ON5 Cytotoxic resistance and endocrine therapy

Primary resistance: No ❌ to administration
Acquired resistance: Initial ❌ –> tumour reappears –> patient ❌
Caused by
- Alterations in drug ❌
- Modifications to ❌

Resistance mechanisms:
1. Reduced drug ❌
E.g. MTX uptake via reduced folate carrier
2. Alteration of ❌ drug targets
e.g. Production of DNA TopII with resistance to ❌
3. Decreased drug concentration (❌ prodrug activation)
e.g. high GST levels inactivate ❌
4. Increased ❌ of drug
e.g. P glycoprotein and multidrug resistance-related protein with ❌

Where do resistant cells come from?

Theory 1: Only ❌ cells survive therapy, and repopulate tumour.
Theory 2: Mutations present post-therapy are ❌ for.
Combined model: Escape from ❌ growth control, ❌ present, over time we see structural/biochemical
❌, cytotoxic therapy then causes resistance.

Sensitive drugs with shorter lifespans are therefore ❌ prone to resistance.

Apparent resistance: Tumour can be sensitive but not show a clinical response due to incorrect ❌. The interval is too ❌. Cell-cycle specific agents with short ❌ needed.
Anatomical ❌ also causes apparent resistance; ALL (acute lymphoblastic leukemia) relapse in children due to failure to penetrate ❌.

Chemo principles:
Principle 1: Treat ❌. ❌ with chemo as an adjuvant successfully only in breast cancer and in children.
Principle 2: Treat with a ❌. Use drugs with different ❌. Will have different unwanted effects - though note there is additive ❌ not ❌. Alternating regimens ❌ toxicity.

Endocrine Therapy Principles:
Cellular proliferation is influenced by hormones.
• ❌ – female breast, endometrial carcinoma
• ❌ – prostate
There is tumour regression following ❌.

Hormonal sensitivity in breast cancer depends on genes, estrogen receptors and growth factor receptors.
• ER+ means there will be ❌ to therapy
• ER+ AND PgR+ increases your chance of ❌
Also carry growth factor receptors (GFRs).

Inverse correlation:
High ER content = few ❌
High GFR content = few ❌

Oestrogen receptor antagonists e.g. Tamoxifen, clomiphene citrate, nafoxidine
- ❌ estrogen receptor modulators (SERM)
- ❌ binds to oestrogen receptors
• Oestrogenic effects (inhibit ❌ resorption, stimulates ❌ synthesis)
• Anti-oestrogenic effects (breast tissue, inhibits synthesis of ❌)

Example: Tamoxifen, for ❌ breast cancer. Is an adjuvant/❌. Metabolised by CYP2D6, 3A4, metabolites have ❌ t1/2. Unwanted Effects: ❌ flushes, nausea, amenorrhoea, ❌ bleeding

Aromatase inhibitors e.g. Anastrozole, Letrozole, Exemestane (steroid)
Aromatase converts androgens to ❌; this is the primary mechanism of BC in ❌ menopausal women, so we can inhibit it. For ❌ breast cancer. No value if patient is ❌. SEs: Stiffness, ❌ pain, loss of bone mineral ❌ (osteoporosis, bone fractures).

Carcinoma of the prostate:
Androgens modulate by:
• Growth of prostatic ❌
• Production of prostatic ❌
• ❌ prostate cancers arise from epithelium

3 main approaches:
1. Remove ❌ source
2. Block hormone ❌ (*5 alpha-reductase)
3. Androgen R ❌

Lowering androgen levels
1. ❌ (orchidectomy)
2. Chemically using synthetic ❌ releasing hormones - ❌ analogues e.g. goserelin, leuprorelin. Causes initial ❌ (high ❌) = Downregulation of GnRH ❌, loss of sensitivity, suppress ❌ formation. Unwanted effects: sexual ❌, hot ❌, growth of ❌ tissue

Antiandrogens e.g. Flutamide can ❌ flare.
• ❌ antagonist
• Prevents ❌ binding to ❌ androgen receptors in ❌
Have no effect on ❌ function and so fewer side effects.