INTRODUCTION TO CHEMOTHERAPY

• Introduction
• Bases of Drug Specificity
• Unique Enzymes
• Shared Enzymes Essential to Pathogen
• Different Pharmacological Properties
• Study Questions
• References

Introduction
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Drug therapy is divided into two major categories depending on the therapeutic intent:

CHEMOTHERAPY --

Chemotherapy refers to the use of drugs to kill or inhibit the growth of foreign organisms in the patient. Cancer cells are included as foreign organisms along with bacteria, fungi, viruses, protozoans, and metazoans.

PHARMACOTHERAPY --

Pharmacotherapy refers to the use of drugs to alter the rate of reactions or processes characteristic of the host itself.

SPECIFICITY (SELECTIVITY)

Sources of Drug Specificity
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chemotherapeutic agents are PARADOXES EXPLOITING DIFFERENCES
between parasites and hosts IN ESSENTIAL PROCESSES

These are:

• UNIQUE ENZYMES
• SHARED ENZYMES ESSENTIAL TO PATHOGEN,and
• DIFFERENT PHARMACOLOGICAL PROPERTIES.

Unique Enzymes
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• Cell wall synthesis inhibitors (beta lactams and others)
• Folic acid synthesis inhibitors (sulfonamides)

Shared Enzymes Essential to Pathogen
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• Nucleic Acid Salvage Pathways (certain protozoans & schistosomes)

Different Pharmacological Properties
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• Many processes HIGHLY CONSERVED in evolution,
• Differences may be pharmacodynamic or pharmacokinetic
• Rational drug design versus Screening

Examples
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• Transport system inhibition
  • Amprolium [CORID], anticoccidial -- Thiamine transport inhibition
  
  
• Cells in susceptible state / rapid rate processes
  • Microtubules -- Vincristine [ONCOVIN]
  
  
• Different binding affinity
  • Tubulin -- Alpha subunits highly varied, Beta subunits well conserved
    Benzimidazoles (e.g., mebendazole) 250-400 stronger binding to
    Ascaris lumbricoides tubulin than for bovine brain tubulin.
  
  
• Differential access to receptor sites
  • Ivermectin
    Access to GABA receptors in parasites
    Vertebrates -- Blood Brain Barrier protects

Study Questions
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1. How could one use knowledge of the basis of a drug's specificity?
2. You should be able to discuss the key differences between the three major categories of specificity and to give examples for the categories of a) unique enzymes and b) different pharmacological properties.
3. You should be able to assign a mechanism to one of the categories when given its essential characteristics.
4. You will save yourself much pain in the future if you will learn the folic acid pathway well now. It is applicable for certain anticancer drugs, antibacterials, antiprotozoals, etc.

References
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