cancer chemotherapies 3

Question 1

what is multi-drug resistance?

Answer 1

Enhanced efflux: expression of transmembrane protein which enhances excretion of drug from cancer cell
- Multi-drug resistance = efflux pump that affects several drugs
- MDR observed in several cancers
Examples of MDR proteins:
- Permeability glycoprotein (P-glycoprotein)
- MDR-associated protein (multiple sub-types)
- Lung-resistance protein
- Breast cancer resistance protein

Question 2

what is p-glycoprotein and where is it expressed?

Answer 2

Aka: multi-drug resistance protein1 (MDR1)
- ATP-binding cassette sub-family B member 1 (ABCB1)
cluster of differentiation 243 (CD243) (has one binding site for drug interactions and another site for ATP binding)
170 KDa transmembrane ATP-binding transporter expressed in:
- intestinal epithelium
- hepatocytes
- pancreatic cells
- renal tubule cells
- capillary endothelial cells (eg. blood brain barrier)

Protects cells against toxins but increased expression in tumour cells interferes with many chemotherapeutic agents

Question 3

how is p-glycoprotein excreted and how do other drugs impact p-glycoprotein

Answer 3

ATP & drug bind
ATP hydrolysis releases phosphate to shift position of drug → excretion
In some cancer cells:
- Estrogen downregulates protein expression of P- glycoprotein
- Tamoxifen – inhibits efflux of some drugs by P-glycoprotein
- Cisplatin or doxorubicin can induce P-glycoprotein expression

Question 4

how do you treat breast cancer?

Answer 4

~13 % of women develop breast cancer ~3 % of women will die of breast cancer Many types/stages
Tumours are heterogeneous
Treatment options:
- Surgery
- Radiation Therapy
- Cytotoxic Chemotherapy
- Hormone Therapy
- Targeted Therapy
- Complementary & Holistic Medicine

Question 5

what are the types and grades of breast cancer?

Answer 5

Most Common:
- Ductal: inside milk duct (in situ or invasive)
- Lobular: inside milk-producing gland (in situ or invasive)
Rare:
- Inflammatory breast cancer - Male breast cancer

Question 6

how do you treat breast cancers of different stages?

Answer 6

STAGE I - surgery
STAGE II no lymph node involvement – surgery & radiation
STAGE II with lymph node involvement (less than 4) surgery &/or radiation and chemotherapy
Several chemotherapy combinations
Hormone sensitive tumors:
- ER positive – tamoxifen/ anastrozole
- Progesterone receptor (PR) positive
- HER-2 positive – antibodies/HER-2 receptor antagonists
Stage III and IV – treatment options often considered palliative rather than curative – some women live several years with metastatic breast cancer

Question 7

what are examples of traditional chemotherapy combinations for breast cancer?

Answer 7

• cyclophosphamide & doxorubicin
• cyclophosphamide, methotrexate & 5-fluorouracil
• cyclophosphamide, paclitaxel & doxorubicin
• cyclophosphamide, 5-fluorouracil & doxorubicin
• cyclophosphamide, methotrexate, 5-fluorouracil, prednisone & vincristine

Question 8

what is the strong case for weekly paclitaxel in breast cancer?

Answer 8

The 2 commonly used schedules were equally effective in women with high-risk stage I to III breast cancer, report lead study author G. Thomas Budd, MD, from the Cleveland Clinic in Ohio, and colleagues.
In the Southwest Oncology Group (SWOG) S0221 trial, estimated 5-year progression-free survival rates were equivalent for paclitaxel administered weekly (82%) and paclitaxel administered every 2 weeks (81%).
However, the low-dose weekly schedule was significantly less toxic than the dose-dense biweekly schedule for neurologic events (17% vs 10%; P < .001) and musculoskeletal pain (11% vs 3%; P < .001).

Question 9

describe targeted therapy - Trastuzumab (Herceptin)

Answer 9

• Antibody – acts as antagonist of HER2 receptor
• Approved for HER2 overexpressing breast cancer Herceptin + paclitaxel is first line treatment of HER2 over-expressing metastatic breast cancer

Question 10

describe targeted therapy - Bevacizumab (Avastin)

Answer 10

• treatment for breast cancer that is HER-2 positive
• Angiogenesis inhibitor
• Antibody – binds VEGF and acts as antagonist of VEGFR2
• Approved by FDA in 2008 for use in combination with
  paclitaxel for metastatic breast cancer but withdrawn
  in 2011. Approved for some metastatic cancers
  (ovarian, kidney, colon and lung).
  VEGF= vascular endothelial growth factor VEGFR2 = VEGF receptor

Question 11

what are the adverse effects of trastuzumab?

Answer 11

• Fever, aches, chills, nausea and diarrhea
• Cardiac dysfunction, including congestive heart failure (downregulates expression of neuregulin 1 which is involved in the activation of cell survival pathways in cardiac myocytes)

Question 12

what are the adverse effects of bevacizumab?

Answer 12

• Inhibition of blood vessel growth for maintenance and healing
• Hypertension, bleeding

Question 13

describe targeted therapy - Olaparib and its adverse effects

Answer 13

• Orally administered poly ADP ribose polymerase (PARP) inhibitor
• FDA approved 2018: metastatic, HER2-negative breast cancer with BRCA gene mutation and have already had chemotherapy.
  (Approved in 2014 for BRCA mutated advanced ovarian cancer)
  Adverse effects:
• bone marrow suppression
• GI disturbances (nausea, vomiting), anorexia
• fatigue
• muscle and joint pain

Question 14

describe targeted therapy - Atezolizumab and its adverse effects

Answer 14

• Monoclonal antibody against the programmed cell death-ligand 1 (PD-L1) protein; administered by slow IV infusion (every 2 to 4 weeks)
• FDA approved 2019: triple-negative breast cancer (does not express ER, PR and HER2)
  (Previously approved for some advanced, resistant and/or high PD-L1 expressing lung, bladder & liver cancers)
  Adverse effects:
• nausea, anorexia
• fatigue
• urinary tract infection