Chemotherapy Flashcards
Log Cell Kill Theory
A given dose of chem drugs will kill a constant percent of cancer cells per dose rather than a constant number of cells.
Use a log plot to represent killing strategies and outcomes where the down arrows represent killing upon admin and the upward arrows represent log growth of remaining cells in btwn doses.
Induction chemotherapy
- Initial chemotherapy (anticancer drugs)
- Goal is cytoreduction (decrease in tumor cell volume) and remission
- Graph arrow steadily zigzags downwards
Complete response to chemotherapy
-Disappearance of disease for at least 1 month. remission
Partial response
-Reduction in tumor volume by at least 50%
Stable disease
-Reduction of tumor volume by less than 50% and no new disease sites for at least 30days
Prgression
An increase in tumor volume of 25 % or move and evidence of new disease sites.
Maintenance of Chemontherapy
- Prolonged low dose chemotherapy
- Goal is too achieve cure (disease eradication) or prolonged remission.
- Graph steadily declines downward like intro and zig zag horizontally to convey steady state of disease.
Adjuvant Chemotherapy
- Given after disease reduction or eradication via surgery or radiation.
- Reduce microscopic disease and prevent local recurrence
- Graph is a SHARP vertical line followed by steady downward zig zags
Neoadjuvant Chemotherapy
- Given prior to surgery or radiation to reduce tumor volume and improve efficacy of treatment.
- Graph is at first steady zigzag downwards then sharp vertical decline followed by steady zig zag downwards
Palliative or Salvage therapy
- Given after the failure of other therapies to control disease, prolong life and reduce cancer related symtoms.
- Graph is just zig zag horizontally following the sigmoidal log solid tumor growth line.
Chemotherapy Agents are classified by their
Chemical structure
Mechanism of action
Cell cycle Specificity
Chemincal compounds
1. Platinum compounds (cisplatin) forms platinum cross links btwn adjacent guanines and adenines. Forms DNA adducts which inhibits replication and transcription. 2. Nitrogen mustards, Nitrosurea alkylating agents forms DNA adducts prevent relication 3. Anthracyclines 4. Camptothecins 5. Antimetabolites 6. Taxanes 7. Vinca alkaloids
MOA
- Drugs affecting biosynthesis of nucleic acids
- Mercaptopurine inhibits purine synthesis) and thioguanine (inhibits DNA synthesis) - Drugs disrupting DNA structure and function
- 5-FLU (inhibit thymidylate synthesis) - Antimetabolites (block DHFR andpurine synthesis)
- Alkylating agents ( forms adducts with DNA)
- TOPO-I
- Antitumor antibiotics (
- Drugs that alter cell signalling and progression
Cel Cycle Specificity
CCS: cell cycle specific act only on dividing cells
CCNS: cell cycle no specific targets both dividing and non dividing cells
-Follow CCNS tx with CCS agent
aADECommon
- Cytotoxic effects on ALL rapidly dividing cells
- Affects regenerating cells
1. Bone marrow
2. Blood cells
3. Gastric mucosa
4. Follicular cells
5. Gametes
Myelosuppresion
- Inhibition of bone barrow growth decrease production of all blood cells
- Dose limiting toxicity
- PMNs (granulocytes have shortest turnover and are likely effected first.
- Treated with hematopoietic GF (GM-CSF, G-CSF, EPO)
N/V
- Most common ADE due to activation of CTZ in medulla by afferent signals from gut and cerebral cortex
- highly emetic agents mechlorethamine, dacarbazine, cyclophosphamide, and cisplatin
- Treat with dexamethasone, seratonin antagonists.
Mucositis
inflamed mucous membrane ( mouth and intestines most common) due to cytotoxic effects on epithelial ells.
- Produces Ulcers, mild to severe Diarrhea
- Treat with local anesthetics and barrier creams
- Palifermin: keratinocyte GF to grow mucous cells and treat severe mucositis.
ALopecia
Apoptosis in hair matrix, reversible
-Chemocaps: to cool scalp and consrict blood vessels and minimize access to scalp is NOT recommended they can make division of micrometastases
Extavasation
Vesicant agents cause tissue damage if they get ito blood
Chemo drugs are vesicants. This happens at site of admin MD needs good admi techniques and some neutraliizing agents are available for some vesicants
Reproduction and Pregos
- ovulation and spermatogenesis stops when treated with alkylatinf agents and TOPO-I poisons.
- Do not start Chemo during 1st trimester avoid antimetabolites during 2nd and 3rd trimester becase they are teratogenic
- Breats cancers, thyroid cancers, hoddgkin lympjoma and non hodgkin lymphoma are cancers diagnosed during prego.
Neuropathy
Chemobrain” refers to cognitive decline when use long term drugs. include memory loss impaired learning anf decreased rate of processing.
- Glove and stocking syndrome: peripheral neuropathy that effects extremeties. tingling sensation bcuz of loss of motor function.
- this is due to : demyelanation, inhibition of axon support and glial cell toxicities.
CV toxicity
due to free radical generations that produce oxiatibe damage to varioys CV tissues and produce dysarhythmias, CHF, peripheral artery disease
-ANTHRACYCLINES are primary agents
Secondary malignacies
Induce DNA damage and instability primarily by alkylating agents and TOPO-I will lead to acute leukemia occurin in 1-5% of ppl getting treatment
Resistance mechanisms
Cancer cells rapidlyevolve because of instability which provides increased opportunities for drug resistance to develop.
Drug Efflux Pump
Multi drug resistance developed through PGP pumps which are pumps that move small molecules out of the cell in concentration independent fashion
Increased DNA repair
-Tumor cells increase their rate of repair this affects alkylating agents, DNa strand terminators and TOPO-I because they directly/indirectly damage DNA and this will decrease their effectiveness,
Cganhe in Target Enzymes
MTX acts as inhibitor of DHFR. Tumor cell can over express DHFR and reduce MTX effectiveness
Inactivation of Drugs
Thiol trapping agents (produced a lot in cancer cells) such as glutathione can form covalent complexes with electrophillic drugs like alkylating agents. They form a stable complex and that contributes to nephrotoxicity.
Decrease activation of prodrugs
Decrease production of enzyme required to activate the chemo drug
Decrease activity of HPRT will minimize conversion of purine analogs to active nucleotides. Tumor cell will make new enzyme to do this reaction and the drugs can only work through the HPRT path and so this will render the drug useless.
Cancer Biomarkers
Molecular tool used to ID cancer specific gene expression (HER2 over expressed in breast cancer). Gene profiling can allow prediction of disease outcome and drug resistance. Very good tool for early detection which is the best way to improve outcomes
Cancer therapeutic strategies
- Cancer is due to genetic and epigenetic factors
- 7-12 mutations required among 100000 of potential genes so there are limitless combo mutations ina particular cancer
- Success of therapy depends on genetic makeup of disease, and combo therapy hits multiple targets
- Cancer bio markers allow us to choose better targets.
Combination Chemotherapy
-Factors for choosing appropriate combo
1. Efficacy: only drugs known to be effective alone should be used alone
2. Toxicity: Don’t overlap toxicity of drug A with same toxicity of drug B
3. MOA: separate MOA for each agent and try to hit multiple cell cycle points
Resistance: Cross resistance btwn agents needs to be at minimum.
