3/29/2013 Radioprotectors Tumor hypoxia and radiosensitizer Radioprotectors Chemotherapy agents Discovery of radioprotector Structural features of radioprotectors Cysteine • A free SH group at one end NH2 Dose Reduction Factor • A strong basic group at the other end SH CH2 CH DRF COOH ((g)amine or guanidine) Dose of RT with the drug • A straight chain of two or three carbon Cysteamine atoms to connect two ends SH CH2 CH2 NH2 Dose of RT without the drug Mechanism of action Development of “more effective” compounds Free radical scavenger amifostine PlllParallel oxygen e fftffect Maximal effect for sparsely ionizing radiation Minimal effect for densely ionizing radiation DRF equal OER with a value 2.5 to 3 1 3/29/2013 Amifostine as a radioprotector in RT Phase I toxicity data • Dose-limiting toxicity– hypotension • Other toxicities include – Nausea/vomiting – Sneezing – Somnolence – Allergic reaction First ever phase III randomized trial with amifostine Radioprotector and chemotherapy • 100 patients with unresectable or recurrent adenomacarcinoma of rectum • RT ± amifostine • Protection against nephrotoxicity, ototoxicity and neurotoxicity from CDDP • Amifostine 15 minutes before RT 4 days a weeks for 5 weeks • Protection of skin, mucous membrane, • Protection against hematologic toxicity from bladder and pelvix structures cyclophosphamide Kligerman MM et al. Int J Radiat Oncol Biol Phys 22:799-802, 1992 2 3/29/2013 Amifostine in the treatment of head and neck cancer 3 3/29/2013 Amifostine in the treatment of lung cancer 4 3/29/2013 5 3/29/2013 Oxygen diffusion from a capillary Tumor hypoxia and radiosensitizer 6 3/29/2013 Overcoming hypoxia Hypoxic cell radiosensitizers • Increase oxygen supply – Hyperbaric oxygene, carbogen • Selectively sensitize hypoxic cells – Blood transfusion • Chemically stable – Stop smoking • Highly soluble and able to diffuse some • High-LET radiations, neutrons, heavy ions distance (200 um) • Chemical radiosensitizers • Be effective at therapeutic RT dose range • Hypoxic cytoxins Misonidazole Nitroimidazoles • Produced appreciable sensitization with cells in culture • Also had a dramatic effect in animal studies • Enhancement ratio of 1.8 was obtained • In clinical trials, no benefit observed Etanidazole & Nimorazole Hypoxic cytoxins selectively kill hypoxic cells • Etanidazole is less toxic than misonidazole • Tirapazamine showed highly selective toxicity toward hypoxic • Higher dose could be given cells both in vitro and in vivo, but again, no significant benefit • No benefit in clinical trials was seen in human clinical trials. • Nimorazole is much less toxic, and less effective • Very high dose can be given • In a Danish trial it produced a significant improvement in local control and survival compared with RT alone in patients with supraglottic and pharyngeal cancer, but no further studies have been done since 7 3/29/2013 Classes of chemotherapy agents • Alkylating agents Chemotherapy agents • Antibiotics • Antimetabolite • NlNucleos ide ana logues • Vinca Alkaloids • Others not belong to the above • Topoisomerase inhibitors • Targeted agents Alkylating agents Antibiotics • Highly reactive, substitute alkyl groups for • Directly bind to DNA, inhibit DNA and RNA hydrogen atoms of DNA synthesis – Nitrogen mustard derivatives – Doxorubicin – Ethylenimine derivatives – Daunorubicin – Alky l sulfona tes – Dactinomycin – Triazine derivatives – Bleomycin – nitrosoureas – Mitomycin • Cell cycle non-specific • Cell cyclic non-specific Antimetabolites Nucleoside analogues • Analogues of normal metabolites – Methotrexate – 5-Flurouracil • Cytarabine – analogue of deoxycytidine • Action mechanisms – Competitive inhibitor of DNA polymerase – Substituting for a metabolite • 5-Azacytidine – analogue of cytidine – Competing with normal metabolite to either – Inhibit process of large molecular weight RNA occupy catalytic site of a key enzyme or at an enzyme regulatory site 8 3/29/2013 Vinca Alkloids Taxanes • From plants • Microtubule-stablizing agents • Bind to cellular microtubular proteins • Block or prolong the transit time of cells in inhibiting microtubule polymerization the G2/M phase of cell cycle • Vincr is tine • Pac litaxe l is the pro to type • Docetaxel is largely synthetic Others Targeted agents • Procarbazine • Cetuximab – Precise action mechanism not clear •Hydroxyurea • bevacizumab – Inhibitor of ribonucleotide reductase – Specifically toxic to cells in S-phase – Cause piling up at a block at G1/S interface • Cis-platinum – Causing both inter and intrastrand crosslinking – Inhibit DNA synthesis – Cell cycle non-specific – May be more toxic to hypoxic cells Dose-response relationship Sublethal and potentially lethal damage repair • Sublethal damage repair – Survival increases if a dose is divided into two or more small doses separated in time • Potentially lethal damage repair – Increase in survival if cells held in non-proliferative state for some time after treatment 9 3/29/2013 The oxygen effect Resistance to chemotherapy and hypoxic cytoxins Drug resistance Drug resistance • Resistance to chemotherapy agents is acquired quickly, uniformly and inevitably • Gene mutation, stem cells and ANC transporter • Use a battery of different drugs to overcome resistance • Pleiotropic resistance – The development of resistance to one drug results in cross-resistance to other drugs, even those with different mechanisms of action • Resiatnce to chemotherapy does not mean resistance to radiation. Combination of chemotherapy and radiation therapy Combination of chemotherapy and radiation therap • Induction chemotherapy • Concurrent chemotherapy • Adjuvant chemotherapy 10 3/29/2013 Cytoxic drugs can also induce Assays for sensitivity of individual tumors second malignancies • Biopsy specimens •In vitro • The greatest relative risk is leukemia • XftiilXenografts in animals • The greatest in number is solid tumors 11.