Lecture 30: Cancer Chemotherapy Flashcards
What is cancer?
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)
What are the causes of cancer?
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)
What is the relationship between cancer and the cell cycle?
cancer is fundamentally a disease of cell growth regulation
cancer arises when genes that regulate cell growth are mutated
What is the cell cycle?
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
What is the G1 phase of the cell cycle?
checkpoint to ensure cell ready for DNA synthesis
What is the S phase of the cell cycle?
DNA synthesis
What is the G2 phase of the cell cycle?
checkpoint to ensure cell ready for mitosis
What is the M phase of the cell cycle?
mitotic phase (cell divides into two daughter cells)
What is the G0 phase of the cell cycle?
quiescent state
What are tumor suppressor genes?
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
What are proto-oncogenes?
are normal genes involved in cell growth and proliferation or inhibition of apoptosis
mutations can increase expression and proliferation (oncogene)
What are point mutations?
small scale deletions or insertions which affect its expression
What is chromosomal translocation?
when two separate chromosomal regions become abnormally fused
What is the Philadelphia chromosome?
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
What is relationship between oncogenes and cancer?
usually multiple oncogenes and mutated tumor suppressor genes will all act in concert to cause cancer
What is cancer therapy?
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)
What are anti-cancer drugs?
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)
Why are the best anti-cancer drugs those that target the S and M phase?
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
What are the four bases that form DNA?
four bases form DNA: two pyrimidine (thymine and cytosine) and two purines (guanine and adenine)
RNA incorporates uracil instead of thymine
What are pyrimidine analogues?
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
What are purine analogues?
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
What are alkylating agents?
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
What is the alkylating agent cisplatin?
platinum analogue
lead to inter-strand crosslinks leading to inhibition of DNA synthesis and function
What are anti-folates?
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
What is the anti-folate methotrexate?
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
What are natural products in cancer treatment?
compounds extracted from plants or bacteria with anti-cancer properties
include vinca alkaloids, taxanes, epipodophyllotoxins, camptothecins
What are vinca alkaloids?
derived from the periwinkle plant (Vinca rosea)
inhibit tubulin polymerization
disrupts the assembly of microtubules involved in mitotic spindle apparatus (M phase)
What are taxanes?
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
What are camptothecins?
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
What are antibiotics?
products of the soil microbe Streptomyces
bind DNA through intercalation, block DNA synthesis and cell replication
What are the four mechanisms of action of anthracyclines?
inhibit topoisomerases
generate free radicals (DNA mutagenesis)
high affinity binding to DNA
bind cellular membrane to alter fluidity and ion transport
What are tyrosine kinase inhibitors?
i.e. imantinib
inhibits the tyrosine kinase domain of the Bcr-Abl oncoprotein
treat leukemia
What are epidermal growth factor receptor (EGFR) inhibitors?
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
What are hormonal anti-cancer agents?
hormonal anti-cancer agents
i.e. tamoxifen
selective estrogen receptor antagonist
blocks binding of estrogen to estrogen sensitive cancer cells in breast tissue
What is primary resistance?
develops spontaneously in the absence of prior exposure to anti-cancer drugs (i.e. p53 mutations)
What is acquired resistance?
develops in response to a given anticancer agent
What are adverse effects of cancer treatment?
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
