Overview of cancer treatments

What are some types of antiproliferative drugs?

• DNA alkylating agents (cross-linkers)

• Direct DNA breaking agents (radical generators)

• Indirect DNA breaking agents (topo inhibitors)

• Microtubules targeting agents (taxanes)

• Antimetabolites (antifolates)

What are 9 classifications of chemotherapy drugs?

1. Alkylating agents

   • Binds DNA g. cyclophosphamide

2. Platinum-based drugs

   • Binds DNA g. cisplastin

3. Antimetabolites

   • Inhibits DNA synthesis, inhibit translation of precursor molecules into nucleotides in the formation of DNA eg. methotrexate

4. Topoisomerase-interactive drugs

   • Inhibit topoisomerase. eg. doxorubicin

5. Anti-microtubule drugs

   • Binds microtubules eg. paclitaxel

6. Hormonal agents

   • Blocks production or action of sex steroids eg, tamoxifen

7. Targeted therapies

   • Block oncogenic proteins eg. trastuzumab, gefitinib

8. Vascular targeting therapies

   • Inhibit angiogenesis eg. bevacizumab

9. Immunotherapies eg - pembrolizumab

Alkylating agent: cyclophosphamide

Is a metabolically activated prodrug, which can be given orally. Converted to phosphoramide mustard which is cytotoxic

Act mainly on guanine N-7 and induce both intra and interstrand cross-link

Also reacts act other sites on DNA and proteins

Platinum agents: cisplastin

Predominantly forms DNA intra-strand cross link

Alters the topology of DNA

The DNA is unwound and bent towards the major groove

Recognised by MMR and leads to apoptosis

Increased tolerance due to loss of MMR, bypass of DNA products, decreased apoptosis

Increased removal due to NER

Doxorubicin - inhibition of topoisomerase

Intercalates DNA, stabilises topo II complex, strand breaks, also can generate ROS due to the quinone on the molecule

Vinblastine, paclitaxel mode of action

Microtubule agents

Binds to the b-sub unit of tubulin

Vinblastine binds to the polymerising ends which prevents the elongation of microtubule

Paclitaxel (from Pacific yew tree) stabilises the microtubule which prevents shortening or depolymerisation

What are some limitations of antiproliferative therapeutics?

• Poor intrinsic selectivity for cancer cells (off target effects on cycling cells eg hair cells, bone marrow supression)

• Limited drug distribution (poor blood flow, low diffusion)

• Resistance mechanism

• Poor natural immune response (cytotoxics often suppress immune response - killing of immune cells)

What is the mechanism of action of anti-folates?

Structural mimicry - analogues of folic acid - targets enzyme inhibition and leads to folate cofactor depletion, which leads to th inablty for DNA to assemble puring ring and dMTP, which leads to DNA synthesis stalls during S phase.

What is 5-fluorouracil - common treatment for colorectal cancer

Two main actions

• Block the activity of TS which depletes dTTP pool leading to DNA Synthesis arrest

• Misincorporation into DNA and RNA → stress

If when enter the cell turns into DHFU → doesn’t work

What is the typical pattern of hormone treatment?

Aromatase inhibitors that creates generations of inhibitors that works along the pathways downstream

For post menopausal women with ER =+ve BC

How can we target epidermal growth receptors?

Tumour cells rely on protein growth factors secreted by the surrounding stromal cells which promote cell growth and survival

Potential targets can be the extracellular domains (monoclonal antibodies) and the internal kinase domain (small molecules)