This study was undertaken to investigate the potential role of xenografts established from human head and neck squamous cell carcinoma (HNSCC) in the selection of new anticancer agents for phase II clinical trials. Eight HNSCC tumor lines were established in NMRI nude mice. The tumor-bearing animals were then treated with drugs at the maximum tolerated dose level. Treatment with drugs known for their activity in 15%-30% of HNSCC patients [cisplatin (CDDP), bleomycin (BLEO), 5-fluorouracil (5-Fu), cyclophosphamide (CY), and doxorubicin (DOX)] caused strong responses in up to 38% and moderate responses in 50%-67% of the HNSCC tumor lines. Methotrexate (MTX), known to cause remissions in about 40% of HNSCC patients, was only minimally active in this model system. A clinically ineffective drug, amsacrine (m-AMSA), was included as a negative control and showed no or minimal activity in all four HNSCC lines tested. A number of experimental drugs that have promising preclinical activity were also tested. Brequinar sodium (Dup 785) and 10-ethyl, 10-deaza-aminopterin (10-EdAM) showed activity in three of five, and two of the four tested tumor lines respectively. N,N-dimethylformamide (DMF) and 5-aza-2'-deoxycytidine (5-aza-dCyd), agents with the capacity to induce differentiation in in vitro systems, showed moderate activity in 43% and 40%, and strong activity in 14% and 40% of the lines, respectively. Our results indicate that the nude mouse xenograft model may play a role in the screening of new drugs, and in particular, it could be of help in the selection of drugs to be tested in phase II HNSCC clinical trials.

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.

Three putative differentiation inducing agents and five conventional drugs which have been shown to be active in patients with squamous cell carcinoma of the head and neck (HNSCC), were tested for activity against HNSCC transplanted in nude mice. Drugs were administered at a maximum tolerated dose level. By testing the effect of conventional drugs the value of the nude mouse xenograft model for testing new drugs was assessed. Bleomycin as well as cisplatin showed antitumour effects in nude mice, although toxicity and thereby the effectiveness of cisplatin varied during the 5-year period in which the experiments were performed. Bleomycin caused responses in 4 out of 13 tumour lines and cisplatin, when administered at a high dose, was active in 2 out of 5 tumours. 5-Fluorouracil and cyclophosphamide were only moderately active, while methotrexate was inactive. These data indicate that the model might be of value in the detection of new anticancer drugs although it may have a tendency to underestimate the activity of some drugs. We used the nude mouse xenograft model to test the antitumour activity of three differentiation inducing agents, the polar-planar solvents hexamethylene bisacetamide (HMBA) and N,N-dimethylformamide (DMF) and the antimetabolite 5-aza-2'-deoxycytidine (5-aza-dCyd). HMBA appeared to be inactive. In contrast, DMF was active in 1 out of 4 tumour lines while 5-aza-dCyd was active in 2 out of 5 lines tested. Furthermore, the whole panel of differentiation inducers and conventional drugs was tested for antitumour activity against three HNSCC tumour lines.(ABSTRACT TRUNCATED AT 250 WORDS)