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Breast Cancer > Chemotherapy > Flashcards

Chemotherapy Flashcards

1
Q

Chemotherapy

A

34% of patients diagnosed with breast cancer have chemotherapy as part of their primary cancer treatment.

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2
Q

The risk of recurrence can be reduced using adjuvant chemotherapy

A

• Adjuvant = after primary surgery
• Neo-adjuvant = before surgery – reduces invasive surgery
o Locally advanced tumours
o Inflammatory tumours
o For larger tumours or those with large amounts of nodal involvement or inflammatory component, neoadjuvant chemotherapy may be used to shrink the tumour before surgery to improve the outcome and preserve remnant breast tissue

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3
Q

Although chemotherapy comprises part of a successful regimen for treating breast cancer…

A

Although chemotherapy comprises part of a successful regimen for treating breast cancer, as many as 50% of patients fail to benefit due to the development of intrinsic and acquired multiple drug resistance
Risk factors associated with onset of a resistant phenotype: genetic predisposition such as mutations in a and b tubulins, and BRCA1/2; induction of expression of multi-drug resistance (MDR) proteins; alterations in spindle assembly checkpoints,cell cycle proteins and apoptosis

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4
Q

Mitotic Inhibitors

A

Disrupt M phase of cell cycle, leading to cell arrest

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5
Q

Taxanes (e.g. Paclitaxel)

A

Other taxanes include Docetaxel and Carbazitaxel. Paclitaxel is extracted from the bark of T. brevifolia (Pacific Yew); 12 slow-growing trees are required for the treatment of 1 patient.

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6
Q

Paclitaxel

A

a microtubule stabiliser, It acts during the telophase of M phase, binding to the β subunit of tubulin – the building block of microtubules. The resulting microtubule/paclitaxel complex does not have the ability to disassemble, blocking progression of mitosis and causing prolonged activation of the mitotic checkpoint. This triggers apoptosis or reversion to the G0-phase of the cell cycle without cell division.
Paclitaxel does not meet the requirements of good drug-likeness (RMM = 50326.5; 15 H-bond acceptors). It is Class IV (poorly permeable, poorly soluble) of the Biopharmaceutical Classification System, so is not ideal for oral delivery.

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7
Q

Formulation & Delivery

A
  • Paclitaxel is given via IV route
  • Formulation with cremophor (polyoxyl castor oil) improves its water solubility, however cremophor has the potential to cause severe allergic reactions, so pre-administration of steroids and antihistamines is recommended. In addition, cremophor can form micelles in plasma, trapping paclitaxel and preventing distribution to tumour cells.
  • A new approach at Paclitaxel formulation sees paclitaxel complexed with albumin to create a nanoparticle colloidal system. This solubilises paclitaxel which accumulates in tumour beds. No cremophor is used, avoiding issues related to toxicity.
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8
Q

Side effects

A

Taxane therapy may cause peripheral neuropathy (numbness, tingling, paraesthesia, and a burning pain in a stocking-glove distribution). This is related to effects on microtubule function in nerve cells and other healthy tissue.
Stress hormones were shown to arrest cells in the G0/G1 phase, which would serve to substantiate the decrease in paclitaxel efficacy, which targets cells in the S phase.

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9
Q

Vinca alkaloids (e.g. Vincristine)

A

Act during the metaphase, inhibiting microtubule assembly & causing cell arrest (microtubule destabilisers)

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10
Q

Alkylating agents - Cyclophosphamide

A
  • Prodrug, converted to phosphoramide mustard
  • Targets S phase
  • Cross-links guanine bases by binding alkyl groups
  • DNA strands are unable to uncoil, so cells can no longer perform mitosis
  • Also adds methyl/ other alkyl groups onto other molecules, causing a miscoding of DNA and cell apoptosis
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11
Q

Mechanisms of resistance:

A

• Increased ability to repair DNA defects
• Decreased cellular permeability to the drug
• Increased glutathione synthesis
• Inactivation of alkylating agents through conjugation reaction
 

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12
Q

Anti-tumour antibiotics (Anthracyclines/ Etoposides) Doxorubicin

A
  • Forms complexes with DNA by intercalation between base pairs
  • Inhibits topoisomerase II activity, preventing the resealing of DNA strands & inhibiting DNA replication
  • May also inhibit polymerase activity, affect regulation of gene expression, and produce ROS, causing free radical damage to DNA and triggering apoptosis
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13
Q

Epirubicin

A
  • Most active during S phase
  • Forms complexes with DNA by intercalation between base pairs
  • Inhibits topoisomerase II activity, preventing the resealing of DNA strands & inhibiting DNA replication
  • Also inhibits nucleic acid & protein synthesis
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14
Q

Antimetabolites

A

Thymidylate synthase & dihydrofolate reductase enzymes are involved in the production of thymine (a DNA base); if these enzymes are disrupted, pyrimidine synthesis will cease, and as a result, so will DNA synthesis.

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15
Q

Fluorouracil (5FU)

A
  • Bio-transformed to ribosyl- and deoxyribosyl- derivatives
  • Targets S phase
  • 5-fluoro-2’-deoxyuridine 5’-phosphate (FdUMP) inhibits thymidylate synthase, therefore inhibits thymidine synthesis, preventing DNA synthesis
  • 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function
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16
Q

Methotrexate (MTX)

A

• Targets S phase
• Inhibits dihydrofolate reductase, preventing DNA synthesis
Mechanisms of resistance:
• Decreased drug transport into the cell
• Altered dihydrofolate reductase enzyme with a lower affinity for methotrexate
• Quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message)

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17
Q

Topoisomerase (Top) inhibitors

A

Top 1 cleaves one strand of DNA and relaxes DNA coil during replication
Top 2 cleaves two strands of DNA and relaxes DNA supercoil during replication

18
Q

Camptothecins (Topotecan and Irinotecan) – Top1 inhibitor

A
  • Targets S phase
  • Interferes with Top 1 activity, preventing re-ligation of single strand breaks causing lethal double-stranded breaks in DNA & apoptosis
19
Q

Etoposide - Top2 inhibitor

A
  • Targets S phase
  • Interferes with Top 2 activity, inhibiting DNA re-ligation. This causes critical errors in DNA synthesis at the pre-mitotic stage of cell division, leading to apoptosis
20
Q

Adjuvant chemotherapy

A

Protein kinases carry out post-translational changes to proteins (e.g. serine, threonine, tyrosine or histidine amino acid residues), which affects their reactivity and properties. Phosphorylation is the transfer of a phosphate group from ATP to amino acid residue on protein) gives structural and/or conformational changes to the protein, activating or deactivating it.

Protein kinases are involved in cellular function; they are very important in cell signalling and division. Uncontrolled activity leads to uncontrolled cell growth and division. Therefore, in cancer, proteins kinases are targets.
Tyrosine kinases are a class of protein kinase, where tyrosine is the phosphorylation site. There are receptor and cytoplasmic tyrosine kinases.
EGFR are a family of 4 receptor tyrosine kinases: EFGR (ErbB-1, ErbB-2, ErbB-3, ErbB-4) and HER-1, HER-2, HER-3, HER-4.
They have extracellular receptor, transmembrane-spanning domain, kinase domain & ATP-binding domain.
21
Q

Monoclonal antibodies against HER-2

Trastuzumab

A

It is a recombinant, humanised Ig1 mAb against the EGFR, HER-2.
• Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2. This prevents the phosphorylation of p95, which is used in the signal transduction pathways
o Inhibition of MAPK and PI3K pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation.
• Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumour sites that overexpress HER-2.
• Disrupts downstream activity and reduces cell growth and division

Trastuzumab must be given via SC injection. Although there are issues associated with SC injection (patient training required, painful at site of injection), it gives good absorption, has a rapid onset of action & is useful if the patient is vomiting or unresponsive.
Trastuzumab halves the risk of relapse (hazard ratio 0.54) but is expensive (£25,000 per patient per year).

22
Q

Tyrosine Kinase inhibitors Imatinib

A
  • Binds to the ATP-binding site of the kinase, intracellularly, interfering with phosphorylation of epidermal growth factor receptor (EGFR), and ERBB2
  • Disrupts downstream activity and reduces cell growth and division

Imatinib meets the requirements of good drug-likeness; it is less than 500 Da, Lop P is < 5, 2 H-bond donors & 6 H-bond acceptors. It is Class I (very permeable, very soluble) of the Biopharmaceutical Classification System, so is ideal for oral delivery.

23
Q

Other biologics

A

Lapatinib is an inhibitor of the intracellular tyrosine kinase domains of both HER2 and EGFR receptors. It is useful in HER-2 positive BRCA.

Everolimus is an mTOR inhibitor; it reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis.
It is useful in post-menopausal women with ER positive, HER2 negative locally advanced or secondary breast cancer whose cancer has progressed or recurred when hormone therapy. 

24
Q

Hormone/ endocrine therapy

A

Oestrogen receptor positive breast cancer cells require oestrogens to proliferate and metastasise. Oestrogen penetrates breast cancers and activates ER receptors, promoting growth.

Post-menopausal
1.	Aromatase Inhibitors
2.	Tamoxifen (non-steroidal Antioestrogen)
3.	Fulvestrant (steroidal Antioestrogen)
Pre-menopausal
1.	Tamoxifen
2.	Goserelin (GnRH analog)
3.	Aromatase Inhibitors
25
Q

Synthesis of oestrogens

A

Cholesterol –> progesterone –> androstenedione –> estrone/ testosterone –> oestradiol
The source of oestrogens depends on whether the patient is premenopausal or post-menopausal.

26
Q

Premenopausal women – E2

A

Most oestrogens are made in ovaries, often by testosterone which is converted in oestradiol (E2).
Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH stimulates ovarian release of oestrogen.

27
Q

Postmenopausal women – E1

A

Most oestrogens are made outside ovaries; adipose tissue is major source. Androstenedione produces estrone (E1). If a post-menopausal woman with ER+ BRCA, their prognosis is worse because more E1 is produced from adipose. E1 is required for tumour growth & proliferation.

28
Q

GnRH analogues – E1

A

GnRH is responsible for the release of FSH, which is responsible for the ovarian release of oestrogen (E2). Goserelin is a GnRH analogue, acting as a potent inhibitor of GnRH secretion. This therefore decreases E2 levels to levels similar to a postmenopausal state (when the medication is stopped, hormone levels return to normal).

29
Q

Aromatase inhibitors – E2

A

Aromatase enzymes convert androgens into oestrogens (E1); inhibitors of aromatase therefore block synthesis of oestrogen.
An example of first-generation aromatise inhibitor is Aminoglutethimide. It blocked all hormone synthesis (cortisol etc) so supplements were needed.
Anastrozole (non-steroidal) & Exemestane (steroidal) are third-generation aromatase inhibitors more specific to treat oestrogen dependent breast cancer.

30
Q

Oestrogen receptor

A

There are a number of oestrogen receptors; are similar to steroidal receptors – intracellular & affect gene transcription.
ER-α and ER-ß are oestrogen receptors. ER-α is dominant in the vagina, breast, bone, hypothalamus and blood vessels; ER-ß is dominant in ovaries in females.
ER0ß is slightly longer with a number of domains. The C region binds to DNA & the hinge region is where oestrogen binds. When oestrogen binds to ER, the receptors dimerise: ER-α with another ER-α or ER-ß with another ER-ß = homodimers; ER-α with ER-ß – heterodimers.

31
Q

Oestradiol (E2) binds …

A

Oestradiol (E2) binds to both receptors with equal affinity. Circulating E2 enters the cell and reaches ER receptor. Heat shock protein 90 (HSP90) is bound to ER, so E2 dissociates HSP90 from ER. E2 then binds to receptors, which dimerise. Once dimerised, ER enters nucleus.
Depending on the cell type, ER binds directly to DNA and affects gene transcription or binds indirectly to DNA (by binding to a transcription factor). There are also extranuclear receptors; G-coupled protein receptor (GPR30 or GPER - oestradiol) sit on membrane, coupled to the bottom by lipid tag. The secondary messenger system is cAMP, which can cause gene transcription when G protein coupled receptor is activated.
Non-genomic oestrogenic effects don’t involve DNA transcription; they cause direct physiological effects.
Oestrogen receptors can also activate without oestrogen; GF signalling leads to activation of ER via kinase phosphorylation. ER activation causes gene transcription.

32
Q

Oestrogen receptor antagonists

Tamoxifen

A

A prodrug that requires bioactivation by cytochrome P450 enzymes CYP2D6 and 3A4 to generate the active metabolite, endoxifen.
It is a selective oestrogen receptor modulators (SERMs); it acts as a competitive antagonist of oestrogen at ER-α, in the breast. It causes a conformational change in the receptor, modulating the expression of oestrogen-dependent genes. The prolonged binding of tamoxifen results in reduced DNA polymerase activity, impaired thymidine utilization, blockade of oestradiol uptake, and decreased oestrogen response.
It is also a partial agonist at other oestrogen receptors, minimising the potential effects of oestrogen deprivation.

Tamoxifen is not cytotoxic and does not cause a loss of bone marrow.

Ten years of adjuvant treatment with tamoxifen provided women with estrogen receptor-positive breast cancer greater protection against late recurrence and death from breast cancer compared with the current standard of five years of tamoxifen, according to a new study

33
Q

Fulvestrant

A

Fulvestrant is a steroidal antioestrogen, used in post-menopausal women with disease progression following antioestrogen therapy (Tamoxifen). It competitively & reversibly binds to ER, downregulates ER so that oestrogen is no longer able to bind to these receptors and degrading the ER. This inhibits the growth of the tumour, as it is not able to utilise oestrogen.
 

34
Q

Immune therapy- Adoptive transfer

A

T cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.

35
Q

Colony-stimulating factors

A

Stimulate the production of blood cells. They do not directly affect tumours, but through their role in stimulating blood cells, they can be helpful in supporting the person’s immune system during cancer treatment, since chemotherapy and radiation therapy can affect blood cells, putting the patient at risk for developing infections, anaemia, and bleeding problems.

36
Q

Tumour vaccines

A

Vaccines constitute an active and specific immunotherapy designed to stimulate the anti-tumour immune response by presenting tumour-associated antigens (TAAs) expressed on normal tissues that are overexpressed on tumour cells. Many TAAs (E.g. MUC1 and HER-2) have been identified and been shown to be specifically recognized by T cells. Induction of strong immunity by cancer vaccines is expected to lead to the establishment of immunological memory, thereby preventing tumour recurrence

37
Q

Monoclonal antibodies

A

Monoclonal antibodies are laboratory-produced substances that can locate and bind to certain proteins. They do this by reacting against tumour-associated proteins on the surface of certain cells.
These antibodies can be used to see where the tumour is in the body (detection), or as therapy to deliver drugs, toxins, or radioactive material directly to a tumour.
Monoclonal antibodies can be given to target particular molecules on the cell surface. E.g. rituximab to target lymphoma cells and Herceptin to target cells, including breast cancer cells.

38
Q

Dendritic cell therapy

A

Dendritic cell therapy provokes anti-tumour responses by causing dendritic cells to present tumour antigens. Dendritic cells present antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. In cancer treatment they aid cancer antigen targeting.

39
Q

Checkpoint inhibitors

A

Tumours often down-regulate immune function by expressing PD-L1, a ligand for PD-1 (programmed cell death-1 inhibitory receptor). Pembrolizumab is a monoclonal antibody against PD-1; the binding of pembrolizumab to PD-1 prevents the suppression of immune anti-tumour response.
 

40
Q

Combination chemotherapy

A

A range of anti-cancer drugs are chosen. They should act at different stages of the cell cycle, with different mechanisms of action. This helps maximise cytotoxic effect and minimise resistance.

41
Q

It is important that anticancer drugs are not all given at the same time; there are interactions and conflicting effects:

A
  • Anthracyclines have a radio-sensitising effect, and should not be given at the same time as radiotherapy
  • Trastuzumab increases cardiotoxicity of anthracyclines
  • Anthracyclines & Antimitotic agents cause myelosuppression (bone marrow), increasing risk of infection
  • Endocrine (hormone) therapy inhbitis the cell cycle; chemotherapies target different phases of the cell cycle so will have no effect when given with hormone therapy
42
Q

The regime is based on a 21-day cycle, and the anti-cancer drugs are given as follows:

A

FEC-T

Order of administration Anti-cancer agent Dose Regime
1 5-fluorouracil (antimetabolite) 500 mg/m2
¬IV bolus Day 1 of 21 for 3 cycles
(once every 3 weeks, over 9-week period)
Epirubicin (anthracycline) 100 mg/ m2
IV bolus
Cyclophosphamide (alkylating agent) 500 mg/m2
IV bolus
2 Docetaxel (antimitotic) 100 mg/m2
IV infusion over 1 hour Day 1 of 21 for 3 cycles
(once every 3 weeks, over 9-week period)
3 Trastuzumab (biologic against HER-2 receptor) 600mg
SC over 5 mins Day 1 of 21 for 18 cycles
(once every 3 weeks, over 54-week period)

Breast Cancer (10 decks)

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