ANTICANCER DRUGS I Flashcards
Cancer Statistics:
1) What is the leading cause of death in Canada
2) What are the projected new cancer cases in males and females in canada
3) What are the projected new cancer deaths in males and females in canada
4) What is the most and least “survivable” cancer
1) Cancer
2)
o Male
♣ Prostate
♣ Lung
♣ Colorectal
o Female
♣ Breast
♣ Lung
♣ Colorectal
3) In both males and females, the leading cause of death by cancer is lung cancer
4) Prostate + breast cancer
♣ Survival over 10 years is reasonable
o Lung + pancreas cancer
♣ Survival over 5-10 years is low
Development of Cancer: Sequence
1) what are the 4 steps of cancer development
2) explain what would happen if the steps (a) and (b) didn’t occur
3) what are the 2 types of routes step (d) can take
4) How does cancer become malignant
1)
a) DNA sequence mutation
b) No DNA repair, mutant cell survives
c) Suicide program fails or cell is protected –> more mutations occur
d) uncontrolled/dysregulation of cell proliferation
2)
a) DNA repair –> normal cell
b) apoptosis –> cell elimination
3)
- No tendency to spread benign tumor
- Spreading malignancy spreading malignancy and invasion of other tissues
4)
- CELL DIFFERENTIATION IS LOST
- ACQUIRE INVASIVE PROPERTIES ALLOWING
1. Violation of the basement membrane of the tissue of origin
2. Entrance into the blood or lymphatic system
3. Eventual dissemination to distant organs in a process called metastasis
Chicken Cancer:
1) Where were oncogenetic viruses first found
2) what did the filterable agent found from hen sarcomas do
3) What was this agent
4) what does this agent do
1) hens
2) was able to transmit cancer to other chickens
3) rous sarcoma virus
4) the virus encodes for oncogenes that dysregulate cell proliferation in the host
♣ Oncogene –> cancer causing gene
Oncogenes of Viral Origin
1) whats an example of a virus that encodes oncogenes into the human genome
2) What are the 2 oncogenes and what do they do
3) What cancer does HPV cause
4) How are we protected against HPV
a) when is the treatment administered
1) HPV
2)
o E7
♣ Inhibits pRB (retinoblastoma protein)
* pRB is a tumor suppressor
♣ Resulting in deregulation of cellular proliferation
* This likely would lead to apoptosis without encoding E6 as well
o E6
♣ Degrades p53
* p53 is a tumor suppressor
♣ p53 blocks apoptosis resulting in outgrowth of deregulates cells
3)
o Vulva
o Vagina
o Penis
o Anus
4) Need to be vaccinated against HPV to remain safe
o Blocks viral infection
o Less cells are exposed to the encoding of the oncogenes E7 + E6
o Virus integrates into genome OR expresses the proteins
4) a) Usually need to vaccinate the population before they are sexually active
♣ Recommend people who are old and sexually active to also get vaccinates
♣ There exist multiple strains of HPV so need to protect by getting >1 dose
Proto-oncogenes and Oncogenes:
1) Are oncogenes only from viral origins?
2) if not then what would these oncogenes be called before becoming oncogenes?
3) What causes them? (5)
1) Oncogenes are not only from viral origins
2) Proto-oncogenes –> genes with potential to cause cancer but normally do not
3) caused due to carcinogens, mutagens, irradiation, viruses or just be genetic predisposition
Proto-oncogene –> oncogene
Proto-oncogenes and Oncogenes:
1) how does exposure convert proto-oncogenes to oncogenes (4 mechanisms)
1) Nucleotide substitution
* Leads to activation of gene that is normally regulated/activated by PTM
*In case of oncogene, it is active all the time
2) Gene fusion
* Alters normal activation/inactivation of the gene
* Fusion oncogene is active all the time
3) Enhancer hijacking
* Develops a more active gene due to the addition of an enhancer upstream of the gene
4) Focal amplification
* Encodes more than one oncogene amplifies signal
Major Approaches to Therapy of Cancer:
1) What is the 3 major utilized approaches to cancer therapy and what is their collective objective
2) what are another 5 approaches to cancer therapy
1) Destroy neoplastic cells
o Radiation
o Drugs (chemotherapy)
o Host immune defenses
2)
1. Removal of mass via surgery
o Followed by chemotherapy to maintain remission
- Prevent metastasis
o By blocking metastatic mechanisms - Convert tumor cells normal cells
o Reverse programming of the cell to revert it back to normal cells - Halt neoplastic cell division
- Block angiogenesis
o Angiogenesis = formation of new blood vessels around the tumor as the tumor grows
o By cutting off blood supply to the tumor blocking the growth of larger tumors
Tumor Growth + Detection
1) how long does it take to reach a tumor size that can be detected and diagnosable
2) The speed at which cancer cells divide depends on what and give examples of 2
3) At what tumor weight is it definitely interfering in other organ systems
1) It takes ~30 doubling events for the tumor to reach 10^9 cells
o This is equal to a tumor mass with
* 1cm diameter
* 1g of mass
2) The speed at which cancer cells divide depends on the type of cancer
o Quick –> lymphocytic leukemia (bone marrow produces too many WBC)
o Slow –> other squamous cell carcinomas (skin cancer)
3) 1kg
Drug Regimens:
1) what are the 5 different drug regimens used in the treatment of cancer
1)
- Use drugs that have different mechanisms of resistance
o So cancer cells don’t become resistant
- Use drugs that have minimal or no overlapping toxicities/side effects
o Reduces the possibility of life threatening side effects
- Use drugs that have different mechanisms of action
- Use drugs that affect tumor cells in different parts of the cell cycle
- “Synthetic Lethal” combination of drugs to lead to selective tumor cell death and limit damage to healthy tissues
Synthetic Lethality:
1) What is synthetic lethality
2) What is this drug regimen based on
3) Based on what the drug regimen is based on, how should it differentially target tumor cells vs healthy cells
4) therefore, what needs to be found in advance to using synthetic lethality combination of drugs
1) Combination of medicine for hard to treat cancers
2) Based on the interdependency between 2 cancer genes
o Where the mutation of 1 gene is more likely to allow for cell survival
o But the mutation of both genes will cause cancer cell death
3) In healthy cell:
o Loss of gene A or gene B alone does not affect cell survival
- In tumor cells:
o A mutation in gene A or B leaves the cell vulnerable to disruption of the other gene that it is dependent on for survival
4) Therefore, need to find genes that when mutated (along with the gene mutation that causes cancer) will only kill cancer cells and leave healthy cells
Cytotoxic Agents:
1) What types of cells are anti-neoplastic agents more effective at targeting?
2) What normal cells rapidly divide and why is this a concern in treating cancer with cytotoxic agents
3) what type of cancer is most responsive to cytotoxic treatment
1) More effective in killing cells progressing through the cell cycle
o Cells are dormant in the G0 phase
2) Especially cells in hair follicles, bone marrow, intestinal epithelium
o These rapidly dividing cells are particularly sensitive to antineoplastic drugs
* These cells contribute to the dose limiting adverse side effects
* i.e. alopecia, weak bones, abdominal pain
3) Faster-growing leukemia + lymphomas are generally more responsive to treatment than slower-growing carcinomas and sarcomas
Antimetabolites:
1) what do antimetabolites mimic
2) what do antimetabolites inhibit (3)
3) give 4 examples of antimetabolites
1) Antimetabolites mimic the structures of normal components required for DNA or RNA synthesis
o Such as substrates
2) They inhibit the enzymes necessary for:
o Folic acid regeneration
o Pyrimidine/purine synthesis
o DNA/RNA synthesis
3)
- Methotrexate
- 5-FU
- Cytarabine
- Gemcitabine
Methotrexate:
1) what enzyme does methotrexate inhibit
2) What reaction does this then inhibit from occuring
1) Inhibits DHFR
2) Inhibits conversion of DHF –> THF
* No THF production needed for the conversion of dUMP –> dTMP
5-FU:
1) what enzyme does 5-FU inhibit
2) What reaction does this then inhibit from occurring
3) What is the mechanism of action of 5-FU (also what if 5-FU dependent on and why)
4) What does 5-FU action result in (2)?
5) What is the amount of dUTP correlated to?
6) 3 mechanisms of resistance
1) Inhibits thymidylate synthase
2) Inhibits the conversion of dUMP –> dTMP
* 5-FU turns into the active metabolite FdUMP by enzymes
3) FdUMP binds to the nucleotide-binding sites of thymidylate synthase and forms a stable complex
* The action of FdUMP is dependent on Leucovorin as the methyl donor to form the stable complex
* This blocks access of dUMP to the nucleotide binding site and inhibits dTMP synthesis
4) Resulting in DNA damaging outcomes:
1. dNTP pool imbalances
2. High levels of dUTP
5) amount of dUTP correlated to amount of damage
6) RESISTANCE:
1. Thymidine kinase salvages dTMP
2. dUTPase reduces dUTP by hydrolysis
3. resistance in enzymes that convert prodrug to active drug
Cytarabine:
1) What is Cytarabine and what does it need to function
2) What is cytarabine’s mechanism of action
3) Cytarabines structure have an OH group so how does it prevent elongation?
4) 2 mechanisms of resistance
1) Cytarabine is a prodrug that Needs to be phosphorylated to triphosphate
* By deoxycytidine kinase
2) Incorporated into DNA and terminates elongation
3) Does so due to its unnatural conformation which makes it act not ideal for elongation
* Instead it acts as a competitive inhibitor of DNA polymerase
4)
1. Converted into Ara-U by cytidine deaminase into its inactive form
2. resistance in kinase that converts prodrug to active drug
