Intrinsic cellular radioresistance : contributing factors and modulation by 9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate (fludarabine)
(1995)
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- Authors
- Supervisors
- Wambersie, André
- Abstract
- Fludarabine did not modify the tolerance of the musculo-connective tissues involved in leg contracture after both single-dose and fractionated irradiation.On the other hand, a slight enhancement of radiation-induced rat spinal cord myelopathy was observed after different fractionated schemes (DMFs of 1.25-1.27). This potentiation, which did not vary with the dose per fraction, likely resulted from a fixed additive toxic effect on the spinal cord rather than from an interaction between fludarabine and radiation. <BR> Altogether, these results indicated that, except for the case where the jejunum was exposed to fludarabine 3h before irradiation, fludarabine enhanced normal tissue radiotoxicity to a lesser extent than mouse tumor local control, yielding therapeutic ratios above unity.<BR> Two main determinants of fludarabine’s enhancement of radiation response have been identified. First, it has been shown in mouse tumors and in mouse skin and jejunum that radiosensitization was associated with the degree of DNA synthesis inhibition in the target cells for radiation. This measurement, which reflects the level of intracellular F-ara-ATP at the time of irradiation, indicates windows of opportunity for the selection of the optimal timing for irradiation in relation to fludarabine administration. This tool, however, only applies to tumors or normal tissues such as skin or aerodigestive mucosa for which target cells for radiation have been identified. For late reacting normal tissues, it is not known whether pharmacokinetics of F-ara-ATP is a major determinant of fludarabine’s enhancement. Second, it has been shown in vitro that cells with a larger repair capacity as expressed by a low α/β ratio tended to be much more radiosensitized by F-ara-A. Although this finding did not hold for all cell lines studied, it would suggest that only cells that are radioresistant because of a proficient repair capacity would benefit form a combined fludarabine and radiotherapy treatment approach. <BR> In conclusion, we have reported in this thesis that the combination of radiation with fludarabine, a repair inhibitor, is an appropriate concept that could bring a positive therapeutic benefit to selectivity enhance radiation response in fractionated radiotherapy. We have pinpointed the various mechanisms of interaction between fludarabine and radiation, and we have identified several determinant of fludarabine’s enhancement. Altogether, these date have paved he way for the design of clinical trials combining fludarabine and radiotherapy. A clinical study is just beginning in the Radiation Oncology Department of the St-Luc University Hospital in Brussels (Belgium). This is a phase I study, aimed at assessing the optimal dose and schedule of fludarabine given daily as a “chemical boost” for the last 10 fractions of a standard course of radiotherapy in locally advanced head and neck squamous cell carcinoma. This regiment was designed based on the molecular mechanism of interaction between fludarabine and radiation and on data from preclinical and clinical studies of fludarabine. It is expected that the design and the outcome of this trial will result in future clinical studies with nucleoside analogues, including phase II and III trials with fludarabine.
- Affiliations
Citations
Grégoire, V. (1995). Intrinsic cellular radioresistance : contributing factors and modulation by 9-beta-D-arabinofuranosyl-2-fluoroadenine monophosphate (fludarabine). https://hdl.handle.net/2078.5/111349