New and Emerging Cancer Treatments Flashcards
Need for targeted therapies
- Traditional chemotherapies = number of SFx
- Ways to maximise localised delivery of drugs are therefore required
- Some cancers don’t have effective clinical regimens; e.g. advanced, metastatic cancers, those that have developed resistance
- Need more targeted treatments
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Prodrugs
- Derivative of an active drug that has no intrinsic activity
- Converted to the active drug in vivo at the appropriate time or place
How are prodrugs activated?
- over-expression of a specific enzyme that activates the prodrug
- modification of the target cell to express the enzyme required for the drug release.
What does ‘ADEPT’ refer to?
Antibody-directed enzyme prodrug
(1) Design of an mAb developed against a tumour associated antigen
(2) Antibody-enzyme complex generated and administered
(3) Specificity of the antibody for the antigen allows the antibody-enzyme conjugate to be selectively delivered to the tumour cells.
(4) Prodrug administered
(5) Once enzyme is bound to tumour cell –> prodrug activated = kill tumour cells
What are some advantages of ADEPT?
- Reduced systemic toxicity
- Opportunity to overcome drug resistance
- Opportunity to revisit drugs that have shown excellent profiles in vitro, or in early clinical trials, but that have not been pursued due to toxicity profiles.
- Amplification of the drug effect
What are some challenges of ADEPT?
- immune responses to antibody-enzyme complexes
- identification of appropriate cancer antigen targets
- cost
What does ‘GDEPT’ refer to?
Gene-Directed Enzyme Prodrug Therapy
- Mirrors ADEPT but gene therapy
- Introduction of a gene into the tumor cells that produces an enzyme specific to tumour cells
- Prodrugs are administered and activated same as ADEPT
- + and - (see ADEPT)
- No GDEPT product currently marketed as a drug
What does ‘PDEPT’ refer to?
-
Polymer-Directed Enzyme Prodrug Therapy
1. Polymeric prodrug + polymer-enzyme conjugate administered
2. Both localise in the tumour due to EPR effect
3. Enzyme which activates the drug is delivered separately to the tumour
4. Pro drug activated
3. Generate cytotoxic drug selectively at the tumour site
What does ‘MDEPT’ refer to?
Melanocyte-Directed Enzyme Prodrug Therapy
- Malignant melanoma; most serious form of skin cancer as metastasis can occur early and it causes a number of deaths even in young people.
- Metastasis: target the lung, liver and colon.
In MDEPT, an enzyme that can specifically target melanocytes, such as tyrosinase or dopachrome tautomerase, is conjugated to a polymer carrier. The prodrug is designed to be inactive or minimally active until it is activated by the enzyme. Once the prodrug is activated, it can selectively kill melanoma cells by inducing apoptosis or blocking cell division.
The polymer carrier in MDEPT serves several purposes. First, it can increase the circulation time of the enzyme in the body, allowing for greater accumulation in the tumor tissue. Second, it can protect the enzyme from degradation, enhancing its stability and activity. Third, it can improve the selectivity and efficacy of the enzyme by promoting its uptake by melanoma cells.
ABCDE
General guideline for symptoms of melanoma
1. Assymmetrical
2. Border
3. Colour
4. Diameter
5. Elevation and enlargement
Breslow Thickness Scale
Scale used to classify the thickness of the tumour
Clark’s Level
Scale used to classify the depth of the tumour
Targeted therapy - Carbohydrate Biosynthesis
- Carbohydrates are synthesised in nature by a series of enzymes
- In some cases the balance and activity of enzymes required for carbohydrate synthesis is disrupted
- Unusual carbs are synthesised and generated on the cell surface
- Confers unusual and often undesirable properties to the cell
- Believed that such processes are responsible for cancer metastasis
How does cancer metastasis occur due to carbohydrate bioynthesis?
- By allowing cell surface carbohydrates to interact with lectins in blood vessels
- Alowing migration of the tumour from one site to another
Chemical modification of biopolymers in vivo
- Utilise the biosynthetic production of sialic acid on cancer cells for targeted treatment
- Through ‘biochemical engineering’.
- Uses the enzymatic machinery of cells to achieve chemical synthesis of novel biomolecules in the cells
