Lec 03 Cancer Chemotherapy Flashcards
Mechanism of action of Cytotoxic Chemotherapy
affect macromolecular synthesis and function (DNA, RNA, Proteins)
What type of drug is Cytosine?
ANTI-METABOLITE
What type of drug is Paclitaxel?
MITOTIC INHIBITOR
What type of drug is Doxorubicin?
ANTIBIOTIC
What type of drug is Chlorambucil?
ALKYLATING AGENTS
Why do we look at proliferating tissues more than normal
tissues affected by cytotoxic agents?
DNA becomes sensitive when the double helix is
unwound and open. Unwinding occurs only during the
time of cell proliferation. That is why proliferating cells
are more sensitive.
Example of Cycle non-specific drugs
nitrosylureas and steroids
Example of Cycle specific drugs
Alkylating agents and anti-tumor antibiotics
How do you improve effectivity of a phase specific agent?
Increase time of exposure. This is to allow the rest of the cells in different phases to enter the sensitive phase.
Antimetabolites work only on?
S phase
Vinca alkaloids work only on?
M phase
Anti-tumor antibiotics work on?
most of S phase including late phases of G1 and early phases of G2
Alkylating agents work on?
all throughout the cell cycle
Taxoids work on what phase?
Taxoids are spindle poisons so they only work on M phase.
What is the usual mode of administration for cytotoxic drugs?
IV because they are poorly absorbed in the GIT and some drugs are irritants and contact to GI tissues may lead to lysis or giant ulcers that may not heal
Name one cytotoxic drug that can be given orally
Cepacitabine - a prodrug converted to 5FU by enzymes in the liver
What are the reservoir areas in males?
Brain and testes
What is the result of poor nutrition in distribution?
Poor nutrition -> less protein -> more free drug
DANGEROUS
What is the FRACTIONAL CELL KILL HYPOTHESIS?
States that each cycle of chemotherapy is capable of
destroying the same proportion of tumour cells.
What is the minimum recovery time for chemotherapy?
3 weeks
What are the assumptions of the Fractional cell kill hypothesis?
o All cells are rapidly dividing and are thus sensitive to
chemotherapeutic agents
o There is constant blood supply to be able to administer the drugs
o First order kinetics (meaning ALL cells are rapidly dividing)
Tumours in which the logarithmic part of the curve is
shorter with a broader plateau phase will be (resistant/sensitive) to chemo
resistant like thyroid CA
tumours with steep logarithmic curve will be (resistant/sensitive) to chemo
sensitive like lymphomas
What are the two types of cell populations in the tumor?
Micrometastases – rapidly dividing and exhibiting logarithmic growth
Primary tumor – in the plateau phase of growth, some cells may be dividing, some may not
What does the GOLDIE-COLDMAN HYPOTHESIS state?
within the tumor itself, there would be small population of tumor cells that are already naturally resistant to the effects of chemotherapy because of the labile genome that the cancer has
How do you overcome resistance due to cell kinetics?
- Debulking/Reduce tumor bulk with locoregional modalities(surgery, RT)
- Use combinations that include drugs that can affect resting populations.
- Schedule drugs to prevent phase escape or to synchronize cell populations and increase cell kill by continuous infusion instead of bolus.
Most common cause of drug resistance in chemotherapy
MDR (multidrug resistance) or pleiotropic drug resistance
What is the product of the MDR gene?
ATP dependent P glycoprotein that pumps the drug back outside. Hence, the drug does not reach the nucleus and cannot kill the cancer cell
How do you overcome biochemical causes of resistance:
o Use combination chemotherapy
o Use biologic response modifiers
o Use a 2nd agent to rescue normal cells
o Follow marrow-lethal doses of chemotherapy with autologous bone marrow transplant
o Combine high dose chemotherapy with blood cell
What is the definition of complete remission according to the RECIST Criteria?
disappearance of all target lesions
What is the definition Progressive Disease (PD) according to the RECIST Criteria?
≥ 20% increase in SLD when compared to smallest SLD since treatment
OR
appearance of new lesions.
When can you give chemotherapy to a pregnant woman?
late 3rd trimester
What are the three phases of vomitting
1) acute (2hrs-1week)
2) delayed (1-2weeks after therapy)
3) psychogenic (triggered response)
Most life threatening symptom of chemo
bone marrow aplasia
symptom of anthracyclin use
Cardiotoxicity
symptom of Bleomycin use
Pulmonary fibrosis
What is the basic principle of ablative therapy?
the Hypothalamus-Pituitary-Organ axis should be interrupted
When do you use Peripheral Androgen Inhibitors?
prostate cancer
When do you use Selective estrogen receptor modulators ie tamoxifen?
Used in ER (+) breast cancer patients
What is a side effect of tamoxifen?
Hot flushes, vaginal bleeding and discharge are associated with tamoxifen use. Vaginal bleeding is secondary to the induced proliferation of the endometrium and can actually lead to endometrial CA. So, if you use tamoxifen, it is advised that you also do an annual pap smear.
What is passive immunotherapy?
Use of monoclonal antibodies for target cell-directed killing by antigen-antibody response
What is adaptive immunotherapy?
acquisition of immunity in a naïve subject as the result of the administration of immunologically activated lymphoid cells.
Imatinib is a selective tyrosine kinase inhibitor of?
KIT, Bcr-Abl, and PDGFR
What is the mode of action of imatinib mesylate?
inhibit ATP phosphorylation in the BCR-ABL binding site, inhibiting the binding of tyrosine residues which further blocks the binding to the effector cell.
GIST is dependent on what oncogene?
KIT oncogene
Trastuzumab, a monoclonal antibody specific for what tumor?
breast tumor
Cetuximab is specific for what tumor?
Lung, Colorectal, Head and Neck, GBM (glioblastoma?)
Panitumumab is specific for what tumor?
colorectal
Nimotuzumab is specific for what tumor?
Head and Neck, GBM
What is the effect if mTOR is blocked?
If blocked: hold proliferation, starve the tumor, prevent metastasis, can make a tumor sensitive to hormonal therapy
What is the function of the 26S proteosome
functions like the “anus” of the cell; takes all the proteins and degrades them so that they can be utilized again. Stopping the degradation will lead to an accumulation of toxic substances in the cell, ending in apoptosis.
