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

Most drugs act on cells in mitosis 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

DNA Bases - Nucleophilic Centra Alkylating Agents DNA Bases - Nucleophilic Centra Also O in phosphate may be alkylated

Other alkylation agents Pt-complexes 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

Other alkylation agents Pt-complexes 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®