PH3113 Unit 2 Chemotherapy

What type of factors affect cytotoxic dosing?

body surface area, weight, neutrophil coun, renal/hepatic function, previous cytotoxic history

What are some problems with handling cytotoxic drugs?

Must be reconstituted before given IV - done in specific areas, PPE, trained personnel, avoided by pregnant staff/child-bearing age females

What is the MoA of alkylating agents? Examples?

Cytotoxic

Contain a good leaving group attached to an alkyl group which is transferred to DNA (usually nucleophilic attack from pair of electrons on Nitrogen in DNA)

Alkylation disrupts interstrand hydrogen bonding, destabilising DNA leading to cell death

Dacarbazine, Busulfan, Cyclophosphamide, Chlorambucil, Thiotepa

Why do alkylating groups cause side effects? what are they?

They are chemically reactive (reason why usually administered as prodrug), non-selective, can interact with other molecules

Side effects associated with selectivity for rapidly dividing cells:

NVD, bone marrow suppression, hair loss

Mechanism of Anthracyclines and other cytotoxic antibiotics? Main example? Major side effect?

Intercalating agents - bind tightly to DNA between adjacent base pairs to disrupt secondary structure → inhibiting replication

Called cytotoxic antibiotics as it is taken from a natural product made by bacteria to kill other bacteria

Doxorubicin - interacts with DNA base pairs by pi-stacking. Sugar portion also inhibits topoisomerase enzymes to prevent DNA unwinding for replication

Dose dependent cardiotoxicity side effect - drug levels must be monitored, can result in HF especially in elderly/Hx of cardiac disease

What is the MoA of Cisplatin? What is a side effect of drugs containing platinum (Pt)? How can this be helped?

Binds to DNA to disrupt DNA shape by DNA alkylation

To prevent DNA replication = cell death

Nephrotoxicity is caused by Pt containing drugs

Carboplatin and Oxaliplatin are 2nd gen Pt-drugs that are less effective at killing cancer but less nephrotoxic

How does a platinum centre of cytotoxics act on cancer cells?

Electrophilic platinum centre forms direct DNA adducts with nucleophilic bases such as N7-Guanine

Forming intrastrand or interstrand cross-links

Mechanism of action of Vinca Alkaloids? Two examples?

Block cell division by targeting microtubules. Also natural products.

Vincristine - bind to tubulin to prevent microtubule assembly, blocking mitosis and cell division

Paclitaxel - bind to tubulin in a formed microtubule to stabilise the spindle and prevent mitosis by preventing breakdown to tubulin monomers

Give examples of mild, moderate and high emetogenic potential cytotoxics?

Mild - fluorouracil, low dose methotrexate, vinca alkaloids

Moderate - taxanes, low dose cyclophosphamide, high dose MTX

High - cisplatin, dacarbazine, high dose cyclophosphamide

What are the 3 types of NAV?

Acute: within 24hrs

Delayed: >24hrs

Anticipatory: before treatment

How do you treat acute mild/high risk NAV? How does delayed differ?

Mild risk = dexamethasone

High risk = dexamethasone with aprepitant 

Delayed = can add rolapitant or metoclopramide HCl

How do you treat anticipatory NAV?

BZD = Lorazepam as amnesic, sedative and anxiolytic

Examples of antibody used in cancer? What side effects do these have?

Herceptin aka Trastuzumab

Targets HER2 gene which is a growth factor receptor (POG)

Antibody binds to extracellular domain of HER2 to block downstream growth signalling

Side effects: similar but less severe than cytotoxics = hair thinning (rather than loss), vomiting

But also anaphylaxis - caused by rapid release of inflammatory mediators and cytokines from mast cells and basophils. Treated with IM adrenaline

What type of drug is Tamoxifen? Mechanism?

Mimics shape of natural oestrogen for treatment and prevention of breast cancer (oestrogen-receptor-positive BC)

Selective estrogen receptor modulator (SERM) as its pharmacology is complicated and varies by tissue

Binds competitively to oestrogen receptors but has mixed and oestrogenic activity - but mainly anti-oestrogenic in breast tissue

How is oestrogen targeted in hormone responsive malignancy?

Oestrogen is normally a growth signalling endogenous hormone (promotes cancer)

What type of drug is Anastrozole? Mechanism?

Competitive aromatase inhibitor which is a cytochrome P450 (CYP19A1)

This causes a 90% drop in oestradiol plasma conc. in post-menopausal women

An adjuvant to maintain low oestrogen levels post-primary treatment of BC

What type of drug is Enzalutamide? Mechanism? What are the first line treatments for its cancer target? Side effects? Drug interaction?

Orally active second gen non-steroidal “Anti-androgen”

Androgens include testosterone and are normally growth signals for PC

Second line treatment for prostate cancer

1st line is conventional cytotoxics docetaxel/cabazitaxel

Gynaecomastia (and subsequent breast pain) caused by imbalance between androgens and oestrogens (higher oestrogens)

Drug interactions as it is a strong multiple CYP inducer and plasma concs are affected by CYP2C8 inhibitors e.g. clopidogrel (CV), trimethoprim (antibiotic), thiazolidinediones (diabetes), montelukast (asthma)

Give an example of a drug that is used for immunotherapy responsive malignancy. What cancer is this? Mechanism of action?

Thalidomide for multiple myeloma

Which is a blood cancer that develops in bone marrow. Characterized by an excess of monotypic plasma cells in the bone marrow, reducing ability to fight infection, does not form a tumour.

1. Anti-angiogenesis

2. Inhibits production of interleukin (IL)-6 which is a GF for the proliferation of myeloma cells

3. Activates apoptotic pathways which is programmed cell death so not a cytotoxic drug

What is a carcinoma?

A mass (tumour) of abnormal cells that start in a single tissue of origin.

What is a sarcoma?

Rare soft tissue cancers that develop in supporting or connective tissue e.g. muscle, nerves, tendons, blood vessels, fatty and fibrous tissues.

Primary bone cancer is a sarcoma.

What are targeted therapies? What is their main target? Benefits?

More selective for therapeutic target so greater efficacy and fewer side-effects from off-target binding but still some binding to off-target kinase enzymes

Mainly target kinase enzymes - often tyrosine kinases

End in -tinib or -nib

To target upregulated growth factor receptor pathways in cancer cells

Small molecule, oral delivery, straightforward design

What is an important MHRA warning of EGFR inhibitors side effects?

Can cause keratitis and ulcerative keratitis leadind to corneal perforation and blindness

As still some binding to off-target kinase enzymes

How is EGFR activated? What does it cause?

Epidermal growth factor receptor

A large transmembrane receptor with a cytoplasmic kinase domain that binds ATP substrate

When activated ATP phosphorylates a Tyr sidechain (and becomes ADP) for signal transduction of cellular proliferation

What is the mechanism of action of Gefitinib? What cancer is it licensed for?

A (tyrosine) kinase inhibitor

It is a competitive inhibitor that mimics ATP structure (structural analogue)

So it competitively binds to the ATP-binding site of the EGFR tyrosine kinase domain, preventing autophosphorylation and activation of the receptor

Used for non-small cell lung cancer (as it overexpresses EGFR)

How can we confirm drugs would be competitive inhibitors?

X-ray crystallography can identify if lead compound also bind to same place

Viewing target protein with modelling software

Add extra groups to form additional bonding interactions

What genes are involved in DNA repair in breast/ovarian cancer that helps them become resistant to therapeutics?

PARP (poly ADP-ribose polymerase)

BRCA1 and BRCA2

How does PARP/BRCA work?

Healthy breast and ovarian cells express the TSGs BRCA1 and BRCA2

Many O/BC patients are deficient in BRCA1/2 genes due to mutation, so they use PARP instead to repair DNA
If given PARP inhibitors, these cells cannot repair DNA, so cancer cell will die, health cells intact

What is personalised medicine? Give an example

Patient given a specific drug based of their genetics and gene screening

e.g. ovarian/BC screened for BRCA mutations

What type of drug is Rucaparib? Mechanism?

Targeted therapy

It is a PARP inhibitor used for ovarian cancer

If patient has BRCA1/2 mutations making them faulty, they can only repair DNA through PARP, so inhibiting PARP → no DNA repair of cancer cells targeted with cytotoxics → kill cancer cells

What were some mechanisms/considerations by which Rucaparib was developed?

Knowledge of PARP substrate which uses NAD⁺ (Nicotinamide Adenine Dinucleotide)

Nicotinamide binds to active site by 3H bonds

AD forms a protein bound polymer which is a cellular signal for DNA repair

Lead compound must be a crude NAD⁺ mimic

Heterocyclic derivatives are highly active PARP inhibitors by restricting the number of conformations to a single isomer

Amides can form H bonds to restrain amide conformation

Changes made to the large hydrophobic pocket, they don’t fit on small pocket

N-H added for extra H bonding

Fluorine (-ve charge) added to create a charge-charge interaction with polarised region of active site (+ve charge)

What are the four aims of cancer treatment? Differences?

Curative

Palliative - reduce tumour load and improve symptoms

Adjuvant - kill remaining cancer cells after surgery

Neo-adjuvant - shrink tumour mass prior to surgery

What is the cell count for cancer remission, detection, and death ?

Remission = 10^5 cells remaining/1mm cubed

Detection - 10^8 cells/ 1cm cubed

Death = 10^12 cells

What are 4 types of factors that affect cytotoxic response?

1. Growth fraction and type of tumour

2. Tumour size

3. Tumour burden, stage, grade, and spread

4. Health, age, pre-existing medical conditions

think: growth, tumour, tumour, health, GTTH

How does growth fraction and type of tumour affect cytotoxics response? Give examples of slow and rapidly dividing tumours

Growth fraction is the proportion of cells that are actively dividing/in the active cell cycle = killed by most cytotoxic

Cells in G0 are not targeted until they enter cell cycle

Cells terminally differentiated = unaffected by cytotoxics

Slow growing cancers e.g. prostate cancers (early stages) are less targeted

Rapidly dividing cancers e.g. Leukaemias respond better to cytotoxics

How does tumour size affect cytotoxics response?

Geometric resistance increases with size

when tumour >2mm, hypoxic cells in centre survive as resistant to harsh conditions = can cause relapse

Only outer cells killed by cytotoxics that have angiogenesis/blood supply = remission

How does tumour size burden, stage, grade, and spread affect cytotoxics response?

Local vs invasive

Metastases to other major organs compromise function = poorer prognosis

Higher histological grade = more anaplasia = poor cell differentiation = loss of morphology = more mitotic activity = more genetic instability

How do health, age and pre-existing medical conditions affect cytotoxics response?

Aggressive cytotoxic therapy is debilitating and is not suitable for old and frail individuals → treatment may be palliative instead

Liver disease affects drug metabolism, serum binding proteins

Anaemia and Immune disorders are exacerbated by cytotoxics

Kidney disease affects drug excretion = toxicity

Lung/Heart disease is CI in some cytotoxics

What are 4 factors that can affect drug delivery?

Blood flow across capillary

Geometric resistance within tumour

Oral administration can undergo first pass metabolism or have different absorption

Plasma protein binding of drugs

How are cytotoxics often administrated?

Intermittent intensive courses

IV infusion

Regional administration to tumour site for higher drug conc there:

• Intravascular administration to specific organs e.g. into hepatic artery for liver tumours

• Intraperitoneal for ovarian cancer

• Intrapleural for mesothelioma

Give 8 reasons drug resistance can develop? 2 decrease, 4 increase, 2 others

Decreased drug uptake

Decreased drug activating enzymes

Increased drug removal from cell

Increased drug deactivating enzymes

Increased levels of target enzyme

Increased DNA repair (in tumour cell)

Altered affinity of target

An alternative metabolic pathway

think: uptake/removal, enzymes (1 decrease, 2 increase), DNA repair, affinity, pathways

What is the main toxicity limiting chemotherapy?

Bone marrow toxicity

What are some considerations of chemo combinations?

Must be active against the tumour type

Act on different biochemical targets

Act at different phases of the cell cycle

Affect different organs and tissues - so limiting additive ADRs/clearance effect

Have minimum or no overlapping toxicity

Are optimum for each drug with consistent timing of the doses

Therapy cycles dictated by bone marrow recovery to limit suppression