Chemotherapy of Cancers and Infections

Selective Toxicity and the concepts of biochemical differences

What will we cover?

  • 1. General introduction: Selective toxicity and the concept of biochemical differences

  • 2. Introduction to the hallmarks of cancer

  • 3. Pharmacotherapy of Cancer: Alkylating agents and anti-metabolites

  • 4. Pharmacotherapy of Cancer: Cytotoxic antibiotics and plant derivatives

  • 5. Pharmacotherapy of Cancer: Hormone-based treatment and drug resistance

  • 6. Pharmacotherapy of Cancer: Future treatments

Paul Ehrlich (1854-1915)

  • Father of immunology, pharmacology and pioneer of chemotherapy

  • Salversan: treatment for syphilis

  • Coined the term “magic bullet”

  • 1908: Nobel Prize in Medicine

Defining the term chemotherapy

  • The term chemotherapy was introduced by Paul Ehrlich to describe the use of synthetic chemicals to destroy infective agents.

  • Antibiotics: substances produced by some micro - organisms that kill or inhibit the growth of other microorganisms.

  • The term chemotherapy is more widely applied to the use of chemicals (natural or synthetic) used to inhibit the growth of cancer cells.

Selective Toxicity

  • Chemotherapeutic agents are chemicals which are intended to be toxic for the parasitic cell but harmless for the host/healthy cell.

  • Selective toxicity depends on the existence of biochemical differences between the parasitic cell and the host cell.

  • Difference depends how far apart host and parasite are evolutionary.

What are the targets?

  • Prokaryotes - e.g. bacteria

  • Eukaryotes - e.g. single-celled protozoa (malaria) and multi- cellular helminths (tapeworms)

  • Viruses - utilize the metabolic machinery of the host cell and thus present a particular kind of problem

  • Cancer cells (host cells that have become malignant) can be considered “foreign” or “parasitic”.

The Three categories of Biochemical reactions

  1. Class I: Generation of energy & small carbon compounds

  2. Class II: Generation of necessary small molecules e.g. amino acids, nucleotides, phospholipids, amino sugars & carbohydrates

  3. Class III: Generation of macromolecules, e.g. proteins, RNA, DNA, polysaccharides and peptidoglycan

Biochemical reactions as potential targets

  1. Class I reactions : NOT good targets for two reasons:

    1. No marked differences between bacteria and human cells in the mechanisms used to derive energy from glucose;

    2. Bacteria can use variety of other compounds (amino acids, lactate) instead of glucose.

  2. Class II reactions - better targets since there are some differences. For example, folate synthesis.

Folate Synthesis (Class II) as a chemotherapeutic target

  • Folate synthesis occurs in bacteria but not human (obtained from diet).

  • Folate is required for DNA synthesis in bacteria and human – in the form of tetrahydrofolate (FH4) used as a co-factor in synthesis of purines and pyrimidines.

  • Bacteria have not evolved the necessary transport systems and therefore must synthesize their own folate.

How can bacterial folate synthesis be inhibited by chemotherapeutics?

Class III Biochemical reactions as chemotherapeutic targets

Good targets since there are very distinct differences between bacteria/viruses and human cells:

  1. Synthesis of peptidoglycan

  2. Protein synthesis

  3. Nucleic acid synthesis

1.Peptidoglycan synthesis inhibitors- Bacterial cell structure

  • No nucleus;

  • No mitochondria (energy generation occurs in the plasma membrane);

  • Cell membrane similar to eukaryotic cells (phospholipid bilayer);

  • Cell wall which contains peptidoglycan - unique to prokaryotic cells!

Penicillin inhibits the synthesis of bacterial cell wall peptidoglycan.

2.Protein Synthesis inhibitors- ribosome structure as targets

Eukaryotic and prokaryotic ribosomes are innately different:

3.Targeting nucleic acids I - Inhibition of nucleotide synthesis

1. Sulphonamides (folate synthesis) – bacteria only

2. FH2 reductase inhibitors (folate reduction)

3. Pyrimidine & purine analogues

3.2.Targeting nucleic acids II - Altering the base-pairing properties of the template

  • Agents that intercalate in the DNA have this effect, e.g. proflavine and acriflavine used as anti-septics

  • Cause frame-shift mutations:

3.3.Targeting nucleic acids III - Inhibition of RNA polymerase and DNA polymerase

  • actinomycin D (cancer chemotherapy) blocks movement of RNA polymerase in human

  • rifamycin and rifampicin specific inhibitors of bacterial RNA polymerase.

  • acyclovir (analogue of guanine) is phosphorylated to acyclovir triphosphate which selectively inhibits DNA polymerase of the herpes virus.

  • cytarabine (cytosine arabinoside) - triphosphate form potent inhibitor of mammalian DNA polymerase.

3.4.Targeting nucleic acids VI - Inhibition of DNA gyrase (topoisomerase II)

  • Fluoroquinolones: inhibitors of bacterial DNA gyrase

  • Doxorubicin: inhibitor of mammalian DNA gyrase

3.5.Targeting nucleic acids V - Direct effects on DNA itself

  • Alkylating agents form covalent bonds with bases which inhibits DNA replication and transcription and promotes apoptosis

    • used in cancer chemotherapy e.g. nitrogen mustard derivatives

  • Purine and pyrimidine analogues

  • No anti-bacterial agents work by these mechanisms