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Anti-cancer compounds / Antineoplastic Agents, chapter 38. Cancer Therapy Surgery Radiation Immunologican Therapy ( interferons - Incr. prod. T-cells and B cells) Chemotherapy Alkylation Agents Antimetabolites / Nucleoside Analogs Antibiotics Antimitotic Agents

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slide1

Anti-cancer compounds / Antineoplastic Agents, chapter 38

  • Cancer Therapy
    • Surgery
    • Radiation
    • Immunologican Therapy (interferons - Incr. prod. T-cells and B cells)
    • Chemotherapy
        • Alkylation Agents
        • Antimetabolites / Nucleoside Analogs
        • Antibiotics
        • Antimitotic Agents
        • Micellaneous Antineoplastic Agents
        • Hormonal Therapy
slide2

Antimetabolites (Nucleoside Analogs, Folic acid analogs)

Antimetabolites:Prevents synthesis of normal cellular metabolites

Often close structural similarities metabolite and antimetabolite

earlier ex. PABA / sulfonamides

slide3

Nucleoside analogs as antimetabolites

  • Possible mecanisms:
    • Incorporation DNA or RNA; misreading
    • Inhibition of DNA polymerase
    • Inhibition of Kinases
    • Inhib. of enzymes involved in pyrimidine / purine biosynthesis
slide4

5-Fluoruracil (5-FU)

Fluorouracil®, Flurablastin®,

slide6

Kapecitabin

Xelodar®,

Additional mechanisms: Incorp. DNA / RNA

5-FU metabolism

Tegafur

UFT®

slide7

Cytarabine (ARA-C)

Cytarabin®, Cytosar®,

Gemcitasbin

Gemzar®,

slide9

Fludarabine

Fludara®

Cladribin

Leustatin®

slide11

Folic Acid analogs as antimetabolites

Metotreksat

Metoject®

Raltitrexed

Tomudex®

slide12

Chemotherapy

      • Alkylation Agents √
      • Antimetabolites / Nucleoside Analogs √
      • Antibiotics
      • Antimitotic Agents
      • Micellaneous Antineoplastic Agents
      • Hormonal Therapy

Metabolites from microorg., too toxic as antibiotics - anticancer comp.

  • Bleomycins
  • Actinomycins
  • Mitomycins
  • Antracyclins
  • Coformycins
slide13

Bleomycins

Isolated from Streptomyces verticillius

Naturally occuring as Cu-chelates

1) Binds Fe(II) inside cells

2) Bleomycin complexed Fe(II) reduce O2

3) .OH radicals produced

4) Cleavage of DNA

Bleomycin

Bleomycin Baxter®

slide14

Actinomycins

Isolated from Streptomyces sp.

Dactinomycin (Actinomycin D)

Cosmegen®

slide15

Quinolones

Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic..

DNA-topoisomerase (humans), anticancer compds. ex. doxorubicin

Unique mecanism, no cross resistance

Broad spectrum: G+ and G- ; also mycobactria, clamydia

slide16

Antracyclines

Isolated Streptomyces sp, several semisynth analogs

Doxorubicin

Doxorubicin® Adriamycin® Caelyx®

R1 = OMe, R2 = OH, R3 = H; R4 = OH

Daunorubicin

Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH

Epirubicin

Farmorubicin®

R1 = OMe, R2 = OH, R3 = OH; R4 = H

Idarubicin

Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH

Valrubicin

Mitoxantrone

Novantrone®

slide17

Mechanism ≈ Actinomycins (Intercalation)

Also interact aminosugar - phosphate

Antraquinone - red/ox react:

prod. reactive oxygen radicals

DNA-Daunomycin Complex

slide18

Mitomycins

Isolated Streptomyces sp,

Mitomycin C

Mutamycin®

slide19

Conformycins

Isolated Streptomyces sp,

Also metab. of anticancer / antiviral

adeninederiv.

Geir Andresen

Cytotox.

Ex. transition state analogs

slide20

Chemotherapy

      • Alkylation Agents √
      • Antimetabolites / Nucleoside Analogs √
      • Antibiotics √
      • Antimitotic Agents
      • Micellaneous Antineoplastic Agents
      • Hormonal Therapy
slide21

Mitosis

Prophase

Metaphase

Anaphase

Telophase

Antimitotic agents bind to microtubuli

Supression of microtubuli dynamics

Metaphase arrest

slide22

Vinca alkaloids

Vinca alkaloids (Indols)

from Vinca rosea

(Catharantus roseus)

MadagaskarPerivinkle

Binds to microtubuli- Supression of microtubuli dynamics-

Metaphase arrest

Depolymerization of microtubuli high conc.

slide23

Taxanes

First isolated from bark of Western / Pacific yew (Taxus brevifolia)

NIH screening of plant extracts 1960s

Mecanism ≈ Vinca alkaloids, different binding sites

slide25

Availability

Dried inner bark of Western / Pacific yew (Taxus brevifolia): 0.01 - 0.04%

1 kg Taxol - 900 kg bark (2000 - 3000 trees)

-Other Taxus sp: Also palitaxel in needles (renewable source)

-Semisynth from deacetylbaccatin III (0.1% in needles Taxus baccata)

(-Total syntheses)

slide26

Colchicine

From Meadow-saffron, Colchicum autumnale (Tidløs) seeds

Binds to microtubuli - metaphase arrest, too toxic too be used in cancer treatment

Used to treat gout (podagra)

slide27

Comming next? - Epothilones

Isolated from Myxobacteria (Epothilone A - F + synth. analogs)

slide28

Chemotherapy

      • Alkylation Agents √
      • Antimetabolites / Nucleoside Analogs √
      • Antibiotics √
      • Antimitotic Agents √
      • Micellaneous Antineoplastic Agents
      • Hormonal Therapy
  • Hydroxyurea
  • Podophyllotoxines
  • Camptothecins
  • Compounds for
  • photodynamic therapy
  • Tyrosine-Kinase Inhibitors

Hydroxykarbamid®

Inhib. ribonucleotide diphosphate reductase

Arrest cells in G1-S interphase

(combi with radiation)

slide29

Podophyllotoxines

From Podophyllum peltarum

May apple

Antiviral, veneric warts

Toxic - lead for anticancer drugs

Etoposide

Eposin® Etopofos®

Vepesid®

Affects DNA topoisomerase II (not intercalating)

DNA strand breakage

slide30

Camptothecins

First isolated Camptotheca acuminata (Chinese tree)

NIH screening

Later found in several plants

Topotecan

Hycamtin®

Irinotecan

Campto®

Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

slide31

Compounds for photodynamic therapy

Metylaminolevulinat

Metvix® PhotoCure

slide35

Imatinib

Glivec®

Leukemia types

Gefitinib

Iressa® - Not in N.

Lung cancer

Side effect: Intestinal lung disease (may be fatal)

0.3 % US

2% Japan

slide36

Chemotherapy

      • Alkylation Agents √
      • Antimetabolites / Nucleoside Analogs √
      • Antibiotics √
      • Antimitotic Agents √
      • Micellaneous Antineoplastic Agents √
      • Hormonal Therapy
slide37

Estrogens and agonists

Antiestrogens

Breast cancer

(estrogen depend.)

Tamoxifen

Nolvadex® Tamoxifen®

slide38

Aromatase Inhibitors

Estrogen depend. breast cancer

Inhib. estrogen biosynth.

Letrozol

Femar®

Exemestan

Aromasin®

Anastrosol

Arimidex®

slide39

Androgens

Anti-androgens

Flutamid

Eulexin® Flutamid®

Prostate cancer

Bicalutamid

Casodex®

Prostate cancer (less tox.)

5a-Reductase Inhibitors

Finasterid

Proscar®

benign prostate