14, 15 - Cancer Flashcards
Define cancer
Diseases in which abnormal cells divide w/o control and are able to invade other tissues
When are cancer cells formed?
When normal cells lose normal regulatory mechanisms that control growth, differentiation, and multiplication
What happens to cancer cells?
Lose the specialized characteristics that distinguish one type of cell from another (loss of differentiation)
What is a neoplasm?
New and diseases form of tissue growth
Which neoplasms are cancerous? Which aren’t?
- Benign neoplasms = not cancerous
- Malignant neoplasms = cancerous, can invade other parts of the body and give secondary tumours (metastasis)
How do carcinogenic chemicals cause cancer?
Induce gene mutations or interfere w/ normal cell differentiation
What can initiate carcinogenesis (birth of cancer)?
A chemical or other mutagen (ex: sunlight)
What is an example of a gene that can give rise to cancer?
BRCA1/ BRCA2 – tumour suppressor proteins, mutation causes protein to not function properly or not be made
What are proto-oncogenes?
Genes which code for proteins involved in the control of cell division and differentiation
What can happen if proto-oncogens mutate?
Can disrupt normal cell function and become cancerous; would now be called oncogenes
What does Ras gene code for? What happens if its mutated?
- Codes for Ras protein (cell division signaling) and is self-regulating
- If mutated, is continually active leading to continuous division
What are anti-oncogenes? What happens to them to cause cancer?
- Tumour suppressor genes
- Inactivation causes cancer
What cellular defects can be caused by genetic defects?
- Abnormal signalling pathways; insensitivity to signals
- Abnormalities in cell-cycle regulation
- Evasion of cell death (apoptosis)
- Limitless cell division
- New blood vessels; tissue invasion and metastasis
What are the 5 types of cancer? Which is most common?
1) Carcinoma - epithelial cells; most common
2) Sarcoma - connective tissue
3) Lymphoma and leukemia - hemopoietic cells, bone marrow-derived cells that normally mature in bloodstream (leukemia) or lymphatic system (lymphoma)
4) Germinoma - germ cells; testicle and ovarian cancers
5) Blastoma - resembles embryonic tissue; tumour of primitive, incompletely differentiated cells
What are the mechanisms of cancer cells?
- DNA synthesis or mitosis to produce new cells
- Cell differentiation to produce specialized cells
- Growth factors and cell surface receptors
- Growth inhibitors and cell surface receptors
- Cell cycle and regulation
What are the basis/causes of cancer?
Mutation, chemical, and/or viral
What are the 2 types of mutations in cancer?
1) Germ-line -> mutation present in germ cells, hereditary
2) Somatic -> non-inherited change in genetic structure
What is the multi-stage theory of cancer?
1) Initial mutations
2) Promotion phase (mutated cell proliferation)
3) Small benign tumour forms and develops (malignant phenotype)
4) Primary malignant tumour forms (progression)
5) Cells break off, lodge at remote sites and secondary tumours form (metastasis)
____ was identified as the cause of scrotal cancer
Benzoapyrene (component of soot)
What do oncogenic viruses do?
- Insert themselves into host genome
- DNA viruses produce proteins that interact w/ growth regulatory proteins or tumour suppressor genes and may lead to/promote cancer
- Viral genome may be near regulatory genes, producing mutations
- RNA viruses produce double stranded DNA provirus that is inserted into host genome usually near proto-oncogenes
How is cancer therapy decided?
Based on specific type, location, and stage of cancer
What are the fundamental techniques for cancer therapy? What is involved in each?
- Surgery -> cancer must be in primary tumour stage; must excise entire tumour
- Radiation therapy -> ionizing radiation used to shrink tissues by causing damage to DNA and apoptosis; requires tumour that is localized
- Immunologic therapy -> utilizes immune system to eradicate cancer, boosting levels of lymphocytes to destroy foreign cells, including premalignant and malignant cells
- Chemotherapy
What is chemotherapy used for?
- To reduce size of a tumour prior to surgery
- Sensitize tumours to radiation therapy or destroy microscopic tumours after surgery
What is chemotherapy used with? What types of tumours is it effective against?
- Used w/ surgery or radiation therapy
- Effective against metastasized tumours or residual tumours after therapy
What is the drawback to chemotherapy?
Lack of selectivity (effect both normal and malignant cells)
Which classes of drugs are alkylating agents?
- Nitrogen mustards
- Phosphamide mustards
- Nitrosureas
- Platins
Which classes of drugs are antimetabolite and nucleoside analogs?
DHFR and thymidylate synthase inhibitors
Which classes of drugs are antimitotic agents?
- Vinca alkaloids
- Taxanes
What are the various drug categories used for cancer therapy?
- Alkylating agents
- Antimetabolite and nucleoside analogs
- Antitumour antibiotics
- Antimitotic agents
- Miscellaneous antineoplastic
- Hormone therapy
- Combination therapies
What do alkylating agents do?
- React w/ DNA, preferentially alkylating in N-7 position of guanine
- May alkylate other sides on DNA bases
What do bifunctional alkylating agents do?
Produce inter and intra-strand crosslinks, preventing DNA separation (cytotoxic)
What do nitrogen mustards do? What cells are they most effective against? How are they generally administered?
- Nitrogen atom activates chloride by proceeding through aziridinium ion intermediate
- Most effective against rapidly proliferating cells
- Generally administered IV
Can cells repair DNA alkylation? If so, how?
- Yes
- Endonuclease cuts damaged strand
Which drugs are nitrogen mustards? Which can be given orally? Which is a pro-drug? Which has an active metabolite?
- Melphalan
- Cyclophosphamide *pro-drug, available orally
- Ifosphamide
- Chlorambucil *active metabolite (phenylacetic acid)
- Estramustine phosphate *given orally
How is melphalan transported into cells?
L-amino acid transporter
Which nitrogen mustard is less likely to form aziridinium ion? Is this beneficial?
- Cyclophosphamide
- Makes it more stable
What is a structural characteristic of nitrogen mustards?
Nitrogen atom w/ 2 chloroethyl arms (may or may not be both attached to nitrogen; only 1 attached for ifosfamide)
What is special about chlorambucil?
Nitrogen is attached to phenyl group, reducing reactivity and basicity
What is special about busulfan?
Has methane sulfonic acid leaving groups, producing mono or di-alkylation of DNA nucleophiles
Which drugs are considered “other alkylating”?
- Busulfan
- Thiotepa
- Procarbazine
- Dacarbazine
What is special about thiotepa?
- Has aziridine-containing three-membered rings where nucleophiles react, relieiving ring strain
- At physiologic pH, aziridine major form is the less reactive free base, and protonation activates aziridinium ion
What is special about procarbazine?
- Alkylation occurs via free radical intermediates instead of electrophile/nucleophile mechanisms (can occur using substituted hydrazines in presence of O2)
- Produces methyl radical which alkylate DNA on C-8 position of guanine
What is the mechanism of dacarbazine?
- Not fully understood
- Appears to be metabolically bioactivated through CYP450 enzymes via initial demethylation to MTIC
- Followed by formation of diazomethane which alkylates N-7 position of guanine
How are nitrosureas activated?
- In water, urea NH is deprotonated
- Negatively charged oxygen displcaes chloride to give cyclic oxazolidine
- This fragments to give 2-chloroethylisocyanate and vinyl diazohydroxide, which decomposes to give electrophilic vinyl cation
Which drugs are nitrosureas? What is special about each compound w/ respect to dosage form?
- Carmustine (more efficiently crosses BBB in comparison to other alkylating agents; IV use)
- Lomustine (more stable in air, used in capsules)
- Streptozocin (sugar group imparts good water solubility)
Which drugs are platins? Which is more potent?
- Cisplatin (more potent)
- Carboplatin
What is the MOA of cisplatin?
- Like other alkylating agents, alkylates N-7 position of guanine forming intra-strand cross-links
- Needs cis configuration to induce intra-strand cross-links
What do intra-strand crosslinks lead to?
- Replication and transcription inhibition
- Cell-cycle arrest and cell death
What are the 2 functions of DNA?
1) Act as a template for DNA self-replication
2) Act as a template for production of messenger-RNA
What are antimetabolites?
- Compounds closely relate to cellular precursor molecules that are capable of preventing proper use or formation of normal cellular products
- Similar enough to interact or be involved in cellular process, but different enough to alter outcome of the pathway
Most antimetabolites are involved in the ______
Biosynthesis of nucleic acids
What are useful targets of antimetabolites?
Purines, pyrimidines, and folates
What is the modification in pyrimidine-based antimetabolites? What are the possible MOAs?
- Modification may be on pyrimidine ring or on pendant sugar group
- MOA = inhibition of kinases; inhibition of enzymes involved in pyrimidine biosynthesis; incorporation into RNA or DNA, causing misreading; or inhibition of DNA polymerase
What is vitamin B9?
Folic acid and folate
What is the difference between folate and folic acid?
- Folate is naturally occurring of vitamin B9 found in food; polyglutamate
- Folic acid is synthetically produced in fortified foods; not biologically active, its derivatives tetrahydrofolate and dihydrofolic acid are; has 1 glutamate group (monoglutamate)
What is folate used for in the body?
To synthesize DNA, repair DNA, methylate DNA, as well as a cofactor
What is the function of thymidylate synthase?
Adds methyl group to dUMP to make dTMP
What is dihydrofolate reductase?
- Enzyme that maintains levels of tetrahydrofolate, allowing dTMP to be produced and be used in DNA synthesis
- Catalyzes reduction of folic acid to FH4 (tetrahydrofolate) via FH2 (dihydrofolate), which is followed by addition of single carbon unit to form N5-N10-methylene-FH4, which is used as one-carbon source for conversion of dUMP to dTMP by thymidylate synthase
What do dihydrofolate reductase inhibitors cause? Which drug is an example of this?
- Decreased levels of folate cofactors, lowering synthesis of dTMP, slowing DNA synthesis and cell division
- Methotrexate
Why is methotrexate effective?
Has additional H-bond doner, producing a stronger binding affinity to DHFR enzyme than FH2, preventing its binding and conversion to N5-N10-methylene-FH4
How can methotrexate resistance occur?
- Enhanced expression of DHFR
- Diminished uptake by reduced folate carrier
What is leucovorin and when and why is it used?
- Folinic acid
- Used w/ methotrexate to “rescue” bone marrow and GI mucosa cells from methotrexate
What is methotrexate used for besides cancer?
- Severe rheumatoid arthritis
- Severe psoriasis
- *Used at much lower doses to reduce toxicity
What is the MOA of pralatrexate?
Selectively enters cells expressing reduced folate carrier type 1 (RFC-1), a protein that is overexpressed in certain cancer cells, to ensure enough folate
What is the MOA of pemetrexed?
- Inhibits 3 enzymes – thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase
- By inhibiting formation of precursor pyrimidine and purine nucleotides, prevents formation of DNA and RNA
What should be given w/ pemetrexed and why?
- Folic acid and vitamin B12
- Prevent bone marrow toxicity
What does 5-fluorouracil do? What is the MOA?
- Pro-drug that directly inhibits thymidylate synthase
- 5-fluorouracil catalyzed to fluorodeoxyuridine (by thymidine phosphorylase) which is then phosphorylated to FdUMP, which covalently reacts w/ thymidylate synthase
How is 5-fluorouracil metabolized? Are any of the metabolites active?
- Metabolized into 3 active metabolites
1) Fluorodeoxyuridine monophosphate (FdUMP)
2) Fluorodeoxyuridine triphosphate (FdUTP)
3) Fluorouridine triphosphate (FUTP)
How is 5-FU converted to fluorouridine monophosphate (FUMP)?
- Either directly by orotate phosphoribosyltransferase (OPRT) w/ phosphoribosyl pyrophosphate (PRPP) as the cofactor
- Or indirectly via fluorouridine (FUR) through sequential action of uridine phosphorylase and uridine kinase
What happens to FUMP?
- Phosphorylated to fluorouridine disphosphate (FUDP)
- FUDP can either be further phosphorylated to active metabolite fluorouridine triphosphate (FUTP) or converted to fluorodeoxyuridine disphosphate (FdUDP) by ribonucleotide reductase (RR)
- FdUDP can either be phosphorylated or dephosphorylated to generate active metabolites FdUTP or FdUMP
What is a second way of producing FdUMP?
- Conversion of 5-FU to fluorodeoxyuridine (FUDR) by thymidine phosphorylase
- FUDR then phosphorylated by thymidine kinase to FdUMP
What is the rate limiting step of 5-FU catabolism in normal and tumour cells?
Dihydropyrimidine dehydrogenase (DPD)-mediated conversion of 5-FU to dihydrofluorouracil
Who are at risk of toxicity of 5-FU?
Those who are genetically deficient in DPD b/c DPD breaks down 80% of 5-FU
What is the detailed MOA of 5-FU?
- 5-FU metabolized into active metabolite FdUMP
- FdUMP binds to nucleotide-binding site of thymidylate synthase (TS), forming a stable ternary complex w/ TS and N5,N10-methylene-FH4, blocking access of dUMP to binding site and inhibiting dTMP synthesis
- Increased levels of dUTP and imbalances in dNTP pool cause DNA damage
What determines the extent of DNA damage from 5-FU?
Levels of pyrophosphatase dUTPase and uracil-DNA glycosylase
What allows 5-FU to remain covalently and irreversibly bound to the active site of thymidylate synthase?
Fluorine atom in the position of the hydrogen atom that is normally eliminated
What is the effect of cytarabine?
- Active triphosphate inhibits production of 2’-deoxycytidylic acid and DNA-dependent DNA polymerase
- Causes miscoding after incorporation into DNA or RNA
What is the effect of gemcitabine?
- First phosphorylated into active triphosphate, which is then incorporated into DNA or RNA leading to cell death
- Also inhibits DNA and RNA synthesis
What is the effect of 6-mercaptopurine?
- Converted to 6-thioinosinate and is an inhibitor of production of 5-phosphoribosylamine from 5-phosphoribosyl pyrophosphate (PRPP) in purine biosynthesis
- 6-thioinosinate also inhibits conversion of inosinic acid (IMP) to adenylic acid, and oxidation of IMP to xanthylic acid
