Lecture 18 - Pharmacology of Anti-Cancer Drugs

What stages of cell growth does chemo therapy target?

All of them

What two key parameters describe how a drug behaves in the body?

1. Pharmacokinetics

   • what the body does to a drug

   • Absorption, distribution, metabolism excretion

2. Pharmacodynamics

   • what the drug biochemically and physiologically does to your body

What are the Six Parameters that determine the efficacy of chemotherapy? (memorize)

1. Half-Life

   • Time required for the amount of drug to fall by 50% → exponential decrease

2. Therapeutic Index

   • The difference between an effective dose and a toxic/lethal dose

3. Distribution

   • how the drug flows through the body

4. Metabolism (biotransformation)

   • what happens in liver

5. Elimination

   • kidneys or liver

6. Adjuvant/Neoadjuvent

What additional consideration needs to be remembered for chemo

• Distribution of drugs differs due to what type of tissue it is

  • Some drugs work better travelling in fat tissue, where as some travel better in muscle

Common uses of Systemic Chemotherapy

1. Non-Local Disease

   • used for stage III and IV cancers with local/distant spread

2. Adjuvant usage

   • minimizes the recurrence risk of micro metastasis

Two Common Biological Side Effects of Chemotherapy

1. Myelosupression

   • decreased production of bone marrow progenitors

2. Inflammation of GI tissues

   • chemo breaks the intestinal barrier, resulting in bacteria in bloodstream and the inability to absorb nutrients

Alkylating Agents Mechanism of Action

Direct binding and modification of DNA

• extra molecule added to the DNA base messes function up

• non-replication dependent

What chemical groups make alkylating agents useful

1-2 reactive alkyl (-EtCl) groups are the ones that bind to the DNA

if compound has two reactive akyl groups, what happens?

Interstrand DNA cross-linking

Two Subtypes of Alkylating Agent Family

Nitrogen Mustards and Platinating Agents

Nitrogen Mustard Features, Mechanism of Action, Limitations

Features: requires biotransformation by oxidases, contains 2 chloroethyl groups

Mechanism: Guanine alkylation —> thymine mispairing/strand break

Limitations: Chemically unstable

Example of Nitrogen Mustard Alkylating Agent

Cyclophosphamide

Platinating Agents Features, Mechanism, Limitations

Features: planar structure consisting of 2 Cl leaving groups and 2 NH2 carrier groups

Mechanism: causes G-A or G-G cross-linking

Limitations: to reach peak drug concentration is toxic to patient

Example of Platinating Alkyl Agent

Cisplatin

Anti-Metabolites Mechanisms of Action

inhibition of nucleotide formation

• cell cycle specific —> target proliferating cells only

Structurally, what make anti-metabolites useful?

they act and look like nucelic acid bases = purine/pyridamine analog

four sub-classes of anti-metabolites

Anti-Folates, 5-Fluropyrimidines, Cytidine Analogs, purine antimetabolites

Anti-Folate Mechanism and Limitation

Mechanism: inhibits thymine nucleotide synthesis (folic acid needed for thymine prod)

Limitations: prolonged exposure affects normal cells, but is reversed by folate injection

Anti-Folate Drug Example

Methotrexate

5-Fluropyrimidine Mechanism and Limitations

Mechanism: inhibits two enzymes used in thymadine production

• FdUTP and FdUMP

Limitations: must be given IV

5-Fluoropyrimidine Drug Example

5-Fluorouracil

Cytidine Analog Mechanism and Limitation

Mechanism: Incorporates into DNA and binds to DNA polymerase, blocking nucleotides being placed on strand after

Limitations: drug needs to spend lots of time above minimum concentration = toxic

Cytidine Analog Drug Example

Gemcitabine

Purine Anti-Metabolite Mechanism and Limitations

Mechanism: same as cytidine analog, but used for purines instead —> inhibition of DNA pol/replication

Limitations: must spend time above minimum concentration = toxic

Purine Anti-Metabolite Drug Example (don’t need to know for exam)

Fludarabine

What do Topoisomerase I and II do

They relax coiled DNA, letting it unwind, allowing DNA replication to occur

Topoisomerase Inhibitors Mechanism of Action

Blocks topoisomerase and stabilizes DNA complex to prevent replication

Topoisomerase Inhibitor Drug Example

Irinotecan

• requires biotransformation = pt needs functional liver

What are two families of Anti-Microtubular Agents

Vinca alkyloids and Taxanes

Vinca alkyloid Mechanism and Limitations

Mechanism: bind to tubulin and prevent mt polymerization

Limitations: myelosuppression and neurotoxicity (since neurons are supported by mt)

Vinca Alkyloid Drug Example

vinblastine / vincristine

Taxane Mechanism and Limitations

Mechanism: bind to tubulin and prevent mt depolymerization

Limitations: myelosuppression and neurotoxicity (since neurons are supported by mt)

Taxane Drug Example

Paclitaxel and Docataxel

What phase of the cell cycle are cancer cells most susceptible to anti-microtubules

During S Phase, and damage manifests during next M-phase

What Three Biological Factors Affect chemotherapy efficacy

1. Dosage

2. Functional Immune System

3. Microbiome

How dose dosage affect chemo?

Higher doses are not always the best option, there is a goldilocks zone

• Drives resistant clones

Why does Chemo require a functional immune system?

Depletion of T cells decreases or eliminates the efficacy of chemotherapies

• Most chemotherapies induce an “immunogenic” form of cell death

Describe the immunogenic form of cell death induced by chemo

As cells are dying, they release proteins and mtDNA, which the immune system thinks is an invader, leading to trigger of T-cells

Why does Chemo require the microbiome?

Microbial metabolism is critical for activation of some drugs

Name four combination strategies to improve Chemo

1. Combine multiple chemodrugs

2. Combine chemo and RT

3. Combine Chemo and diagnostics

4. Combine chemo and alternate delivery route

How does combining chemo drugs increase potency and effectiveness

drugs can have additive anti-tumor effects, spatial cooperation, and enhance cell response

Mechanisms for Chemo RT combinatorial effect

1. Spatial cooperation

   • Radiation for bulk disease + drug for metastases

2. Resistance complementation

   • Each kills clones resistant to the other modality

3. Inhibition of repopulation

   • Drugs inhibit fractionation-induced repopulation

4. Prevention of neovascularization

   • Drugs kill radio-resistant endothelial precursors

5. Hypoxia-activated or selective drugs

   • Drugs kill radio-resistant hypoxic cells

Describe Theranostics

Make a particle carrier that contains the chemo drug with antibodies on the surface to allow for imaging

How can using alternative delivery routes increase chemo effectiveness

targeted delivery of the drug to the tumor location can minimize healthy tissue damage

• use nanoparticles or lipid envelopes that can be release drug by magnets, light, heat, ultrasound, etc