10 Anti-Cancer Drugs - University of Victoria - Web.UVic.ca by chenmeixiu

VIEWS: 2 PAGES: 28

									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


                     MALES
                     Lung          29%
                     Colorectal    12%
                     Prostate      11%

     38,400          Total         38,400



                     FEMALES
                     Lung          26%
                     Breast        15.5%
                     Colorectal    12%


     34,300          Total         34,300
    CANCER: FIVE YEAR CANCER SURVIVAL RATES

               US     BC(06) Cases in US(06)   CAN (06)
PROSTATE       97%    91%            237,700   20,700
TESTES         91%    95%                      840
MELANOMA       89%    90%            63,000    4,500
UTERUS         84%    87%            40,800    3,900
BREAST         86%    86%            210,600   22,300
BLADDER        82%    77%            56,000    6,400
CERVIX         71%    72%            10,000    1,350
COLON/RECTUM   62%    60%            147,000   20,000
ORAL           51%*   62%            42,000    3,200
OVARY          53%    38%            20,300    2,300
LEUKEMIA       46%    46%            35,000    4,100
BRAIN                 23%                      2,500
STOMACH        22%    23%            22,000    2,800
ESOPHAGUS      *      13%                      1,500
LUNG           15%    16%            175,000   22,700
PANCREAS       4%     6%             28,000    3,500
             Cancer Death Rates*, for Men, US,1930-2002
100
                    Rate Per 100,000

                                                                             Lung
 80



 60

             Stomach
                                                                                                     Prostate
 40                                                          Colon & rectum


 20
                                                                                                Pancreas

                               Leukemia                                               Liver
  0
      1930


             1935


                        1940


                                1945


                                       1950


                                              1955


                                                      1960


                                                               1965


                                                                      1970


                                                                               1975


                                                                                       1980


                                                                                              1985


                                                                                                      1990


                                                                                                             1995


                                                                                                                    2000
                    *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.
         Cancer Death Rates*, for Women, US,1930-2002
100
             Rate Per 100,000

 80



 60


                                                                                                      Lung
 40           Uterus
                                                                   Breast


 20          Stomach
                                                                                 Colon & rectum
                     Ovary
                                                          Pancreas
  0
      1930


              1935


                     1940


                             1945


                                    1950


                                           1955


                                                   1960


                                                            1965


                                                                   1970


                                                                          1975


                                                                                 1980


                                                                                        1985


                                                                                               1990


                                                                                                         1995


                                                                                                                2000
              *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.
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 P                            O
                                 N                        O P
Cyclophosphamide               N H                             N
                                                             N H
(CYTOXAN)               Cl           Cl
                                                  O                     O
                                                      +             +
                                                      N            N
                                              N                             N

cross links two guanine bases             N       N   N            N    N       N
in different DNA strands                                  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         NH3                                          O
                                                                        NH3
             Pt                                                    Pt
       Cl         NH3                                          O        NH3
                                                         O

      cis-PLATIN                                          Carboplatin
       (Platinol)                                         (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
                                   sugar-phosphate         sugar-phosphate
      H
      N    O                       N    O                  N    O
                                            cells
          NH                         NH                        NH
 F                            H                      CH3
      O                            O                       O
               X

 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
SIMILARLY
6-Mercaptopurine gets incorporated instead of adenine

        SH                   NH2
    N        N                     N
                         N
        N    NH                    NH
                             N

6-mercaptopurine             adenine
  (Purinethol)
2-5 mg/kg daily for 4 weeks, orally for Leukemia
H2N        N     N

       N
                 N   NH    CONH   CHCH2CH2COOH   Folic acid
           OH
                                  COOH

 H2N       N     N

       N
                 N   N     CONH   CHCH2CH2COOH   Methotrexate
           NH2
                     CH3          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

                 Estradiol               Diethylstilbestrol DES
                                 NMe2
                        O
                                                                            N

                                                                       O



                                         HO           S                OH
           R
                     Tamoxifen                       Raloxifene
                                                          NMe2
Tamoxifen (R = H) is metabolized to R = OH and
then binds to a site (ERE) that acts as a gene        O

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
                                                      R
tumor growth can still occur
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%

                      N                                                    O
                                                 CF3
                              N
                          N              O2N
                                                           O

                                                       N
                                                       H       O
             NC                     CN



                  Letrozole                    Flutamide           Exemestane

 Canada (05):                     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     OH
   Z   O       O   Z         Z = small cyclic                           COCH2OH
                                  peptides, e.g.                        OH
           N           NH2
                                   Val Pro         CH3O    O     OH O
           O                 Thr
                                           Sar
                             O     Met
                                     Val                       NH2
                                                          HO


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       OH                                                          HO   O       OH
         O                                                                           O

                                                                                 O
             NH   O                                                                      NH   O
                                               O                                                                        O
                      O               H                                                           O            H
                              OH O O                                                                   OH O O
              OH                                                                          OH
                              O                                                                        O
                                           O            O                                                           O
                                                            O   O       OH

     Paclitaxel
                                                   HO               H
                                                                             O
                                                                                                  Docetaxel
                                                            OH O O
                                                            O
                                  Baccatin                               O
 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
                                                     SO3-
                     CHOHCH3
                                            Cl
 CH3CHOH         N
                                                      N         SO3-
           NH         HN
                           CH2CH2COOH            N   Al     N
                 N
                                                      N

    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       in cells excited to 1O2 (singlet oxygen) = destroys tissue
     2


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*
        M* = or  emitter
         Beta emitters                                         +
       HO2C             CO2H          N      N
              N   N
                                      N     m
                                           99        N
              N   N                         Tc
       HO2C             CO2H          OC             CO
                                                CO
              DOTA
                                     Gamma emitter
        M* = Ln3+ =                  DNA intercalator
        153Sm, 166Ho, 169Yb
                                                      Cardiolite: heart
                                                      gamma imaging
                           Iobenguane (mIBG)

123I   gamma imaging
131I   beta and gamma
           therapy
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   Li

   1
       0n
                 10
                     5   B                         [B12H11SH]2-

            4
                                                     BSM
            2   He

								
To top