Cell Cycle Targets

Cell Cycle Targets

1. Alkylating agents

   • cell-cycle non-specific
   • Transfer alkyl groups to DNA and target rapidly dividing cells
   • Some need cytochrome P450 for metabolic transformation into the active drug
   • cross the BBB so are used in brain cancer therapy
   • e.g. mechlorethamine, cyclophosphamide, ifosphamide, carmustine, dacarbazine, temezolomide

2. Antimetabolites

   • cell-cycle specific
   • Methotrexate
     • structurally similar to folic acid and inhibits dihydrofolate reductase
     • can be rescued by leucovorin
     • used against ALL, breast cancer, head and neck cancer
     • targets cells in S phase
     • given intravenously, intramuscularly and intrathecally
   • 6-mercaptopurine
     • used in maintenance of ALL
     • inhibits purine biosynthesis
     • incorporated into DNA and RNA, leading to non-functional molecules
   • 5-fluorouracil
     • often given with 6-mercaptopurine
     • depletes intracellular nucleotide pools
   • Gemcitabine
     • analogue of deoxycytidine
     • used in treatment of metastatic pancreatic cancer
     • myelosuppression is major side-effect
   • Cytarabine
     • cytosine arabinoside or AraC
     • chain terminator of DNA synthesis
     • can cause myelosuppression
   • Dactinomycin/ Actinomycin D
     • binds to minor groove in DNA to interfere with transcription
     • often used in combination with MTX
     • may also cause DNA strand breaks
     • not cell-cycle specific

3. Topoisomerase II inhibitors

   • Etopiside/ Teniposide
     • Irreversibly bind to transient complex of enzyme-DNA complex leading to double-strand breaks in DNA
     • USE etopiside as EG
       • used in combination with with bleomycin and cisplatin for testicular cancer
     • S phase specific
     • Teniposide used for all gliomas and neuroblastomas
     • given intravenously
   • Anthracyclines
     • Doxorubicin/ Daunorubicin
       • Intercalate into DNA and generate free radicals that break DNA strands
       • target cells in S/G2 phase

4. Platinum coordination complexes

   • Cisplatin
     • Used in solid tumours e.g. testicular cancer and bladder cancer
   • Carboplatin
   • Oxaliplatin
     • Used in advanced colorectal cancer
   • Act in G1 and S phases
   • Similar to alkylating agents
   • Forms intra and inter strand crosslinks in DNA

5. Topoisomerase I inhbitors

   • Inhibit topisomerase I in S phase by binding to enzyme-DNA intermediate, preventing re-ligation of DNA after nick
   • Topotecan
     • Used against metastatic ovarian cancer and lung cancer
   • Topoisomerase I makes reversible single-stranded nicks in the DNA duplex to relieve torsional strain during positive supercoiling
   • Irinotecan
     • Metabolises in cancer cells to form the active form of the drug, SN-38
     • Used against colon and rectal cancer along with 5-FU and leucovorin
   • given intravenously

6. Telomerase inhibitors

   • Direct enzyme inhibitors e.g. Imetelstat
   • Modified oligonucleotides compete for binding with telomerase RNA

7. Vinca alkaloids

   • block mitosis in metaphase
   • bind to tubulin and inhibit its polymerisation in to microtubules
   • induce spindle dysfunction
   • Vincristine (can be neurotoxic inducing peripheral neuropathy)
   • Vinblastine (can be a myelosuppressant)
   • Used against rapidly dividing tumours in combination with other tumours

8. Taxanes

   • Block mitosis in metaphase
   • bind to B-tubulin and promote polymerisation and stability of microtubules, 'freezing' them and preventing chromosome segregation. the resulting microtubules are non-functional
   • e.g. Paclitaxel and Docetaxel
   • used to treat ovarian and breast cancers and non-small cell lung cancer
   • Dose-limiting toxicity is neutropenia

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