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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 (antimitotic agents, bind. to microtubuli) Cell death G0: Non-proliferating cell Quiesence
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
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®