Ionization

Question 1

Ionizing Radiation and Chemo

Answer 1

Chemotherapy: systemic toxicity (doesn’t diff btwn normal and tumor dividing cells). Radiotherapy. These both damage DNA: normal cells arrest cell cycle and repair DNA while cancer cells with mutations in repair mech enter apop. Resistance - p53 mut

Question 2

Cancer cell repair mechs

Answer 2

1. BRCA1/BRCA2 = repair of ss breaks by recomb

2. PARP (poly-ADP-ribose polymerase) repairs ssDNA breaks

Question 3

Cancer cells repair of choice

Answer 3

Cancer cells upreg PARP so inhib’s important for treatment. Breast cancers (BRCA1/2) are extremely sensitive to PARP inhib’s.

Question 4

Anti-Cell cycle Drugs

Answer 4

Microtubule inhib = Vincristine

DNA synth inhib = Antimetabolites (methotrexate, 5-FU), Topoisomerase inhib (Etopoxide, Doxorubicon)

Dmg DNA = alkylation (cyclophosphamide), intercalating agents (Platinum complexes)

Question 5

Platinum Coordination Compounds

Answer 5

Reactive form complexes between guanine nucleotides leading to mutation, DNA x-link, base excision and ds breaks. Adducts - chemical group attaches to base and leads to abnormal base pairing. Cisplatin and Carboplatin.

Question 6

Alkylating Agents

Answer 6

Instead of a chem compound, an alkyl group attaches. Weak carcinogens but antineoplastic. Cyclophosphamide. Alykylate DNA (guanine) forms an abnormal base pair between guanine and thymine leading to mutation. Also excision of alkylating guanine residues (depurination) leading to strand breakage. Cross linking may also occur, preventing strand seperation

Question 7

Anti metabolites

Answer 7

Lack nucleotides for synth
S phase inhibitors: Interferes with production of nucleic acids. Inhibit enzymes for nucleoside triphosphate synth. Substitute for purines and pyrimidines

Question 8

Purine Analog

Answer 8

Mercaptopurine

Question 9

Pyrimidine Analog

Answer 9

5-Fluorouracil

Question 10

Folic Acid Analog

Answer 10

Methotrexate

Question 11

Mech of 5-FU and Methotrexate

Answer 11

5FU is converted to 5-FdUMP - becomes perm bound to thymidylate synthase. DHF is reduced to THF by dihydrofolate reductase = inhib by methotrexate.

Overall, it blocks production of base that needs to be produced and incorporated into new DNA = blocks S

Question 12

Topoisomerase function

Answer 12

Topoisomerase (1: nicks 1 strand; 2: nicks both). Regions of DNA untangled to allow transC and replication. Temporarily breaks DNA allowing topological changes then reseals

Question 13

Topoisomerase inhib

Answer 13

Inhibits 2 = Doxorubicon, Daunorubicon binds topoisomerase and blocks ability to reseal DNA breaks leading to cell death

Question 14

Mitotic spindle inhib

Answer 14

Binds tubulin

APC halts cell cycle in M until all chromo aligned on metaphase plate

Question 15

Taxans

Answer 15

Paclitoxel (Taxol) binds and stabilizes microtubules therefore no disassembly and shortening

Question 16

Vinca Alkaloids

Answer 16

Vinblastine and Vincristine blocks formation of tubules, binds tubulin subunits preventing polymerization

Question 17

p53 targets

Answer 17

adenoviral p53 gene therapy (TroVax) helps tumor cells express p53

Question 18

SMAC/BAD/BID mimetics

Answer 18

normally inhibit IMPs which inhibit caspases, BAD and BID normally bind bcl-2/XL not allowing them to inhibit pore formation

Question 19

BCL-2 targets

Answer 19

Oblimersen, Genasense antisense strategy for bcl-2 are small molec inhib of bcl-2/XL in clinical trials. Short RNA sequences that bind to mRNA and decrease protein expression

Question 20

Bortezomib (Velcade)

Answer 20

blocks proteosome activity leading to active BAX and BAK.
Treatment for multiple myeloma. Blocks proteosome preventing IKB degrade leading to build up of BAX and BAK (pore formers). MM cells have increased NFKB activity leading to survival (TF for IAPs, bcl-XL) and increased proliferation (TF for IL-4,6). NFKB normally sequestered by IKB.

Question 21

Kinases as primary targets

Answer 21

Challenge is to find very specific inhibitors. All kinases carry out same reaction (phos of Tyr or Ser/Thr)

Question 22

EGFR TKi

Answer 22

Tarceva and Iressa

Question 23

Philadelphia Chromosome: BCR-Abl

Answer 23

BCR ABL is constantly active TK activity leading to activation of RAS-MAPK and PI3K-PKB pathways

Question 24

BCRABL inhib

Answer 24

Gleevac/ Imatinib (Tx for CML)

Question 25

Growth factor antagonist

Answer 25

Bevacizumab (Avastin): mab for VEGF (colorectal cancer)