1. 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

2. 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

3. Prophase
Metaphase
Anaphase
Telophase

4. Most drugs act on cells in mitosis
Control by growth factors
Most drugs act on cells in mitosis
Control by growth factors

5. DNA and DNA replication
DNA bases
Base pairs
Double a-helix

6. 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

7. 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)

8. 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)

9. 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

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

11. 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)

13. Chlorambucil
Leukeran®,
Melfalan
Alkeran®,
Aryl decrease reactivity
L-isomer
Active transport mech (L-AA)
Cyclophosphamide
Sendoxan®
Pro-drug
Ifosfamide
Holoxan®
Pro-drug

14. MESNA Co-admin.
Activation by CYP450 (CYP3A4); enzym indusing drugs may increase activity
CYP3A4 inhibitors
Decrease activation of cyclophosfamide

15. Estramustine phosphate
Estracyt®
Pro-drug

16. 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

17. Temozolomide
Temodal®
Lomustine
Lomustine medac®
 Nitrosoureas

18. Alkylating Agents
Nitrogen mustards
Other alkylation agents
Pt-complexes

20. 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®