2. Dose-Response Relationships

3. Dose-Response Relationships

4. TISSUE CLASIFICATIONS Low Intermediate High Very High Mature red cells, muscle cells, mature connective tissues, mature bone and cartilage, ganglion cells Endothelium, growing bone and cartilage, fibroblasts, glial cells, glandular epithelium of breast, pulmonary epithelium, renal epithelium, hepatic epithelium, pancreatic epithelium, thyroid epithelium, adrenal epithelium Urinary bladder epithelium, esophageal epithelium, gastric mucosa, mucous membranes, epidermal epithelium, epithelium of optic lens Lymphocytes, immature hematopoietic cells, intestinal epithelium, spermatogonia, ovarian follicular cells

8. Dose-Response Curves

9. Dose-Response Curves Withers, 1982

10. Early and Late Effects

12. Overall Time Factor Extra dose required to counteract proliferation does not become significant until ~2 weeks after the start of daily fractionation Delay – population turnover time Delay reflect mitotic death? Steep Rise, not T 0.11 Denekamp, 1973 (Gray Lab)

14. Accelerated Repopulation 28 Days Withers: head and neck cancers Dashed line: predicted from a constant 2 month clonogen doubling rate

33. Nitroimadazoles Short T½, less toxic Doesn’t cross blood-brain barrier (less neurotoxic). Not effective in RT trials Less effective than others, but much less toxic Promising results from H&N cancer RT trials Etanidazole Nimorazole Good SER (At 10 mM, eliminates effect of hypoxia on radiation sensitivity) Preferential cytotoxicity to hypoxic cells that is increased with hyperthermia Dose-limiting toxicity (peripheral neuropathy) Poor results with fractionation Misonidazole First compound studied Minimal effects (at 10 mM, SER is 1.6) Metronidazole