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
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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
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Prophase
Metaphase
Anaphase
Telophase
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Prophase
Metaphase
Anaphase
Telophase
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Control by growth factors
Most drugs act on cells in mitosis
Control by growth factors
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DNA and DNA replication DNA bases
Base pairs
Double a-helix
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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
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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)
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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)
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• 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

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Alkylating Agents
DNA Bases - Nucleophilic Centra
Also O in phosphate may be alkylated
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Other 7.9-Dialkylpurinium compds
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• 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)
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Chlorambucil Leukeran,
Melfalan Alkeran,
Aryl decrease reactivity
L-isomer Active transport mech (L-AA)
Cyclophosphamide Sendoxan Pro-drug
Ifosfamide Holoxan Pro-drug
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MESNA Co-admin.
Activation by CYP450 (CYP3A4) enzym indusing
drugs may increase activity
CYP3A4 inhibitors
Decrease activation of cyclophosfamide
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Estramustine phosphate Estracyt Pro-drug
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• 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
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Temozolomide Temodal
Lomustine Lomustine medac
? Nitrosoureas
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• Alkylating Agents
• Nitrogen mustards
• Other alkylation agents
• Pt-complexes

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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