tretinoin and dimethylacetamide

Polar solvents such as N,N-dimethyl acetamide (DMA) are known inducers of tumor cell differentiation in vitro. Nothing is known about their ability to induce differentiation in vivo. Using PCC4 AZArL murine embryonal carcinoma (EC) cells we examined the time course and dose response relationship of DMA induced EC differentiation in vitro. The effective continuous dose range of 0.1% to 0.15% gave a linear increase in differentiation index with the probability of attaining complete differentiation. EC tumors were raised subcutaneously in the flanks of strain 129 mice and DMA injected intraperitoneally at a dose calculated to attain tissue levels of between 0.1% and 0.15%. DMA induced significant differentiation primarily into neuroepithelium when compared to negative controls, but DMA was not as effective as retinoic acid. The extent of differentiation was dosage dependent, but the maximal dose of DMA was limited by toxicity mainly to the liver and lymphoid tissues. A graduated dosage schedule of DMA treatment reduced toxicity. These preliminary studies suggest that "differentiation therapy" with polar solvents such as DMA may be an effective adjunct to standard therapies.

Topics: Acetamides; Animals; Carcinoma, Embryonal; Cell Differentiation; Dose-Response Relationship, Drug; Humans; Mice; Neoplasm Transplantation; Tretinoin; Tumor Cells, Cultured

Retinoic acid induces the differentiation of NTERA-2 cl. D1 human embryonal carcinoma (EC) cells into neurons, cells permissive for the replication of human cytomegalovirus (HCMV), and other cell types that cannot as yet be classified but are distinguishable from the stem cells. We tested several additional agents for their ability to induce the differentiation of these EC cells. No differentiation was induced by butyrate, cyclic AMP, cytosine arabinoside, the tumor promoter 12-0-tetradecanoylphorbol 13-acetate (TPA), or the chemotherapeutic agent cis-diaminedichloroplatinum, although morphological changes were detected at the highest concentrations of these agents that permitted cell survival. However, retinal, retinol, 5-bromouracil 2'deoxyribose (BUdR), 5-iodouracil 2'deoxyribose (IUdR), hexamethylene bisacetamide (HMBA), dimethylacetamide (DMA), and dimethylsulfoxide (DMSO) all induced some neuronal differentiation, but to a lesser extent than retinoic acid. Also, BUdR, IUdR, HMBA, and DMA induced the appearance of many cells permissive for the replication of HCMV. Differentiation was, in all cases, accompanied by the loss of SSEA-3, a globoseries glycolipid antigen characteristically expressed by human EC cells. However, another glycolipid antigen, A2B5, which appears in 60%-80% of differentiated cells 7 days following retinoic acid induction, was detected in less than 20% of the cells induced by the other agents studied. This implies that the HCMV-permissive cells induced by retinoic acid are not identical to those induced by BUdR, IUdR, and DMA.

Topics: Acetamides; Bromodeoxyuridine; Butyrates; Butyric Acid; Cell Differentiation; Cell Line; Cisplatin; Clone Cells; Cyclic AMP; Cytarabine; Dimethyl Sulfoxide; Humans; Idoxuridine; Kinetics; Neurons; Teratoma; Tetradecanoylphorbol Acetate; Tretinoin

We found that monolayer cultures of F9 cells induced to differentiate with trans-retinoic acid (RA) contain two major subpopulations of cells. These two cell types can be distinguished by their cellular morphology, their pattern of laminin accumulation, and their ability to undergo further differentiation in response to N6-O2-dibutyryl adenosine 3':5' cyclic monophosphoric acid (dBcAMP). Furthermore, the developmental pathway induced by RA appears to lead to two alternative pathways, and differentiation at the branch point is either directly or indirectly controlled by cAMP. Differentiation along one branch of this pathway can be induced by 5-bromodeoxyuridine, whereas differentiation along an unrelated pathway is induced by N'-N'-dimethylacetamide. In all cases, differentiation is closely paralleled by suppression of the tumorigenic phenotype, indicating that these two processes are tightly linked and probably share a common step.

Topics: Acetamides; Bromodeoxyuridine; Cell Differentiation; Cell Line; Cell Transformation, Neoplastic; Cyclic AMP; Fluorescent Antibody Technique; Laminin; Phenotype; Teratoma; Tretinoin

PCC4azal embryonal carcinoma tumors were grown in strain 129 mice by s.c. transplantation. When palpable, the tumors were treated with a combination of retinoic acid and dimethylacetamide. In vitro, this embryonal carcinoma cell line shows minimal spontaneous differentiation and is exquisitely sensitive to retinoic acid and/or dimethylacetamide induction of differentiation. Ten daily 20-microliter intratumor injections of a solution of 10 mg retinoic acid per ml of dimethylacetamide resulted in nearly complete induction of morphological differentiation mainly into neuroepithelial and glandular derivatives. Control tumors showed minor spontaneous differentiation. Differentiation was associated with decreased tumor growth rate, decreased mitotic index, decreased extent of necrosis, and increased survival time of the hosts. In 4 of 18 cases, long-term survival of the hosts was effected by a complete differentiation of the malignant embryonal carcinoma tumors into benign teratomas. Retinoic acid:dimethylacetamide was also effective in inducing differentiation with the same dosage and schedule when administered systemically, i.e., i.p. or s.c.

Topics: Acetamides; Animals; Cell Differentiation; Drug Evaluation, Preclinical; Mice; Mitotic Index; Neoplasm Transplantation; Neoplasms, Experimental; Neoplasms, Germ Cell and Embryonal; Teratoma; Tretinoin

Topics: Acetamides; Animals; Autoradiography; Bone Marrow; Cell Cycle; Cell Differentiation; Cell Line; Cell Nucleolus; Embryo, Mammalian; Fibroblasts; Mice; Mitotic Index; Neoplasms, Experimental; RNA, Ribosomal; Silver Nitrate; Staining and Labeling; Teratoma; Tretinoin