10 Anti-Cancer Drugs

Download Report

Transcript 10 Anti-Cancer Drugs

INCIDENCE RATES
Cancer in Canada (2007)
MALES
Prostate 27%
Lung
15%
Colorectal 14%
Bladder
6%
82,700
Total 82,700
FEMALES
Breast
29%
Lung
14%
Colorectal 12%
Uterus
5%
77,200
Total 77,200
Canadian Cancer Death Rates 2007
38,400
34,300
MALES
Lung
Colorectal
Prostate
29%
12%
11%
Total
38,400
FEMALES
Lung
Breast
Colorectal
26%
15.5%
12%
Total
34,300
CANCER: FIVE YEAR CANCER SURVIVAL RATES
PROSTATE
TESTES
MELANOMA
UTERUS
BREAST
BLADDER
CERVIX
COLON/RECTUM
ORAL
OVARY
LEUKEMIA
BRAIN
STOMACH
ESOPHAGUS
LUNG
PANCREAS
US
97%
91%
89%
84%
86%
82%
71%
62%
51%*
53%
46%
22%
*
15%
4%
BC(06) Cases in US(06)
91%
237,700
95%
90%
63,000
87%
40,800
86%
210,600
77%
56,000
72%
10,000
60%
147,000
62%
42,000
38%
20,300
46%
35,000
23%
23%
22,000
13%
16%
175,000
6%
28,000
CAN (06)
20,700
840
4,500
3,900
22,300
6,400
1,350
20,000
3,200
2,300
4,100
2,500
2,800
1,500
22,700
3,500
Cancer Death Rates*, for Men, US,1930-2002
100
Rate Per 100,000
Lung
80
60
Stomach
Prostate
40
Colon & rectum
20
*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.
2000
1995
1990
1985
1980
1975
1970
1965
1960
Liver
1955
1950
1945
1940
1935
Leukemia
1930
0
Pancreas
Cancer Death Rates*, for Women, US,1930-2002
100
Rate Per 100,000
80
60
40
Uterus
20
Stomach
Lung
Breast
Colon & rectum
Ovary
*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.
2000
1995
1990
1985
1980
1975
1970
1965
1960
1955
1950
1945
1940
1935
Pancreas
1930
0
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 marrow
are 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
O
O
O P
Cyclophosphamide
(CYTOXAN)
N
N H
Cl
O P
N
N H
O
Cl
N
cross links two guanine bases
in different DNA strands
N
N
O
+
+
N
N
N
N
N
N
N
DNA DNA
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
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
PLATIN DRUGS (1969)
Guanines displace chlorides
O
Cl
O
NH3
Pt
Pt
Cl
NH3
O
NH3
NH3
O
cis-PLATIN
(Platinol)
Carboplatin
(Paraplatin)
Good for testicular (90% cure), ovarian cancers
OK for bladder
Hard 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)
ANTIMETABOLITES
use compounds of similar structure to RNA/DNA
nuscleosides, which get incorporated but are useless
H
N
O
NH
F
O
H
X
5-FU (5-fluorouracyl)
[Adrucil]
sugar-phosphate
N
O
cells
NH
sugar-phosphate
N
O
NH
CH3
O
O
In cells, uracil gets converted to the
methyl derivative but the F prevents
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
SIMILARLY
6-Mercaptopurine gets incorporated instead of adenine
SH
NH2
N
N
N
NH
6-mercaptopurine
N
N
N
NH
adenine
(Purinethol)
2-5 mg/kg daily for 4 weeks, orally for Leukemia
N
H2N
N
N
N
NH
CONH
OH
N
H2N
N
Folic acid
COOH
N
N
NH2
CHCH2CH2COOH
N
CH3
CONH
CHCH2CH2COOH
Methotrexate
COOH
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
OH
OH
HO
HO
Diethylstilbestrol DES
Estradiol
O
NMe2
N
O
HO
S
R
Tamoxifen
Raloxifene
OH
NMe2
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 antiestrogen blocking replication (transcription)
BUT: in some patients, the AP1 (activating protein)
promoter site is activated so transcription and
tumor growth can still occur
O
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%
O
N
CF3
N
O2N
N
O
N
H
NC
Letrozole
Canada (05):
O
CN
Flutamide
Exemestane
AE: Tamoxifen
AA: cyproterone, flutamide, nilutamide
ES: anastrozole, exemestane, letrozole
E: diethylstilbestrol (DES)
AE = antiestrogen; AA = anti-androgen; ES = blocks estrogen synthesis; E = estrogen
ANTIBIOTIC TYPE CANCER DRUGS
Actinomycin Type
Adriamycin
O
Z
O
O
N
O
Z
NH2
OH
COCH2OH
OH
Z = small cyclic
peptides, e.g.
Thr
O
Val Pro
CH3O
O
OH O
Sar
Met
Val
HO
NH2
Generally, these antibiotics are too toxic for usual antibiotic use:
interfere with peptide (small protein) synthesis
Bleomycin:
used for testicles, head and neck tumors
Adriamycin: broad spectrum anti-cancer (all types)
Actinomycin, Cactinomycin, Dactinomycin: wide variety of cancers
BUT extremely toxic (heart failure)
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 patient
BACCATIN (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
NH
O
OH
O
O
O
OH
HO
O
NH
O
OH O O
O
OH
O
O
OH
O
O
H
O
O
H
OH O O
O
O
O
O
OH
Paclitaxel
HO
Baccatin
O
H
OH O O
O
O
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 site
Should absorb in red ~630nm (flesh absorbs less here)
Should produce a species toxic to the tumor
Porphyrins and phthalocyanines are suitable
SO3CHOHCH3
Cl
CH3CHOH
N
HN
NH
N
CH2CH2COOH
N
N
Al
N
SO3N
HOOCCH2CH2
SO3-
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 days
irradiate with red laser light ~ 630 nm for 30 mins:
3O
2
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
ligand with an affinity
for a particular organ
M* +
M* = or  emitter
M*
+
Beta emitters
CO2H
HO2C
N
N
N
N
N
N
CO2H
HO2C
N
m
99
Tc
N
CO
OC
CO
DOTA
M* = Ln3+ =
153Sm, 166Ho, 169Yb
Gamma emitter
DNA intercalator
Iobenguane (mIBG)
123I
gamma imaging
131I
beta and gamma
therapy
Cardiolite: heart
gamma imaging
Boron Neutron Capture Therapy (BNCT)
10B
has a high neutron capture cross-section:
neutron absorption results in fission to 7Li, 4He and generation
of a gamma ray with sufficient energy to penetrate about one cell
diameter
Ionization by gamma ray damages DNA and kills cell
cancerous cell
7
3
1
10
0n
5
4
2
Li
B

He
[B12H11SH]2BSM