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