Anti-cancer compounds / Antineoplastic Agents, chapter 38
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Anti-cancer compounds / Antineoplastic Agents, chapter 38. Neoplasm: New and diseased form of tissue growth Benign (godartet) neoplasm : Easy to separate from surounding tissue, no metastases Malign (ondartet) neoplasm : Invassive to surounding tissue Metastases. Cancer.

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Anti-cancer compounds / Antineoplastic Agents, chapter 38

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Anti-cancer compounds / Antineoplastic Agents, chapter 38

Neoplasm: New and diseased form of tissue growth

Benign (godartet) neoplasm: Easy to separate from surounding tissue,

no metastases

Malign (ondartet) neoplasm: Invassive to surounding tissue

Metastases

Cancer

Metastase: Secondary tumors, different location

Malign cells separated from primary tumor

and spread by vascular- or lymph systh.

Terminology differents types of cancer confusing


Cell cycle: Proliferating cells

G1: Newly born cell

Short period proliferating cells

S: Replication of DNA

G2:

M: Mitosis

Cell death

G0: Non-proliferating cell

Quiesence


Prophase

Metaphase

Anaphase

Telophase


Prophase

Metaphase

Anaphase

Telophase


Control by growth factors

Most drugs act on cells in mitosis

Control by growth factors


DNA and DNA replication

DNA bases

Base pairs

Double a-helix


DNA helicases: Unwinding

DNA binding proteins: Prevents winding back

DNA primase: formation of DNA/RNA primer (from free nucleosides in cell)

DNA polymerase: Catalyse elongation of new strand (5’ - 3’)

Lagging strand:

DNA ligase: Connects Okasaki fragments


Biochemical Basis of Cancer

  • Mutation

  • Chemicals

  • Oncogenic Viruses

  • Altered Gene Expression

Mutation

  • Mutation(s) = initiation (not cancer alone)

  • Promotion; proliferation of mutated cells, exposure to chemical

    (not carciogenic alone, ex estrogen)

Chemicals

Compounds (or metabolites) that reacts with DNA (alkylation agents)

or initiate free radical processes that eventually damage DNA (Ex ionizing radiation)


Biochemical Basis of Cancer

  • Mutation

  • Chemicals

  • Oncogenic Viruses

  • Altered Gene Expression

Oncogenic Viruses

Viral DNA (or proviral RNA from RNA viruses) inserted in host DNA .... Mutation

Altered Gene Expression

Incorrect expression of proto-oncogene

Increased express. oncogene - Increased prod. of growth factors

Decreased expression of tumor-supressor genes (anti-oncogenes)


  • 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


Alkylating Agents

DNA Bases - Nucleophilic Centra

Also O in phosphate

may be alkylated


Other 7.9-Dialkylpurinium compds


Alkylating Agents

Nitrogen mustards

Other alkylation agents

Pt-complexes

Metabolism of alkyl halides

Phase II conjug. glutathion

Rel. selective tox. to lymphoid tissue

(Hodkins disease, Lymphomas)

More water sol.

Tox. to rapid proliferating cells (short time for DNA repair)


Chlorambucil

Leukeran®,

Melfalan

Alkeran®,

Aryl decrease reactivity

L-isomer

Active transport mech (L-AA)

Cyclophosphamide

Sendoxan®

Pro-drug

Ifosfamide

Holoxan®

Pro-drug


MESNA Co-admin.

Activation by CYP450 (CYP3A4); enzym indusing drugs may increase activity

CYP3A4 inhibitors

Decrease activation of cyclophosfamide


Estramustine phosphate

Estracyt®

Pro-drug


Alkylating Agents

Nitrogen mustards

Other alkylation agents

Pt-complexes

Not reg. N

Mono or dialkylation

Better leav. gr, not 3-embered ring intermed

cf dimethyl sulfate

Busulfan

Thiotepa

Not reg. N


Temozolomide

Temodal®

Lomustine

Lomustine medac®

 Nitrosoureas


Alkylating Agents

Nitrogen mustards

Other alkylation agents

Pt-complexes


Certain proteins binds to bent DNA, and prevents normal repair

Pt replace Zn in necessary transcription factors

DNA polymerase “collides” with Pt, DNA strain breaks mechanically

Carboplatin

Carboplatin® Carbosin® Paraplatin®

More stabile comp. (reacts less readily with water)

Cisplatin

Platinol® Platistin®


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