Anti-tumor and differentiation-inducing activity of N,N-dimethylformamide (DMF) in head-and-neck cancer xenografts.
The anti-tumor activity of the putative differentiation-inducing agent dimethylformamide (DMF) was assessed in 7 head-and-neck xenograft (HNX) lines transplanted into nude mice. The drug was administered intra-peritoneally at the maximum tolerated dose. A significant growth-inhibitory effect was observed in 3 out of 7 tumor lines tested. When compared with 5 conventional drugs active in patients with squamous-cell carcinoma of the head and neck (HNSCC), DMF was as effective as the most active drugs (cisplatin and bleomycin). The most sensitive xenograft line, the poorly differentiated tumor HNX-14C, was used to test the hypothesis that differentiation induction might play a role in the anti-tumor activity of DMF. Light microscopic examination did not show clear-cut alteration of differentiation characteristics such as keratin and keratin pearl formation. Furthermore, we used a monoclonal antibody to study the expression of cytokeratin 10 which is useful as a differentiation marker of human HNSCC tumors. Keratin 10, not present in HNX-14C tumors grown under control conditions, became expressed in some cells upon DMF treatment. Further evidence for a differentiation-inducing activity of DMF was found in electron-microscopic studies. In treated HNX-14C tumors, in addition to cells with normal ultrastructural features, better-differentiated cells were observed, as manifested by an increase in the number of tonofilaments and desmosomes. The results show that DMF has a potential value for the treatment of patients with head-and-neck cancer, and that differentiation induction might play a role in the anti-tumor action of the drug.
van Dongen
G A
GA
Department of Otolaryngology, Free University Hospital, Amsterdam, The Netherlands.
Braakhuis
B J
BJ
Leyva
A
A
Hendriks
H R
HR
Kipp
B B
BB
Bagnay
M
M
Snow
G B
GB
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D002454:Cell Differentiation / Q000187:drug effects; D004126:Dimethylformamide / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007633:Keratins / Q000032:analysis; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D007633:Keratins; D004126:Dimethylformamide