1、Anti-cancer compounds / Antineoplastic Agents, chapter 38,Neoplasm: New and diseased form of tissue growthBenign (godartet) neoplasm: Easy to separate from surounding tissue, no metastasesMalign (ondartet) neoplasm: Invassive to surounding tissueMetastases,Cancer,Metastase: Secondary tumors, differe
2、nt locationMalign 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 cellShort period proliferating cellsS: Replication of DNA G2: M: Mitosis,G0: Non-proliferating cell Quiesence,C
3、ell death,Prophase,Metaphase,Anaphase,Telophase,Prophase,Metaphase,Anaphase,Telophase,Control by growth factors,Control by growth factors,Most drugs act on cells in mitosis,DNA and DNA replication DNA bases,Double a-helix,Base pairs,DNA helicases: Unwinding DNA binding proteins: Prevents winding bac
4、k 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) = i
5、nitiation (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),Bioche
6、mical 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-oncogeneIncreased express. oncogene - Increased prod. of growth factor
7、sDecreased 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
8、 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 t
9、issue (Hodkins disease, Lymphomas)More water sol.,Tox. to rapid proliferating cells (short time for DNA repair),L-isomer Active transport mech (L-AA),Aryl decrease reactivity,Chlorambucil Leukeran,Melfalan Alkeran,Cyclophosphamide SendoxanPro-drug,Ifosfamide HoloxanPro-drug,MESNA Co-admin.,Activatio
10、n by CYP450 (CYP3A4); enzym indusing drugs may increase activity,CYP3A4 inhibitors,Decrease activation of cyclophosfamide,Estramustine phosphate EstracytPro-drug,Alkylating Agents Nitrogen mustards Other alkylation agents Pt-complexes,Busulfan,Not reg. N Mono or dialkylation Better leav. gr, not 3-e
11、mbered ring intermed cf dimethyl sulfate,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 repairPt replace Zn in necessary transcription factors,DNA polymerase “collides” with Pt, DNA strain breaks mechanically,Cisplatin Platinol Platistin,Carboplatin Carboplatin Carbosin Paraplatin More stabile comp. (reacts less readily with water),
