Chemotherapy

Question 1

Gompertzian Model of Tumor Growth

Answer 1

• (kinetics for most solid tumors)
• Growth fraction of a tumor is not constant; it peaks at 37% max size and then exponentially dec
• SO… it is optimal to use chemo at high growth fraction (chemo destroys growing cells) THUS more advanced cancers are less responsive to chemo

Question 2

M Phase Specific Chemo

Answer 2

• Taxanes - docetaxel, paclitaxel (work b/n G2 - M)

- Vinca Alkaloids - vinblastine, vincristine, vinorelbine

Question 3

G1 Specific Chemo

Answer 3

• Hormonal drugs & anti-neoplastic enzymes (asparaginase, pegaspargase)

Question 4

S Phase Specific Chemo

Answer 4

• Anti-Metabolites - Folate analogs (methotrexate), purine analogs (cladribine, fludarabine, mercaptopurine, pentostatin, thioguanine), pyrimidine analogs (fluorouracil, floxuridine, gemcitabine, cytarabine, capecitabine), hydroxyurea
• Topoisomerase Inhibitors - topotecan, irinotecan

Question 5

G2 Specific Chemo

Answer 5

• Bleomycin

- Epipodophyllotoxin Derivatives - etoposide, teniposide

Question 6

Cell Cycle Independent Chemo

Answer 6

• Alkylating Agents - cyclophosphamide, ifosfamide, nitrogen mustard, melphalan, busulfan, nitrosureas
• Anthracyclines - doxorubicin, daunorobicin, mitoxantrone, idarubicin, epirubicin
• Camptothecins (topo I inhibitor) - irinotecan, topotecan
• Platinum analogs - cisplatin, carboplatin, oxaloplatin

Question 7

Generally, what determines sensitivity to chemo?

Answer 7

-how much the tumor cell growth deviates from normal cell growth

Question 8

Chemo Resistance (2 types)

Answer 8

• Intrinsic
  
  • More unstable the tumor is genetically, the more mutation to drug-resistance
  • Mutations –> loss of checkpoint control
    
    • p53 mutations or deletions
    • MMR
    • NF-kB
    • Bcl-2 family
• Acquired
  
  • Less drug makes it intracellularly
    
    • Inc export - MDR, MRP
    • Dec inport
  • Inc drug inactivation
  • Dec conversion of drug to active form
  • Altered amount if target enzyme or receptor for given drug
  • Dec affinity for enzyme or receptor
  • Enhanced repair of whatever defect the drug causes
  • Dec activity of enzyme needed for cytotoxic effect

Question 9

Overall Survival v Disease Free Survival

Answer 9

• Overall Survival - from date or dx or date they started treatment
• Disease Free Survival - time from end of primary tx when no signs of cancer to next relapse (easier to meas than OS - shorter)

Question 10

Duration of Response

Answer 10

• time from partial response/complete response/stable disease to the time when disease progression is noted
• Complete response - no signs
• Partial response - 30% dec diameter
• Stable Disease - not sufficient shrinkage to qualify as PR but not sufficient inc to qualify as PD
• Progressive Disease - 20% inc in diameter or appearance of 1+ new lesions

Question 11

Objective Response Rate v. Clinical Benefit Ratio or Disease Control Rate

Answer 11

• Objective Response Rate - (CR + PR) combo of complete and partial response
• Clinical Benefit Ratio or Disease Control Rate - (CR + PR + SD) b/c you can improve overall survival by inc the amount of time someone is in stable disease / inc the duration of response until next signs and symptoms

Question 12

Hormone Therapies

Answer 12

• Slow or stop growth in hormone-sensitive tumors
• Prevent production or block activity of a hormone that the tumor needs
• Ex) tamoxifen prevents estrogen from binding receptor in breast cancer
• Ex) Aromatase inhibitors block aromatase –> estrone –> estradiol (deprive breast cancer cells of estradiol)

Question 13

Gene Expression Modulators

Answer 13

• Modify proteins that control gene expression
• Ex) azacytidine (AZA) and decitabine (DCA) both dec methylation of tumor suppressor genes so that these genes are expressed again

Question 14

Apoptosis Inducers

Answer 14

Ex) Venteoclax is a small molecule that inhibits BCL-2 which normally sequesters pro-apoptosis proteins (esp for CLL)

Question 15

Angiogenesis Inhibitors

Answer 15

• Prevent production of new blood vessels that tumors need for growth (need oxygen and nutrients)
• Ex) Bevacizumab - binds VEGF so it cannot bind receptor (colon cancer)
• Ex) Sunitinib & Sorafinib - inhibit receptor tyrosine kinases of VEGF; sorafinib also inhibits cell proliferation downstream (liver cancer)

Question 16

2 Types of Immunotherapies

Answer 16

• Trigger immune system to destroy cancer cells

1- Cancer cells overcome immune system by having normal cell proteins on their surface that when recognized by T cells inhibit T cell activation (form of immune escape)

- Checkpoint Inhibitors inhibit this function
- Ex) CTL4 Inhibitors - CTL4 is on T cells and when binds certain proteins (CD80 or CD86) it inhibits that T cell
- Ex) PD-1 or PDL-1 Inhibitors - PD-1 is on T cells and binds PDL-1 on normal cells --> inhibits T cell from attacking

2- Monoclonal antibodies that bind CD20

- Ex) Rituximab - more complement -dep killing
- Ex) Obinituzumab - more antibody and apoptosis-dep killing