Lecture 30: Cancer Chemotherapy

Question 1

What is cancer?

Answer 1

cancer is the leading cause of death in Canada (1 in 4 deaths)

over 100 types of cancers

characterized by abnormal cell growth with potential to spread to other parts of the body (metastasis)

Question 2

What are the causes of cancer?

Answer 2

caused by environmental and genetic factors

tobacco, ionizing radiation, environmental pollution (asbestos, radon)

viral infections (HIV with Hodgkins and non-Hodgkins Lymphoma; Human Papiloma Virus with cervical cancer)

genetics (BRCA 1 in breast cancer)

Question 3

What is the relationship between cancer and the cell cycle?

Answer 3

cancer is fundamentally a disease of cell growth regulation

cancer arises when genes that regulate cell growth are mutated

Question 4

What is the cell cycle?

Answer 4

the cycle is a series of events leading to duplication of DNA and division of cytoplasm to produce two daughter cells

genes important in the regulation of cell cycle are divided into two daughter cells

Question 5

What is the G1 phase of the cell cycle?

Answer 5

checkpoint to ensure cell ready for DNA synthesis

Question 6

What is the S phase of the cell cycle?

Answer 6

DNA synthesis

Question 7

What is the G2 phase of the cell cycle?

Answer 7

checkpoint to ensure cell ready for mitosis

Question 8

What is the M phase of the cell cycle?

Answer 8

mitotic phase (cell divides into two daughter cells)

Question 9

What is the G0 phase of the cell cycle?

Answer 9

quiescent state

Question 10

What are tumor suppressor genes?

Answer 10

tumor suppressor genes (and the proteins they encode) repress cell cycle or promote apoptosis

inhibit cell division
initiate apoptosis following irreversible DNA damage
DNA repair proteins (BRCA)

p53 is a tumor suppressor protein that regulates cell cycle

p53 is mutated in 50% of all tumor

Question 11

What are proto-oncogenes?

Answer 11

are normal genes involved in cell growth and proliferation or inhibition of apoptosis

mutations can increase expression and proliferation (oncogene)

Question 12

What are point mutations?

Answer 12

small scale deletions or insertions which affect its expression

Question 13

What is chromosomal translocation?

Answer 13

when two separate chromosomal regions become abnormally fused

Question 14

What is the Philadelphia chromosome?

Answer 14

is a specific genetic abnormality in chromosome 22 found in leukemia cancer cells (abnormal translocation of chromosome 9 and 22)

the broken end of chromosome 22 contains the BCR gene which fuses with a fragment of chromosome 9 that contains the ABL1 gene

fusion creates a new gene BCR-ABL

leads to unregulated expression of protein tyrosine kinase activity (ABL gene) leading to unregulated cell cycle and cell division

Question 15

What is relationship between oncogenes and cancer?

Answer 15

usually multiple oncogenes and mutated tumor suppressor genes will all act in concert to cause cancer

Question 16

What is cancer therapy?

Answer 16

1/3 cured with local treatment strategies (such as surgery or radiotherapy)

in remaining cases, systemic approach with anti-cancer drugs is required (because metastasis)

anti-cancer drugs alone cure less than 10% of all cancer patients when tumor is diagnosed at advanced stage (usually given in combination with surgery and radiation)

Question 17

What are anti-cancer drugs?

Answer 17

anti-cancer drugs interfere with cell cycle

some anti-cancer drugs act at specific phases in the cell cycle, mainly at the S and M phase

other drugs are cytotoxic at any point in the cell cycle (i.e. estrogen receptor antagonist Tamoxifen)

Question 18

Why are the best anti-cancer drugs those that target the S and M phase?

Answer 18

tumor cells generally have a higher percentage of proliferating cells than normal cells, so are more susceptible to S and M phase anti-cancer drugs

normal tissues that proliferate rapidly (bone marrow, hair follicles, and intestinal epithelium) are also susceptible to damage from cytotoxic drugs

few categories of medication have a narrower therapeutic index and greater potential for causing harmful effects than anti-cancer drugs

Question 19

What are the four bases that form DNA?

Answer 19

four bases form DNA: two pyrimidine (thymine and cytosine) and two purines (guanine and adenine)

RNA incorporates uracil instead of thymine

Question 20

What are pyrimidine analogues?

Answer 20

pyrimidine analogues compete with normal pyrimidines precursors for the enzyme thymidylate synthase (TS)

TS required for the conversion of dUMP to dTMP (i.e. thymine+deoxyribose sugar)

i.e. 5-Fluorouracil (5-FU)

inactive in its parent form and requires activation to active metabolite FdUMP

Question 21

What are purine analogues?

Answer 21

6-mercaptopurine inhibits purine nucleotide biosynthesis and metabolism by inhibiting an enzyme called phosphoribosyl pyrophosphate aminotransferase (PRPP aminotransferase)

production of inosine monophate (IMP) is the rate limiting factor for purine synthesis, alters the synthesis and function of RNA and DNA

Question 22

What are alkylating agents?

Answer 22

alkylating agents are highly reactive compounds which covalently link to chemical groups (phosphates, amines, sulfhydryl and hydroxyl groups) commonly found in nucleic acids

lead to cross-linking between strands of DNA and strand breakage

N7 atom of guanine is particularly susceptible to the formation of covalent bond with alkylating agents

cancer cells are most susceptible to this class of drugs in late G1 and S phases of the cell cycle

Question 23

What is the alkylating agent cisplatin?

Answer 23

platinum analogue

lead to inter-strand crosslinks leading to inhibition of DNA synthesis and function

Question 24

What are anti-folates?

Answer 24

folic acid is an essential dietary factor that is converted by enzymatic reduction to FH4 cofactors

provide methyl groups for the synthesis of precursors of DNA and RNA (thymine or uracil)

folic acid analogues interfere with FH4 metabolism thereby inhibiting DNA replication

Question 25

What is the anti-folate methotrexate?

Answer 25

folic acid analogue that bind with high affinity to the active catalytic site of dihydrofolate reductase

effective during S phase and are most effective when cells are proliferating rapidly

Question 26

What are natural products in cancer treatment?

Answer 26

compounds extracted from plants or bacteria with anti-cancer properties

include vinca alkaloids, taxanes, epipodophyllotoxins, camptothecins

Question 27

What are vinca alkaloids?

Answer 27

derived from the periwinkle plant (Vinca rosea)

inhibit tubulin polymerization

disrupts the assembly of microtubules involved in mitotic spindle apparatus (M phase)

Question 28

What are taxanes?

Answer 28

derived from the Pacific yew tree (Taxus brevifolia)

promote microtubule assembly through high affinity binding

inhibits mitosis and cell division (M phase)

i.e. paclitaxel

Question 29

What are camptothecins?

Answer 29

derived from the Camptotheca acuminata

DNA topoisomerases are nuclear enzymes that reduce torisonal stress in supercoiled DNA (through stranded breakage and resealing)

Camptothecins bind and stabilize the normally transcient DNA-topoisomerase 1 complex

although the initial cleavage action of topoisomerase is not affected, the re-ligation step is inhibited, leading to the accumulation of single-stranded breaks in DNA

these are S-phase specific drugs because ongoing DNA synthesis is necessary for cytotoxicity

Question 30

What are antibiotics?

Answer 30

products of the soil microbe Streptomyces

bind DNA through intercalation, block DNA synthesis and cell replication

Question 31

What are the four mechanisms of action of anthracyclines?

Answer 31

inhibit topoisomerases

generate free radicals (DNA mutagenesis)

high affinity binding to DNA

bind cellular membrane to alter fluidity and ion transport

Question 32

What are tyrosine kinase inhibitors?

Answer 32

i.e. imantinib

inhibits the tyrosine kinase domain of the Bcr-Abl oncoprotein

treat leukemia

Question 33

What are epidermal growth factor receptor (EGFR) inhibitors?

Answer 33

EGFR is over-expressed in a number of solid tumors

activation of EGFR promotes cell growth and proliferation, invasion, and metastasis, and angiogenesis

i.e. Cetuximab is a monoclonal antibody directed against the extracellular domain of EGFR

Question 34

What are hormonal anti-cancer agents?

Answer 34

hormonal anti-cancer agents

i.e. tamoxifen

selective estrogen receptor antagonist

blocks binding of estrogen to estrogen sensitive cancer cells in breast tissue

Question 35

What is primary resistance?

Answer 35

develops spontaneously in the absence of prior exposure to anti-cancer drugs (i.e. p53 mutations)

Question 36

What is acquired resistance?

Answer 36

develops in response to a given anticancer agent

Question 37

What are adverse effects of cancer treatment?

Answer 37

dose related

occur primarily in rapidly growing tissues, such as bone marrow, intestinal mucosa, and reproductive system

symptoms include impaired immune system, diarrhea, hair loss, nausea and vomiting

many anti-cancer drugs are carcinogenic in nature, thus increased risk of secondary malignancies