Abstract:
The presentation reviews the modus operandi of the dose modifying drug Pentoxifylline and the
dose enhancement factors which can be achieved in different cell types. Preclinical and clinical data
show that Pentoxifylline improves the oxygenation of hypoxic tumours and enhances tumour
control by irradiation. In vitro experiments demonstrate that Pentoxifylline also operates when
oxygen is not limiting and produces dose modifying factors in the region of 1.2 – 2.0. This oxygen
independent effect is poorly understood. In p53 mutant cells irradiation induces a G2 block which
is abrogated by Pentoxifylline. The enhancement of cell kill observed when Pentoxifylline and
irradiation are given together could arise from rapid entry of damaged tumour cells into mitosis
and propagation of DNA lesions as the result of curtailment of repair time. Recovery ratios and
repair experiments using CFGE after high dose irradiation demonstrate that Pentoxifylline inhibits
repair directly and that curtailment of repair time is not the explanation. Use of the repair defective
xrs1 and the parental repair competent CHO-K1 cell line shows that Pentoxifylline inhibits
homologous recombination repair which operates predominantly in the G2 phase of the cell cycle.
When irradiated cells residing in G2 phase are exposed to very low doses of cisplatin at a toxic
dose of 5 %. (TC: 0.05) massive toxicity enhancements up to a factor of 80 are observed in
melanoma, squamous carcinoma and prostate tumour cell lines. Enhancements of radiotoxicity
seen when Pentoxifylline and radiation are applied together are small and do not exceed a factor
of 2.0. The capacity of Pentoxifyline to inhibit homologous recombination repair has not as yet been
clinically utilized. A suitable application could be in the treatment of cervical carcinoma where
irradiation and cisplatin are standard modality. In vitro data also strongly suggest that regimes
where irradiation is used in combination with alkylating drugs may also benefit.
