EXAM #2: ANTINEOPLASTIC AGENTS Flashcards
What are the three major cell cycle checkpoints?
G1/S
G2/M
Metaphase/Anaphase
What are the specific criteria necessary to proceed through the G1/S checkpoint?
1) Cell nutrition, size, and environment must be favorable for replication
2) DNA must be intact
This check ensures the cell is prepared for DNA replication and to enter S-phase.
What are the specific criteria necessary to proceed through the G2/M checkpoint?
DNA must be completely replicated
This is the checkpoint that ensures the cell is ready to enter mitosis.
What are the specific criteria necessary to proceed through the metaphase/anaphase checkpoint?
1) DNA intact must be intact
2) Chromosomes must be attached to the mitotic spindle
This check ensure that the cell is ready for chromatid separation and is prepared for cytokinesis.
What are the three mechanisms of oncogene formation?
First, an oncogene is a mutated form of a normal gene that supported cellular proliferation i.e. “proto-oncogenes”
1) Point mutations
2) Chromosomal translocation
3) Proto-oncogene duplication/ amplification
How can point mutations lead to the development of an oncogene?
- Change in an amino acid regulatory region in the proto-oncogene product
- Amino acid change that makes the proto-oncogene resistant to degradation
How do chromosomal translocations result in oncogenes? Give an example.
Chromosomal translocation that causes the fusion of two genes, the product of which is the “fusion gene”
E.g. “Philadelphia” chromosome (9 x 22) ABL and BCR in CML
What is a major oncogene that is found in roughly 30% of all cancers?
Ras
Ras in involved in cell signaling/ GPCR signaling; mutations leave Ras permanently turned on.
Define first order killing of cancer cells i.e. what is the cell kill hypothesis?
This is the chemotheraputic elimination of a FIXED percentage of cancer cells.
This is first order kinetics*
What are the four goals of cancer drug therapy?
1) Curative intent
2) Adjuvant therapy
3) Neoadjuvant therapy
4) Palliation
List the general characteristics of chemotheraputic drug therapy.
- Drugs are cytotoxic and only PARTIALLY selective
- Low TI
Thus, adverse effects are common.
What are the general mechanisms of resistance to chemotherapeutic agents?
1) Genetic instability
2) Drug efflux pumps/ mutated drug transporters
3) DNA damage repair
4) Cell death inhibition
5) Drug inactivation
- Up-regulation of enzymes that metabolize drugs
6) Drug target alteration
7) Epithelial-Mesenchymal Transition
What types of tumors are easiest to treat with chemotherapy?
Tumors that are RAPIDLY growing
Define curative intent.
Drug therapy is intended to CURE the disease
Define adjuvant therapy.
- Drug given AFTER primary treatment e.g. surgery
- Prevent recurrence
Define neoadjuvant therapy.
Drug given FIRST to SHRINK tumor, making it amenable to surgery
Define palliative therapy.
Therapy intended to relieve symptoms and improve quality of life.
Do most cancers follow the cell-kill hypothesis? Why or why not?
NO
B/c of the cytotoxicity of chemotherapeutic, it is not possible to dose patients in a manner necessary to achieve 1st order kill.
What is a drug efflux pump?
A cellular transporter than “pumps” drugs out
E.g. MDR-2
What is Epithelial- Mesenchymal Transition (EMT)?
- Cell loses adhesive properties and becomes motile
- Changes can also cause drug resistance
What are the three general cytotoxic mechanisms to kill cancer cells?
1) Perturb normal DNA replication
2) Perturb mitosis
3) Starve cells of amino acids
What are the three targeted mechanisms to kill cancer cells?
1) Perturb hormone and growth factor signaling
2) Inhibit blood supply to tumor e.g. VEGF
3) Target activating proteins
What are cell-cycle non-specific drugs?
DNA alkylating agents that kill cells in ANY stage
Preferentially kill replicating cells
What are the S-phase specific drugs?
DNA synthesis inhibitors
What is the mechanism of action of the “antimetabolites?”
Inhibiting de novo nucleotide biosynthesis and generally target cells in S-phase
What is the function of ribonucleotide reductase?
Turning ribonucleotides into deoxyribnucleotides
What is the mechanism of action of methotrexate?
- Anti-metabolite that targets s-phase
- Inhibition of dihydrofolate reductase i.e. the enyzme that makes THF from dihydrofolate
- THF is crucial in the action of thymidylate synthetase (dUMP–>dTMP), which is required for DNA synthesis
Essentially, inhibiting DNA synthesis by preventing the action of folate
Why can extremely high does of Methotrexate be administered to pateints?
Leucovorin rescue (folinic acid)
Leucovorin is a reduced form of folic acid. Administration within the proper window can allow for nearly fatal doses of methotrexate do be administered (hopefully targeting cancerous/ rapidly dividing cell), followed by Leucovorin rescue to prevent harmful toxic effects of such a high dose to normal tissue.
What are the mechanisms of Methotrexate resistance?
1) Impaired transport
2) Altered DHFR (isozyme) that decrease the affinity of methotrexate’s target
3) Elevated DHFR expression
DHFR= dihydrofolate reductase
What are the unique toxicities seen with Methotrexate?
- Interstitial pneumonitis
- Nephrotoxicity
What is the mechanism of action of 5-fluorouracil?
- Pyrimidine analog
- Anti-metabolite that targets s-phase
- 5-FU is metabolized:
1) 5dUMP, which INHIBITS THYMIDYLATE SYNTHASE and prevents DNA synthesis
2) FUTP that is falsely incorporated into RNA
3) FdUTP that is falsely incorporated into DNA
False incorporation causes defects in RNA/DNA function and sturucture leading to cell death.*
What are the unique adverse effects seen with 5-FU administration?
Oral and GI ulcers
What is Capecitabine?
- Antimetabolite
- Targets S-phase
This Prodrug of 5-FU that can be given orally; same mechanism of action as 5-FU (inhibition of thymidylate synthase etc.
What is Cytarabine used to treat?
This is the most important antimetabolite for AML
It is only used to treat HEMATOLOGIC MALIGNANCIES*
What is the mechanism of action of Cytarabine?
- Pyrimidine analog/ anti-metabolite
- Targets cells in S-phase
1) Cytarabine or Ara-C is transported into the cell and converted to Ara-CMP by DEOXYCYTIDINE KINASE
2) Ara-CMP is converted to Ara-dCTP
3) Ara-dCTP is incorporated into DNA and inhibits DNA synthesis
What is the specific toxicity that is associated with Cytarabine?
Cerebellar Syndrome
*****Note that inactivation of Ara-C required CYTIDINE DEAMINASE; there are low levels of this enzyme in the brain, making brain more susceptible to adverse effects of drug.
What are the symptoms of Cerebellar Syndrome?
1) Dysarthria
2) Nystagumus
3) Ataxia
What are the major mechanisms of cytarabine resistance?
1) Loss of DEOXYCYTIDINE KINASE
2) Inability of tumor cells to transport Ara-C into cells
3) Cytidine demainase upregulation
What is the mechanism of action of Gemcitabine?
- Pyrimidine analog/ anti-metabolite that targets S-phase
1) Converted to active form by DEOXYCYTIDINE KINASE, like Cytarabine
1) Incorporated into DNA–inhibits DNA synthesis
3) Inhibits RIBONUCLEOTIDE REDUCTASE, which also inhibits DNA synthesis
What are the mechanisms of Gemcitabine resistance?
1) Reduced activity of DEOXYCYTIDINE KINASE
2) Increased production of deoxycytidine b/c of inhibitive effect on deoxycytidine kinase
What is the mechanism of action of 6-MP and 6-TG?
- Purine analogs/ antimetabolites that inhibit s-phase of the cell cycle
1) Activated by HGPRT into thio-IMP and thio-GMP respectively
2) thio-IMP converted into thio-GMP
3) thio-GMP blocks BOTH SALVAGE and DE NOVO purine synthesis i.e. inhibits DNA replication
What is the common mechanism of resistance in 6-MP and 6-TG?
Decreased HGPRT activity
What enzymes inactivates 6-MP? Why is this important?
Thiopurine methyltransferase (TPMT)
Polymorphism causes reduced TPMT activity that can lead to life-threatening toxicity and need for lower doses
What is the mechanism of action of Fludarabine?
- Purine analog/ antimetabolite that targets cells in s-phase
1) Activated by DEOXYCYTIDINE KINASE and incorporated into DNA and RNA
2) Inhibits RIBONUCLEOTIDE REDUCTASE and DNA POLYMERASE
3 Inhibits RNA function and mRNA translation
What is the common mechanism of Fludarabine resistance?
Decreased of DEOXYCYTIDINE KINASE
What is the mechanism of action of Cladribine?
- Purine analog/ antimetabolite that targets cells in s-phase
1) Activated by DEOXYCYTIDINE KINASE and incorporated into DNA
2) Causes DNA strand breaks
3) Inhibitor of RIBONUCLEOTIDE REDUCTASE
List the alkylating agents.
Nitrogen mustards
- Mechlorethamine
- Cyclophosphamide
Nitrosureas
- Carmustine (BCNU)
What is the general mechanism of action of the alkylating agents? What phase of the cell cycle do they target?
- Alkylation of the N7 position on guanine to cause DNA cross-linking and strand breakage
- Cytotoxic to the WHOLE cell cycle
What is the mechanism of action of Cyclophosmphamine?
- Prodrug that is metabolized to active form
- Alkylating agent
Note that the active drug can be converted to another drug, “Acrolein” which is specifically cytotoxic to the bladder
What are the specific toxicities associated with Cyclophosphamide?
Hemorrhagic cystitis
Recall, it is a prodrug that is converted to an active form; active form is converted to ACROLEIN, which is specifically toxic to the bladder.
What drug can be administered with Cyclophosphamine to reduce the risk of hemorrhagic cystitis?
Mensa
This drug INACTIVATES ACROLEIN
What is Carmustine (BCNU) commonly used to treat? Why?
- Alkylating agent
- Used to treat BRAIN TUMORS b/c it is highly lipophilic
Often included in wafers that are placed post-op*
List the general adverse effects of alkylating agents.
1) Mutagenic, teratogenic, myelosuppressive
2) Dose-limiting factor is bone marrow suppression and damage to intestinal mucosa
3) Cause Leukemia
4) Strong vesicant/ blistering properties
What are the mechanisms of resistance to the alkylating agents?
- Inactivation by GLUTATHIONE/ increased production of
- Reduced uptake
- Accelerated DNA repair/ double strand break repair
- Increased expression of MGMT, which removes alkyl groups from guanine before cross-links form
What is the function of MGMT?
Prevention of DNA damage by removing alkly groups from guanine i.e. prevents drugs from “alkylating”
List the non-classical alkylating agents.
Platinum compounds
- Cisplatin
- Carboplatin
- Oxaliplatin
What is the mechanism of action of the platinum compounds?
- Generally, these drugs cause DNA cross-linking WITHOUT actually alkylating DNA
- Active throughout the whole cell cycle
Note that these compounds are actively transported into the cell via the Cu++ transporter
What are the side effects that are specific to Cisplatin?
- Neurotoxicity i.e. peripheral motor and sensory neuropathy
- Nephrotoxicity
- Anaphylaxis
What are the side effects that are specific to Carboplatin?
Less nausea, neuropathy and nephrotoxicity, but can induce anaphylaxis like Cisplatin
How is the nephrotoxicity of Cisplatin decreased?
Coadministration of IV saline
What is Procarbazine used to treat?
This is a non-classical alkylating agent used to treat Hodgkin’s Disease
What is Dacarbazine used to treat?
This is a non-classical alkylating agent used to treat Hodgkin’s lymphoma, melanoma, and sarcoma
What is Temozolamide used to treat?
This is a non-classical alkylating agent used to treat Glioblastomas and metastatic melanoma
Describe microtubule dynamic instability.
- Equilibrium between forming and falling apart
- MTs need to be able to do BOTH function normally
List the antimicrotubule agents.
Vinblastine
Vincristine
Paclitaxel
Docetaxel
What is the mechanism of action of Vinblastin and Vinctistine? What cell cycle phase do they kill in?
- Vinblastine and Vincristine prevent MT polymeratiztion
- Without properly forming MTs, the mitotic spindle cannot form; thus, these compounds kill in MITOSIS
What is the major adverse effect of vincristine?
Neurotoxicity
Note that this is NOT seen with Vinblastine but does have myelosuppression*
What is the mechanism of action of the Taxanes? What cell cycle phase do they kill in?
- Prevent MT destruction/ depolymerization
- Thus, the mitotic spindle can form in MITOSIS, but the PULLING phase is inhibited
What is the major adverse effect of Paclitaxel?
1) Peripheral neuropathy
2) Mylosuppression
3) Anaphylaxis in ~5% of patients
What drugs are commonly given with Paclitaxel?
1) Filgrastim= G-CSF to reduce myelosuppression
2) Dexamethasone and antihistamines that prevent hypersensitivity reactions
What is the normal function of Topoisomersase in the cell?
- Recall that DNA is normally stored in a condensed form
- TOPOISOMERASE cuts DNA for replication, unwinds it, and repairs the cut
List the Topoisomerase I inhibitors.
Irinotecan
Topotecan
List the Topoisomerase II inhibitors.
Etoposide
What is the mechanism of action of Doxorubicin?
Anthracycline antibiotic
- Intercalates with DNA and inhibits DNA polymerase
- Inhibits topoisomerase II
What is the major adverse effect seen with Doxorubicin?
- Binds iron and generates ROS
- Causes irreversible CARDIOMYPOATHY
What can reduce the cardiotoxicity of Doxorubicin?
Dexrazoxane
This is an iron chelator that reduces the formation of free radical formation
What is the mechanism of action of Bleomycin?
This is a small peptide that binds DNA and causes single and double strand breaks
What phase of the cell cycle does Bleomycin target?
G2
What is unique about the toxicity of Bleomycin?
Cumulative, irreversible PULMONARY toxicity
Only minimally myelosuppressive*
What is the clincal utility of Glucocorticoids in cancer treatment?
1) Inhibit lymphocyte proliferation
2) Reduce ICP w/ brain tumors
3) Reduce nausea and vomiting associated with chemotherapy
What is the mechanism of action of Tamoxifen?
Partial estrogen receptor antagonist
What cancer is Tamoxifen used to treat?
Breast cancer
How is estrogen synthesized in post-menopausal women?
In post-menopausal women, AROMATASE converts testosterone into estrogen in peripheral tissues
What is the mechanism of action of Anastrazole? What cancer is it used to treat?
Anaztrazole is an aromatase antagonist used to treat breast cancer that is estrogen receptor positive in post-menopausal women
What are androgen receptor inhibitors used to treat? What is the mechanism of action?
Prostate cancer
These drugs prevent DHT from binding to androgen receptors, which normally drives prostate cancer growth
What are Leuprolide and goserelin?
- GnRH AGONISTS
- Causes DESENSITIZATION of the GnRH receptor in the pituitary in the long-term
- Decreases LH and FSH
- Decreases Testosterone
Used to treat prostate cancer*
What is the mechanism of Degarelix?
GnRH ANTAGONIST used to treat prostate cancer
What is the mechanism of action of Trastuzumab?
Monoclonal antibody that targets HER-2 (EGFR TRK amplified in invasive breast cancer) and prevents signaling
Used to treat HER-2+ breast cancer
What is the major toxicity associated with Trastuzumab?
Cardiotoxicity
What is the mechanism of Cetuximab?
Monocolonal antibody used to treat EGFR+ COLORECTAL tumors
What is a mechanism of Cetuximab resistance?
Activating mutations in Ras
Thus, Ras activity is tested prior to use of this drug*
What is Bevacizumb’s mechanism of action?
Monoclonal antibody for VEGF i.e. prevent angiogenesis
What are the adverse effects assocaited with Bevacizumb?
- HTN
- Increased risk of bleeding/ thrombosis
- Increased risk of GI perforation
- Decreased wound healing
What is the mechanism of action of Lapatinib?
Small molecule that inhibits EGFR and HER-2 kinase activity in THE CELL
Used specifically with capecitabine to treat HER-2+, Trastuzumab refractory breast cancer*
What is the mechanism of action of Erlotinib?
Small molecule EGFR inhibitor as a first line treatment for NON-SMALL CELL LUNG CARCINOMA
What is Imatinib used to treat?
CML caused by Philadelphia chromsome translocation
What is Imatinib’s mechanism of action?
Small molecular inhibitor BCR-ABL constitutively active Tyrosine Kinase
What are the mechanisms of resistance to Imatinib?
Point mutations in BCR-ABL that causes reduced drug affinity
What is the mechanism of action of Asparaginase?
- This is an enzyme used to treat childhood ALL
- Hydrolyzes plasma L-asparagine into L-aspartate
Tumor cells cannot synthesize enough L-asparagine, but normal cells can; thus, this drug starves the tumor of essential nutrients
What is the unique toxicity assocaited with Asaparaginase?
Anaphylaxis
What is the mechanism of action of Bortezomib?
Proteasome inhibitor that elevates levels of p53 (important tumor suppressor)
p53 causes apoptosis in cancer cells*
What is the major toxicity seen with Bortezomib?
Peripheral neuropathy
What is the mechansim of action of Temsirolimus?
- Inhibition of mTOR complex 1 (mTORC1)
- mTORC1 is normally involved in protein translation
- Thus, this drug it inhibits protein translation in rapidly dividing cells
What are the unique side effects of Temsirolimus?
Hyperglycemia
Hypertriglyceridemia
What is the resistance mechansim of Temsirolimus?
- There are two mTORs, mTORC1 and mTORC2
- Temsirolimus inhibits mTORC1, which can cause an upregulation of mTORC2
Which antineoplastic agents are nephrotoxic?
Cisplastin
Methotrexate
Which antineoplastic agents are neurotoxic?
Vincristine Cytarabine Cisplastin Bortezomib Paclitaxel
Which antineoplastic agents are cardiotoxic?
Doxorubicin
Trastuzumab
Which antineoplastic agents cause bladder toxicity?
Cyclophosmphamide
Which antineoplastic agents cause hypersensitivity reactions/ anaphylaxis?
Asparaginase
Paclitaxel
What are 6-mercaptopurine and 6-thiguanine commonly used to treat?
These are purine analogs/ antimetabolites that inhibit s-phase; commonly used to treat AML and ALL
What is Fludarabine commonly used to treat?
This is a purine analog/ antimetabolite that inhibits s-phase; it is commonly used to treat CLL
What is Cladribine commonly used to treat?
This is a purine analog/ antimetabolite that inhibits s-phase; it is commonly used to treat Hairy Cell Leukemia
