Walker, Mary Claire; (1990) Inherent sensitivity and acquired resistance in human testicular germ cell tumours in vitro. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Advanced testicular germ cell tumours, in contrast to the majority of adult solid tumours, are curable using chemotherapy. The reasons for their sensitivity to chemotherapeutic drugs are unknown. A mode I system is required to study the mechanisms. Ten continuous cell lines derived from human non-seminomatous testicular germ cell tumours, cultured under identical conditions, were characterized in terms of population doubling time, intermitotic time, cell loss rate, colony-forming efficiency, proportion of S-phase cells, DNA ploidy levels, isozyme pattern, tumorigenicity in nude mice and xenograft morphology. To determine whether testicular tumour cell Lines retain chemosensitivity in vitro, the responses of five testicular and five bladder tumour cell lines were compared. Using a colony-forming assay, the testicular tumour cell lines were, on average, five times more sensitive to cisplatin and adriamycin (comparing IC70s). Thus chemosensitivity is inherent to the cells, and is not due solely to humoral factors such as blood supply or immunogenicity. One mechanism that may be involved is differential binding of drug to DNA. Binding of cisplatin was compared in a testicular and a bladder cell line using atomic absorption spectrophotometry. Identical amounts of cisplatin were bound, indicating that testicular tumour cells may be less able to repair damaged DNA. Activity of an enzyme involved in a specific DNA repair pathway, prevention of crosslink formation by 6 chloroethylnitrosoureas, 06-alkylguanine-DNA alkyltransferase, was measured. Development of resistance to cisplatin is a major cause of treatment failure. One testicular and one bladder cell line with stable cisplatin resistance were developed by continuous exposure to increasing concentrations of cisplatin. The growth characteristics, isozyme pattern and chromosome composition of the cell lines were compared, and degree of cross-resistance to other anticancer agents was measured. Thus in vitro model systems for studying inherent sensitivity and acquired drug resistance in testicular tumours were developed and characterized, and used to investigate two possible mechanisms. In the long term, understanding the mechanisms underlying differential sensitivity may result in more effective treatment for the resistant tumours.

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