Cell Cycle Targets

Nota:

• cell-cycle non-specific

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

Nota:

• cell-cycle specific

1. Methotrexate
   1. structurally similar to folic acid and inhibits dihydrofolate reductase
   2. can be rescued by leucovorin
   3. used against ALL, breast cancer, head and neck cancer
   4. targets cells in S phase
   5. given intravenously, intramuscularly and intrathecally
2. 6-mercaptopurine
   1. used in maintenance of ALL
   2. inhibits purine biosynthesis
   3. incorporated into DNA and RNA, leading to non-functional molecules
3. 5-fluorouracil
   1. often given with 6-mercaptopurine
   2. depletes intracellular nucleotide pools
4. Gemcitabine
   1. analogue of deoxycytidine
   2. used in treatment of metastatic pancreatic cancer
   3. myelosuppression is major side-effect
5. Cytarabine
   1. cytosine arabinoside or AraC
   2. chain terminator of DNA synthesis
   3. can cause myelosuppression
6. Dactinomycin/ Actinomycin D
   1. binds to minor groove in DNA to interfere with transcription
   2. often used in combination with MTX
   3. may also cause DNA strand breaks
   4. not cell-cycle specific

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

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

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

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

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

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