of Medicine, Columbia, South Carolina 29208 [S. G. D. M., S. M. E.], and Laboratory of Biology, National Cancer Institute, Bethesda, Maryland 20205 [J. D. P.]

The cyclic nucleotides, cyclic adenosine 3':5'-monophosphate (cAMP) and cyclic guanosine 3':5'-monophosphate (cGMP) or their dibutyryl and monobrominated derivatives, may either increase or decrease morphological transformation of Syrian hamster embryo cells exposed to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG). The effect on transformation is primarily a function of the parent cyclic nucleotide and the duration of exposure to the nucleotides. At concentrations of 5 mM or larger for a minimum 24-hr exposure cAMP, cGMP, and their congeners reduced the colony-forming ability of nontransformed Syrian hamster embryo cells not exposed to MNNG; however, cGMP and its derivatives caused less toxicity than cAMP or its analogs. cAMP and its monobrominated and dibutyrylated derivatives decreased the transformation frequency associated with MNNG irrespective of whether the various adenylnucleotides were administered before or after MNNG. The greatest inhibitory effect on MNNG-induced transformation was obtained with N⁶,O²-dibutyryl cyclic adenosine 3':5'-monophosphate followed in order by 8-bromocyclic adenosine 3':5'-monophosphate and cAMP. At equimolar doses, the dibutyryl and brominated analogs of cGMP but not unsubstituted cGMP enhanced transformation when adminstered prior to exposure of the Syrian hamster embryo cells to MNNG but reduced the transformation frequency when added after MNNG. The enhancing and inhibitory effects of the guanine cyclic nucleotide-induced alteration of MNNG-associated transformation frequencies were dose and time dependent and occurred in the order N⁶,O²-dibutyryl cyclic guanosine 3':5'-monophosphate > 8-bromocyclic guanosine 3':5'-monophosphate >> cGMP. Butyric acid neither diminished nor increased MNNG-induced transformation frequency. The latter suggests that butyrate ions formed by metabolism of the cyclic nucleotide analogs were not a factor in the observed alterations of transformation frequency.

¹ This study was supported in part by Grants IN-107C and IN-107E from the American Cancer Society and 1-SO7RR05815-01 from NIH. A preliminary report was presented at the 67th Annual Meeting of the American Association for Cancer Research, May 4 to 8, 1976, Toronto, Canada (24).

² Dr. Mironescu died during the preparation of this manuscript; however, reprint requests addressed to Dr. S. G. D. Mironescu in Columbia, S. C., will still be honored.

³ Present address: Department of Pathology; New Jersey School of Osteopathic Medicine; College of Medicine and Dentistry of New Jersey, 300 Broad way, Camden, N. J. 08103.

Received 4/ 6/81. Accepted 12/18/81.