ON5 Cytotoxic resistance and endocrine therapy

Primary resistance: No [blank_start]response[blank_end] to administration Acquired resistance: Initial [blank_start]regression[blank_end] –> tumour reappears –> patient [blank_start]relapses[blank_end] Caused by - Alterations in drug [blank_start]metabolism[blank_end] - Modifications to [blank_start]drug target[blank_end]

Resistance mechanisms: 1. Reduced drug [blank_start]uptake[blank_end] E.g. MTX uptake via reduced folate carrier 2. Alteration of [blank_start]intracellular[blank_end] drug targets e.g. Production of DNA TopII with resistance to [blank_start]anthracyclines[blank_end] 3. Decreased drug concentration ([blank_start][blank_end] prodrug activation) e.g. high GST levels inactivate [blank_start]cisplatin, alkylating agents[blank_end] 4. Increased [blank_start]removal[blank_end] of drug e.g. P glycoprotein and multidrug resistance-related protein with [blank_start]vincas, taxanes, anthracylines[blank_end]

Where do resistant cells come from? Theory 1: Only [blank_start]resistant[blank_end] cells survive therapy, and repopulate tumour. Theory 2: Mutations present post-therapy are [blank_start]naturally selected[blank_end] for. Combined model: Escape from [blank_start]normal[blank_end] growth control, [blank_start]mutations[blank_end] present, over time we see structural/biochemical [blank_start]abnormalities[blank_end], cytotoxic therapy then causes resistance. Sensitive drugs with shorter lifespans are therefore [blank_start]less[blank_end] prone to resistance.

Apparent resistance: Tumour can be sensitive but not show a clinical response due to incorrect [blank_start]scheduling[blank_end]. The interval is too [blank_start]long[blank_end]. Cell-cycle specific agents with short [blank_start]t1/2[blank_end] needed. Anatomical [blank_start]isolation[blank_end] also causes apparent resistance; ALL (acute lymphoblastic leukemia) relapse in children due to failure to penetrate [blank_start]BBB[blank_end].

Chemo principles: Principle 1: Treat [blank_start]rapidly[blank_end]. [blank_start]Radiation/surgery[blank_end] with chemo as an adjuvant successfully only in breast cancer and in children. Principle 2: Treat with a [blank_start]combination[blank_end]. Use drugs with different [blank_start]targets[blank_end]. Will have different unwanted effects - though note there is additive [blank_start]efficacy[blank_end] not [blank_start]toxicity[blank_end]. Alternating regimens [blank_start]decreases[blank_end] toxicity.

Endocrine Therapy Principles: Cellular proliferation is influenced by hormones. • [blank_start]Oestrogen[blank_end] – female breast, endometrial carcinoma • [blank_start]Androgen[blank_end] – prostate There is tumour regression following [blank_start]ovariectomy[blank_end].

Hormonal sensitivity in breast cancer depends on genes, estrogen receptors and growth factor receptors. • ER+ means there will be [blank_start]response[blank_end] to therapy • ER+ AND PgR+ increases your chance of [blank_start]remission[blank_end] Also carry growth factor receptors (GFRs). Inverse correlation: High ER content = few [blank_start]GFRs[blank_end] High GFR content = few [blank_start]ERs[blank_end]

Choose the incorrect statement.

Oestrogen receptor antagonists e.g. Tamoxifen, clomiphene citrate, nafoxidine - [blank_start]Selective[blank_end] estrogen receptor modulators (SERM) - [blank_start]Competitively[blank_end] binds to oestrogen receptors • Oestrogenic effects (inhibit [blank_start]bone[blank_end] resorption, stimulates [blank_start]PgR[blank_end] synthesis) • Anti-oestrogenic effects (breast tissue, inhibits synthesis of [blank_start]GF[blank_end]) Example: Tamoxifen, for [blank_start]recurrent, metastatic[blank_end] breast cancer. Is an adjuvant/[blank_start]prevention[blank_end]. Metabolised by CYP2D6, 3A4, metabolites have [blank_start]long[blank_end] t1/2. Unwanted Effects: [blank_start]hot[blank_end] flushes, nausea, amenorrhoea, [blank_start]vaginal[blank_end] bleeding

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

Carcinoma of the prostate: Androgens modulate by: • Growth of prostatic [blank_start]epithelium[blank_end] • Production of prostatic [blank_start]fluid[blank_end] • [blank_start]Most[blank_end] prostate cancers arise from epithelium 3 main approaches: 1. Remove [blank_start]primary[blank_end] source 2. Block hormone [blank_start]synthesis[blank_end] (*5 alpha-reductase) 3. Androgen R [blank_start]antagonists[blank_end]

Lowering androgen levels 1. [blank_start]Surgically[blank_end] (orchidectomy) 2. Chemically using synthetic [blank_start]gonadotrophin[blank_end] releasing hormones - [blank_start]GnRH and LHRH)[blank_end] analogues e.g. goserelin, leuprorelin. Causes initial [blank_start]flare[blank_end] (high [blank_start]LH and FSH[blank_end]) = Downregulation of GnRH [blank_start]receptors[blank_end], loss of sensitivity, suppress [blank_start]androgen[blank_end] formation. Unwanted effects: sexual [blank_start]dysfunction[blank_end], hot [blank_start]flushes[blank_end], growth of [blank_start]breast[blank_end] tissue

Antiandrogens e.g. Flutamide can [blank_start]inhibit[blank_end] flare. • [blank_start]Selective[blank_end] antagonist • Prevents [blank_start]testosterone[blank_end] binding to [blank_start]nuclear[blank_end] androgen receptors in [blank_start]prostate[blank_end] Have no effect on [blank_start]pituitary[blank_end] function and so fewer side effects.