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Use of Resistant or Hypersensitive Variant Clones of Friend Cells in Analysis of Mode of Action of Inducers¹

The Wistar Institute of Anatomy and Biology, Philadelphia, Pennsylvania 19104

Twenty-one variant clones of Friend erythroleukemia cell were isolated and characterized. Seventeen clones were resistant to induction of hemoglobin synthesis by one of eight drugs that have been reported to induce erythroid differentiation in clone 745. Four clones responded hypersensitively to dimethyl sulfoxide or hypoxanthine. The variant clones were treated with inducing drugs to determine whether patterns of cross-resistance or cross-sensitivity could be identified. On the basis of the results obtained, we divided the drugs into three classes. The first, arbitrarily named Class A, was the most common and included dimethyl sulfoxide, hypoxanthine, hexamethylene bisacetamide, 1-methyl-2-pyrrolidinone, tetramethylurea, pyridine N-oxide, N-methylacetamide, and 6-thioguanine. Every clone resistant to induction of hemoglobin synthesis by one of these drugs was found to be cross-resistant to induction by all other inducers of this class. Clones hypersensitive to dimethyl sulfoxide were also hypersensitive to hypoxanthine, and hypoxanthine-hypersensitive clones were hypersensitive to dimethyl sulfoxide. Clones that could not be induced to synthesize hemoglobin by butyric acid, a Class B inducer, could be induced to synthesize hemoglobin both by drugs of Class A and by hemin. Clones hypersensitive to dimethyl sulfoxide and hypoxanthine were not hypersensitive to induction by butyric acid. Butyric acid could induce synthesis of hemoglobin in clones resistant to induction by Class A inducers and in clones noninducible by hemin. Hemin, a Class C inducer, characteristically induced the synthesis of hemoglobin containing and ß minor globin chains, but not ß major, both in wild-type cells and in some clones resistant to induction of hemoglobin synthesis by Class A and B inducers. Clones selected for survival in the presence of hemin were inducible by Class B inducers, but response to Class A inducers varied, and the composition of the globin chains induced differed from that of the wild-type cells.

¹ Supported, in part, by USPHS Research Grants CA-19454, CA-10815, and CA-09171 from the National Cancer Institute and Grant RR-05540 from the Division of Research Resources.

² Leukemia Society of America Scholar. To whom the requests for reprints should be addressed.

Received 5/22/78. Accepted 8/16/78.