DIT review - Oncology 1 Flashcards
1
Q
Describe the role of Cyclin D in cell replication
A
o Cyclin D activates CDK4 (kinase complex)
o This kinase complex will phosphorylate Rb protein
o Phosphorylated Rb becomes unbound from transcription factor E2F, allowing cell to progress from G1 to S phase
2
Q
What is the most common oncogene?
A
RAS
3
Q
What cancers are associated with RAS mutation?
A
Pancreatic adenocarcinoma
Cholangiocarcinoma
4
Q
What is the most common tumor suppressor mutation?
A
p53 mutation
5
Q
Is RB a tumor suppressor or an oncogene, and what tumors is it associated with>
A
- Tumor suppressor
- Blocks transition from G1 to S phase and G2 to M phase
- Causes apoptosis by inducing the transcription of pro-apoptotic genes (such as BAX)
- Associated with:
- Retinoblastoma
- Osteosarcoma
6
Q
What is the oncogene and tumor suppressor associated with breast cancer
A
Oncogene = Her2
Tumor suppressor = BRCA1/2
7
Q
What cancer is associated with c-MYC mutation
A
Burkitt lymphoma
8
Q
What cancer is associated wth BCR-ABL mutation?
A
- BCR-ABL
- Oncogene
- t(9;22) – Philadelphia chromosome
- Associated with
- Chronic myelogenous leukemia (CML)
9
Q
What tumor will be CEA+
A
Colon cancer
Pancreatic cancer
10
Q
What cancer will be CA 19-9+
A
Pancreatic cancer
11
Q
What cancer will be alpha-fetoproteion (AFP)+
A
Hepatocellular carcinoma
12
Q
What cancer will be CA-125+
A
Ovarian cancer
13
Q
What cancer will be S-100+
A
S-100 = marker of neural crest
Melanoma
Schwannoma
14
Q
What cancer will be alkaline phosphatase +
A
Metastasis to bone
Biliary disease
Paget disease of the bone
15
Q
In what diseases will you see Psammoma bodies?
A
Papillary thyroid carcinoma
Serous cystadenocarcinoma of the ovary
Mesothelioma
Meningioma
16
Q
What tumors secrete erythropoietin
A
- Potentially Really High Hematocrit
- Pheochromocytoma
- Renal cell carcinoma
- Hepatocellular carcinoma
- Hemangioblastoma
17
Q
Describe the synthesis of the pyrimidine, thymidine
A
- Glutamine + CO2 + ATP converted to carbamoyl phosphate via carbamoly phosphate synthetase II
- Carbomoyl phosphate converted to orotic acid
- Orotic acid converted to UMP via UMP synthase
- UMP to UDP
- UDP to dUDP via ribonucleotide reductase
- dUDP to dUMP
- dUMP methylated to dTMP via thymidilate synthase
- THF is what provides the carbon needed for methylation (THF to DHF)
- Thymidylate synthase catalyzes the transfer of methyl group
- DHF gets converted back to THF via dihydrofolate reductase
- THF is then re-methylated to continue the cycle
18
Q
MOA of Methotrexate
A
- Folate analog that competitively and irreversibly binds to dihydrofolate reductase, preventing convserion of DHF into THF
- Inhibition of DHF reductase leads to a build-up of DHF
- This means you have no THF to create dTMP
- Interferes with the synthesis of DNA, RNA, and other rapidly dividing cells
- Rapidly dividing cells are the ones that are preferentially targeted
- Most effective during S phase (when cells are undergoing synthesis of new DNA)
19
Q
Uses of Methotrexate
A
- Multiple malignancies
- E.g. leukemias, lymphomas, breast cancer, head and neck cancer, lung cancer
- Other diseases characterized by abnormal cellular proliferation:
- Abortifacient (MTX + Misoprostol)
- Inhibits trophoblast cellular division, hindering implantation and encouraging expulsion
- Early, unruptured ectopic pregnancy
- Molar pregnancy trophoblastic tumors, choriocarcinoma
- Psoriasis (hyperproliferation of epidermis)
- Abortifacient (MTX + Misoprostol)
- Chronic inflammatory conditions (can inhibit proliferation of immune cells)
- Rheumatoid arthritis (disease modifying antirheumatic drug – DMARD)
- Immunosuppressive thereapy (e.g. IBD, lupus, vasulitits, dermatomyocytis)
20
Q
Adverse effects of Methotrexate
A
- Folate deficiency
- Megaloblastic anemia
- Myelosuppression and Pancytopenia
- Increased risk of infection due to immunosuppression
- Pulmonary fibrosis (restrictive lung disease)
- Hepatotoxicity (should monitor LFTs)
- Alopecia
- Mucositis
21
Q
How do you reverse the toxicity of Methotrexate
A
-
Leucovorin (folinic acid – reduced form of folate)
- Sketchy = lucky feline (cat statue)
- Can be used to reverse the toxicity effects of MTX (“leucovorin rescue”)
- Folinic acid does not require DHF reductase
22
Q
MOA of 5-Fluorouracil (5-FU)
A
- 5-FU is a cytotoxic pyrimidine analog
- 5-FU is metabolized by intracellular reaction to it’s active form FDuMP
- FDUMP forms a complex with THF and inhibits thymidylate synthase (conversion of dUMP to dTMP using carbon from THF)
- Inhibition of thymidylate synthase by 5-FU will lead to a build-up of dUMP
23
Q
Adverse effects of 5-FU
A
- Diarrhea (cytotoxic damage to rapidly dividing cells of intestinal mucosa)
- Photosensitivity
- Myelosuppression and Pancytopenia
- Increased risk of infection due to immunosuppression
24
Q
MOA of hydroxyurea
A
- Recall:
- The precursor of all pyramidine nucelotides is UMP, which is then phosphorylated to UDP
- Ribonucleotide reductase will convert UDP to dUDP
- dUDP can then be de-phosphorylated into dUMP
- Hydroxyurea works by inhibiting ribonucleotide reductase so that UDP cannot be converted to dUDP, thus blocking the de novo synthesis of thymidine
25
MOA of Azathioprine
* Is a prodrug of the cytotoxic purine analog 6-mercaptopurine (6-MP)
* AZA must be activated to 6-MP via hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
* AZA/6-MP act by blocking the synthesis of IMP = decreased de novo purine nucleotide synthesis = blocked DNA and RNA synthesis
* Decreased GMP = decreased B- and T-cell proliferation + decreased antibodies
26
MOA of Mycophenolate Mofetil
* Is an IMP dehydrogenase inhibitor, preventing conversion of IMP to GMP
* Activated lymphocytes are dependent on de novo synthesis of purine nucleotides
27
MOA of Cladribine
* Sketchy:
* caveman clad in bear skin
* Cytotoxic _purine_ analog (--\> purine stone hammer)
* Is resistant to adenosine deaminase, enzyme that normally degrades purine analogs
* Can incorporate into DNA causing
* DNA breaks
* Inhibition of DNA synthesis and repair by inhibiting DNA polymerase alpha and beta
28
Uses of Cladribine
Hairy cell leukemia
Other leukemias and lymphomas
29
MOA of Cytarabine
* Sketchy = saber toothed tiger
* Cytotoxic _pyrimidine_ analog (hexagon spots on tiger)
* Inhibits DNA pol alpha and beta
30
Uses of Cytarabine
Only useful against hematologic malignancies (not solid tumors)
31
MOA of Gemcitibine
* Sketchy = geods with gems inside
* Mechanism of action
* Cytotoxic pyrimidine analog
* After being converted to triphosphate form, it inhibits DNA pol alpha and beta, blocking DNA synthesis and repair
32
Uses of Gemcitibine
* Active against both hematologic malignancies AND solid tumors
33
Adverse effects of all drugs that block DNA polymerase (Cladribine, Gemcitibine, Cytarabine)
Myelosuppression
Increased risk of infection
34
What are the alkylating agent anti-neoplastics?
Cyclophosphamide - cyclops
Busulfan - beautiful sirens
Nitrosoureas - centaurs ("-mustine" - mustang)
35
MOA of Cyclophosphamide
* Mechanism of action:
* Works by attaching an alkyl group to the guanine base of DNA at the #7 nitrogen atom
* This leads to intra- and inter-strand cross-links
* Cell division halts and the cell undergoes apoptosis
* This is cell cycle NON-specific
36
Uses of Cyclophosphamide
* Hematologic and solid malignancies (e.g. leukemias and lymphomas, breast cancer, ovarian cancer
* Immunosuppressive (e.g. nephrotic syndrome, nephritic syndrome, vasculitis, autoimmune hemolytic anemia)
37
Adverse effects of cyclophosphamide
* Myelosuppression (leading to cytopenias)
* Hemorrhagic cystitis
* Cyclophosphamide is metabolized by the kidney into a molecule that is toxic to uroepithelial cells if in contact with the cells for too long
* Increased risk for bladder cancer (high grade transitional cell carcinoma)
* Hyponatremia due to SIADH
* Toxic to ovaries and testes
* Can cause infertility and premature menopause
* Can cause decrease in sperm count and irreversible azoospermia
38
How do you prevent hemorrhagic cystitis from use of Cyclophosphamide
* Prevent with aggressive hydration and co-administration with **_2-mercaptoethanesulfonate (MESNA)_**, which will bind and inactivate the toxic metabolite
* Cyclophosphamide is metabolized by the kidney into a molecule that is toxic to uroepithelial cells if in contact with the cells for too long
39
40
MOA of Busulfan
* Sketchy = beautiful sirens
* Alkylating agent that forms DNA intra-strand cross-links, preventing DNA replication and leading to apoptosis
41
Uses of Busulfan
* Used as a conditioning agent prior to bone marrow transplant – aka significantly depletes the bone marrow
42
Adverse effects of Busulfan
* Lung toxicity (e.g. acute lung injury, interstitial fibrosis, alveolar hemorrhage)
* Skin darkening (“busulfan tan”)
43
Names of nitrosourea drugs
Sketchy = centaurs
* Drugs:
* “-**_mustine**_” suffix (e.g. _**Carmustine, Lomustine_**)
* - centaur is a mustang horse
* **_Streptozotocin_**
* - striped zebra centaur
44
MOA of nitrosoureas
* Alkylating agents that form DNA cross links, preventing DNA replication and leading to apoptosis
45
Uses of nitrosoureas
* Brain tumors (e.g. glioblastoma multiforme)
* Are highly lipophilic so can cross the BBB
46
Adverse effects of nitrosoureas
* Neurotoxicity (e.g. convulsions, dizziness, atazia)
