Lack of Effect of Methotrexate on Human Head and Neck Tumours Transplanted in Athymic Nude Mice

Abstract

Human head and neck tumour tissues derived from 16 different patients were transplanted in athymic nude mice. Treatment of tumour-bearing animals with methotrexate had little or no effect on the doubling time of the xenografts. Included were three tumour lines derived from patients in whom methotrexate did demonstrate antitumour activity. These results are also in contrast to clinical experience with methotrexate, showing remissions in 50% of patients with head and neck cancer. It is unlikely that this lack of effect of methotrexate is attributed to a difference in drug pharmacokinetics between man and nude mouse, since a xenografted rat tumour was found to be sensitive. With regard to possible resistance mechanisms underlying methotrexate inactivity, we found no evidence of increased dihy-drofolate reductase activity in the methotrexate-insensitive human xenografts. It is possible that in this model a selection occurs favouring the outgrowth of a resistant subpopula-tion of tumour cells.

Key Words:

• cancer chemotherapy
• dihydrofolate reductase
• experimental chemotherapy
• methotrexate resistance
• xenograft