Cancer in Canada (2007)
MALESProstate 27%Lung 15%Colorectal 14%Bladder 6%
Total 82,700
FEMALESBreast 29%Lung 14%Colorectal 12%Uterus 5%
Total 77,200
INCIDENCE RATES
82,700
77,200
Canadian Cancer Death Rates 2007
MALESLung 29%Colorectal 12%Prostate 11%
Total 38,400
FEMALESLung 26%Breast 15.5%Colorectal 12%
Total 34,300
38,400
34,300
CANCER: FIVE YEAR CANCER SURVIVAL RATES
US BC(06) Cases in US(06) CAN (06)PROSTATE 97% 91% 237,700 20,700TESTES 91% 95% 840MELANOMA 89% 90% 63,000 4,500UTERUS 84% 87% 40,800 3,900BREAST 86% 86% 210,600 22,300BLADDER 82% 77% 56,000 6,400CERVIX 71% 72% 10,000 1,350COLON/RECTUM 62% 60% 147,000 20,000ORAL 51%* 62% 42,000 3,200OVARY 53% 38% 20,300 2,300LEUKEMIA 46% 46% 35,000 4,100BRAIN 23% 2,500STOMACH 22% 23% 22,000 2,800ESOPHAGUS * 13% 1,500LUNG 15% 16% 175,000 22,700PANCREAS 4% 6% 28,000 3,500
Cancer Death Rates*, for Men, US,1930-2002
*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-2002, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.
0
20
40
60
80
10019
30
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
Lung
Colon & rectum
Stomach
Rate Per 100,000
Prostate
Pancreas
LiverLeukemia
Cancer Death Rates*, for Women, US,1930-2002
*Age-adjusted to the 2000 US standard population.Source: US Mortality Public Use Data Tapes 1960-2002, US Mortality Volumes 1930-1959,National Center for Health Statistics, Centers for Disease Control and Prevention, 2005.
0
20
40
60
80
10019
30
1935
1940
1945
1950
1955
1960
1965
1970
1975
1980
1985
1990
1995
2000
Lung
Colon & rectum
Uterus
Stomach
Breast
Ovary
Pancreas
Rate Per 100,000
ANTI-CANCER DRUGS (~16B$ /y - worldwide)
Cancer - many types of disease, but always growth of cells out of control
More dangerous types:
1) rapidly dividing cells which proliferate
2) those that invade normal cells and destroy them
3) METASTASIS: ability to grow at sites distant from origin; cancer cells transported by blood or lymphatic system - most difficult to treat
Anti-cancer drugs are (generally) equally toxic to cancerous and normal cells: work because cancerous cells are dividing faster so affected most
BUT: linings of gut and mouth hair follicles bone marroware normally rapidly dividing, hence most anti-cancer drugs affect these too and so:
Common Side Effects are mostly the same for all drugs: nausea, ulcers+ sore mouth hair loss depress bone marrow, reduce platelets = infections
DNA STRAND CROSS LINKING AGENTS (unable to separate for replication)
ALKYLATING AGENTS (nitrogen mustards) ANTINEOPLASTICS
1940's: The WWI mustard gas S(CH2CH2Cl)2 is highly toxic to blood, lymph, bone marrow cells since these are fast dividing: suggested a possible treatment
Generally now use a Nitrogen mustard: R-N(CH2CH2Cl)2
Cyclophosphamide (CYTOXAN) cross links two guanine bases in different DNA strands
Widely used on skin cancer, Hodgkin’s disease (enlarged lymph nodes, spleen) and in COCKTAILS with other drugs
Dose: 40-50 mg/kg IV at rate 10-20 mg/kg per day (too toxic to give all at once)
Has been used to de-fleece sheep!
Bone marrow very sensitive, sometimes removed & put back
O
PNH
O
N
ClCl
O
PNH
O
N
NN
NN
N
O
N N N
N
O
N
DNA DNA
++
Note on Dosages:
Doses of cancer drugs in general are often expressed in mg/m2
Surface Area S = Mass 0.425 x Height 0.725 x 71.84 (in cm2) kg cm
for Dave 118 192 S = 24,676 cm2
or 2.47 m2
PtCl NH3
NH3Cl O
Pt
ONH3
NH3
O
O
PLATIN DRUGS (1969)Guanines displace chlorides
cis-PLATIN Carboplatin (Platinol) (Paraplatin)
Good for testicular (90% cure), ovarian cancersOK for bladderHard on kidneys and nervous system + vomiting
Other antineoplastics in use in Canada: Bisulfan, Thiotepa, Temozolomide, Chlorambucil, Estrumustine, Ifosfamide, Mechlorethamine, Melphalan, Carmustine, Lomustine, Streptozocin (see the CPS for details)
NH
N
F
O
O
NH
N
H
O
O
sugar-phosphate
NH
N
CH3
O
O
sugar-phosphate
cells
H
5-FU (5-fluorouracyl) In cells, uracil gets converted to the methyl derivative but the F prevents
[Adrucil] this from happening and the cell does not recognize F as different from H
Useful for breast, rectum, colon, ovary, pancreas, liver
800 mg IV / day for 5 days, repeat in a month
X
ANTIMETABOLITESuse compounds of similar structure to RNA/DNA nuscleosides, which get incorporated but are useless
SIMILARLY
6-Mercaptopurine gets incorporated instead of adenine
N
N NH
N
SH
N
N NH
N
NH2
6-mercaptopurine adenine
(Purinethol)
2-5 mg/kg daily for 4 weeks, orally for Leukemia
N
N
N
N
NH
H2N
OH
CONH CHCH2CH2COOH
COOH
N
N
N
N
N
H2N
NH2
CONH CHCH2CH2COOH
COOHCH3
Folic acid
Methotrexate
We need to eat FOLIC ACID (vitamin B9), methotrexate binds to an enzyme involved in folic acid metabolism more strongly than folic acid itself: fools cells into stopping synthesis of nucleic acids = cell death Used for leukemia (kids), breasts, ovary, colon
POWERFUL TERATOGEN: CANNOT USE IF PREGNANT
NOTE: bacteria can make folic acid so we will trick these later with sulfonamide drugs, the precursors to penicillin.
ANTI-HORMONES (BREAST CANCER)
Breast cancer needs estrogen to encode the proteins for growth
Circulating estrone and estradiol related to breast cancer
(similarly dihydrotestosterone to prostate cancer)ESTROGENS
HO
OH
Estradiol
HO
OH
Diethylstilbestrol DES
ONMe2
R
Tamoxifen
S
O
N
OHHO
Raloxifene
Tamoxifen (R = H) is metabolized to R = OH and then binds to a site (ERE) that acts as a gene promoter for protein synthesis: acts as an anti-estrogen blocking replication (transcription) BUT: in some patients, the AP1 (activating protein) promoter site is activated so transcription and tumor growth can still occur
O
NMe2
R
Raloxifene (Evista) is better to promote bone growth, no effect on uterine tissue: reduced risk of breast cancer 72% in study of 5000 post-menopausal women at 60 mg dose
Letrozole (Femara) inhibits estrogen biosynthesis: 2.5 mg suppresses blood estrogens by ~80%
Canada (05): AE: TamoxifenAA: cyproterone, flutamide, nilutamideES: anastrozole, exemestane, letrozoleE: diethylstilbestrol (DES)
AE = antiestrogen; AA = anti-androgen; ES = blocks estrogen synthesis; E = estrogen
NN
N
CNNC
NH
O
CF3
O2N
O
O
Letrozole Flutamide Exemestane
ANTIBIOTIC TYPE CANCER DRUGSActinomycin Type Adriamycin
Generally, these antibiotics are too toxic for usual antibiotic use:
interfere with peptide (small protein) synthesis
Bleomycin: used for testicles, head and neck tumorsAdriamycin: broad spectrum anti-cancer (all types)Actinomycin, Cactinomycin, Dactinomycin: wide variety of cancers
BUT extremely toxic (heart failure)
O
N
Z O O Z
NH2
Z = small cyclic peptides, e.g.
ValThr
Pro
SarMet
Val
O
CH3O
O
O
OH
OH
COCH2OH
OH
O
HONH2
TAXOL (Bristol-Myers-Squibb trademarked name)Paclitaxel is the actual chemical: occurs in Pacific Yew bark (70-400 ppm) and leaves (20-70 ppm): 3 trees required per patientBACCATIN (from clippings) was used by Rhone-Poulenc to make Taxotere (Docetaxel) – approved by FDA for breats cancer in ‘96
TAXOL and Taxotere promotes tubulin assembly in cells: cannot break down to grow so cells die
O
O
O
OHOO
O
OH O
O
O
O
OH
NH
O
HO
O
O
OHOOH
OH O
O
O
O
OH
NH
O
H
O
O
O
O
OHOO
O
OH O
O
OH H
Paclitaxel
Baccatin
Docetaxel
OTHER THERAPIES
Designer drugs: ene-diynes
The ene-diyne is like a mouse trap: tumor cell DNA triggers the trap, allows cyclization to a benzene DIRADICAL – the diradical rips hydrogen atoms from the tumor cell DNA to form benzene, cleaves the strands and kills the cell
eg. Dynemycin (next slide)
PHOTODYNAMIC THERAPY
Drug needs to concentrate at tumor siteShould absorb in red ~630nm (flesh absorbs less here)Should produce a species toxic to the tumor
Porphyrins and phthalocyanines are suitable
NHN
NHN
CH3CHOH
CHOHCH3
CH2CH2COOH
HOOCCH2CH2
NN
NNAl
SO3-
SO3-
SO3-
Cl
a heme porphryn an Al phthalocyanine
Photofrin (porfimer sodium) is a mixture of ~200 porphyrins
initially by QLT (Vancouver): approved 1977/8
Inject 2-5 mg/kg, wait 1-2 daysirradiate with red laser light ~ 630 nm for 30 mins:
3O2 in cells excited to 1O2 (singlet oxygen) = destroys tissue
Body is photosensitive for ~ 1 month
Canada: Bladder, Esophagus (75%+); USA (also early Lung)
Improved versions use synthetic benzoporphyrins, shorter sun sensitivity, but useful also for macular degeneration in eye.
Radiotherapy
X-ray and Gamma Knife therapy:
external radiation source focused on tumor – lots of collateral damage (burning, scarring)
Magic bullet approach:
send the radioactivity to the tumor
M* + M*
M* = or emitter
ligand with an affinity for a particular organ
N
Tc99
CO
N
OC CO
N
N
m
+
NN
N NHO2C CO2H
CO2HHO2C
DOTA
M* = Ln3+ = 153Sm, 166Ho, 169Yb
Beta emitters
Gamma emitter DNA intercalator
Cardiolite: heart gamma imaging
Iobenguane (mIBG)
123I gamma imaging
131I beta and gamma therapy
B105
Li73
He42
10n
cancerous cell
[B12H11SH]2-
BSM
Boron Neutron Capture Therapy (BNCT)10B has a high neutron capture cross-section: neutron absorption results in fission to 7Li, 4He and generationof a gamma ray with sufficient energy to penetrate about one celldiameter
Ionization by gamma ray damages DNA and kills cell