Interacts directly with molecules in cell (DNA)

Dominant with high LET radiation

Not modified by chemical sensitizers or protectors

Interaction with cell (esp water) to produce free radicals that damage critical targets.

H₂0 --> H₂0⁺+ e^-

H₂0⁺+H₂0 --> H₃0⁺ + OH• --> damages DNA

Lifetimes

ion 10^-10 second

OH• radical 10^-9 second

DNA radicals 10^-5 second

Indirectly ionizing

Interact with nuclei and set in motion fast recoil protons, α-particles that do damage.

p53 (responds to DNA damage by RT)

bcl-1

bax

IRF-1

c-myc

c-fos

c-jun

MAPK

caspases

TNF

bcl-2

PKC

NF-κB

ds-DNA break leads to activation of ATM

↓

ATM increases p53

↓

p53 increases p21/waf-1

↓

p21/waf-1 inhibits cyclin dependant kinases, preventing activation of Rb and E2F, leading to cell cycle arrest to fix DNA

G1 → cyclin D & E

S → cyclin A

G2 → cyclin A & B

M → cyclin B

Promotion

ckd6/cyclin D complex

↓

phosphorylates Rb causing it to release E2F

↓

allows cell to progress from G1→S

Inhibition

DNA damage activates ATM → activates p53 → p21 produces cell cycle arrest by associating with PCNA

p16 inhibits cdk4 so it can't bind to cyclin D

Promotion

cyclin A & cyclin B bind to cdk1

↓

promotes phosphorylation of nuclear laminin (causing nuclear envelope to dissolve), and phosphorylation of histone H1 (chromosomes condense).

cyclin B binds to cdc2 creating mitosis promotion factor (MPF)

Inhibition

p53 (unclear mechanism)

cdk-phos

Most to least radiosensitive

M

G2 (esp late G2)

late G1

early G1

early S

late S

Angiogenesis

increase p53 levels → apoptosis

increase heat shock protein (hsp70 and hsp80)

decrease O2 consumption rate by switching to glycolysis

amplification of multi-drug resistance (MDR) genes

Stimulating factors

Angiopoietin

FGF

PDGF

prostaglandins E1 and E2

tgf β

TNF-α

VEGF

angiostatin

endostatin

interferon-α

interferon-β

thrombospondin

inhibitor of MMP

100 keV/uM

This corresponds to an average separation between ionizing events of ~2nm (diameter of DNA), so maximizes the dsDNA breaks.

halogenated pyrimidines: BUdR, IUdR

hypoxic-cell radiosensitizers: misonidazole, etanidazole, nimorazole

hypoxic cytotoxins: mitomycin C, tirapazamine

MI = proportion of cells undergoing mitosis

MI = λ T_M/T_C

T_M = length of mitosis

T_C = length of cell cycle

λ = correction factor that acocunts for the fact that cells aren't evenly distributed through cell cycle ~0.67

LI = proportion of cells undergoing DNA synthesis

LI = λ T_S/T_C

T_S = duration of DNA synthesis

T_C = length of cell cycle

λ = correction factor

T_pot = λ T_S/LI

T_S = length of mitosis

LI= labeling index = fraction of cells undergoing synthesis

λ = correction factor

Φ = 1 - T_pot / T_d

T_d = actual tumor doubling time

T_pot = potential tumor doubling time

Repair of sublethal damage

Reassortment of cells in the cell cycle

Repopulation

Reoxygenation

fraction size and

overall treatment time

fraction size and

NOT overall treatment time

Rb - retinoblastoma

WT - Wilm's tumor

NF1 - neurofibromatosis

FAP - familial adenomatosis polyposis

p53 - breast cancer, SCC lung ca, cervical, bladder

DCC - colon ca

N-ras - neuroblastoma

lms - acute non-lymphocytic leukemia

H-ras - sarcoma

bcr/abl - t9-22 (philadelphia chromosome) - CML

c-myc - B-cell or Burkitt's lymphoma

N-myc - Burkitt's lymphoma

High dose --> 8% per Sv

Low dose --> 4% per Sv

Men

temporary 0.15 Gy

permanent 3.5-6 Gy in 1 fx, or 2 Gy in multiple fx.

Women

permanent 2.5-3.5 Gy, or 20 Gy in multiple fx.

become menopausal

day 0-9

most sensitive to lethal effects of RT

if embryo survives, it grows normally

LD₅₀ = 1 Gy

day 10 - wk 6

40% malformation risk at 0.5 Gy

late cancer risk 14% per 1Gy

Wk 6 - birth

microcephaly and mental retardation in early period (16-25 wks)

permanent growth retardation in late period

#2 mutation in human malignancy

activated by SOS

G-protein = active form bound to GTP, inactive form bound to GDP

When activated it activates fos, jun, mos, and myc

her2/neu oncogene

receptor tyrosine kinase

upstream of ras

abl is an oncogene

bcl-abl translocation = philadelphia chromosome t(9:22)

#1 mutation in malignancy - tumor suppressor

activates apoptosis: ↑ proaptotic Bax, ↓ anti-apoptotic bcl-2

G1 checkpoint arrest: RT upregulates ATM by dsDNA break, ↑p21, which prevents G1→S

p53 leads to increased Gadd45, then Gadd45 binds to PCNA to stimulate DNA excision repair.

Consequences of mutant p53: increased genomic instability and tumor aggresiveness; decreased apoptosis and radiosensitivity.

tumor suppressor

regulates G1→S transition

CDK4 phosphorylates CDK4, preventing Rb inactivation and thus G1→S transition.

defect in mismatch repair

Genes: MSH, MLH and PMS

defective nucleotide excision repair

XP gene

sensitive to UV radiation, and prone to skin cancer

no abnormal sensitivity to XRT

defective nucleotide excision repair

increased sensitivity to UV radiation

Mutation in ATM

Mutated ATM means that cells don't respond to DNA damage, and progress through cell cycle after ionizing radiation damage.

increased radiosensitivity

ligase deficiency

characterized by genetic instability and early predisposition to cancer

fixes dsDNA damage

rejoins strands via alignment of 2 homologous DNA complexes

Rad51 and Rad52 involved

Rad50/MRE-11/NBS protein complex involved

BRCA1 can complex with RAD51

activated in response to DNA damage

ATM phosphorylates Cdk2, leading to Rb-dependent G1 arrest

ATM phosphorylates p53, leading to p21/WAF1, which prevents G1→S

induces proliferation of fibroblasts, inflammatory cells, and endothelial cells leading to late RT complications.

Serum concentrations of TNF correlate with severity of radiation pneumonitis, hepatic dysfunction, renal insufficiency, and demyelination.

Equation for probability of cure

(from number of clonogens)...

p = e^-(M)(SF)

where M = initial number of clonogens

SF = surviving fraction after RT.

Example: if you start with 10⁶ clonogens, and your SF after radiation is 10^-6, then your probability of cure is e^-1=37%.

aka  Bexxar

a radiolabeled antibody against the CD20 antigen over-expressed in non-Hodgkin’s lymphoma cells

Nucleoside analog that is incorporated into DNA, and interferes with ribonucleotide
reductase, causing depletion of deoxynucleotide triphosphates necessary for DNA synthesis.

Strongly synergistic with RT.

S-phase specific

Inhibits ribonucleotide reductase.

Weakly synergistic with RT.

Inhibits dihydrofolate reductase. Encephalopathy if given intrathecal at high dose.

Weak synergism with RT.

aka Herceptin.

Antibody against HER2/neu growth factor receptor. Cardiotoxicity.

Blocks EGFR receptor dimerization and tyrosine kinase phosphorylation.

Rash is common.

Strong synergy with RT.

aka Gleevec.

CML.

Tyrosine kinase inhibitor that inhibits bcr-abl, c-kit and PDGF receptors.

Antibody against CD20 in B-cells.

Allergic reactions common.

Inhibits the mitotic spindle apparatus by stablizing tubulin polymers, leading to mitotic death.

Mild neuropathy.

aka VP16.

Topoisomerase II inhibitor.

aka CPT-11.

Topoisomerase I inhibitor.

Vinblastine, vincristine, vinorelbine (navelbine). Inhibit tubulin polymerization (G2 phase specific).

Neurotoxicity (worst with vincristine).

Goserlin acetate (zoladex), leuprolide (lupron).

Shut down pituitary-gonadal axis function.

aka casodex.

Anti-androgen

aka arimidex.

Blocks estrogen production selectively.

Free-radical scavanger.

Hypotension.

Radiation protector.

Double strand break.

↓

DNA end recognition by Ku70, Ku80D, and DNA-PKc's.

↓

END processing by Artemis.

↓

DNA polymerase μ

↓

End bridging by XRCC4 and Ligase IV.

Ataxia-Telangiectasia ↔ ATM

Seckel's syndrome ↔ ATR

SCID mice ↔ DNA PKcs

SCID human ↔ Artemis

Ataxia-Telangiectasia-like disorder (ATLD) ↔ Mre11

Nijmegen breakage syndrome (NBS) ↔ Nbs

Fanconi anemia ↔ eight different genes (BRCA2 is one)

Base damage >1000

ssDNA breaks 1000

dsDNA breaks 40