Chemotherapy Flashcards
Cell-Cycle Specific Drug Classes
- Antimetabolites
- Topoisomerase Inhibitors
- Microtubule Inhibitors
Methotrexate
Antimetabolite that inhibits dihydrofolate reductase
Pazopanib, Levantinib, Cabozantinib
Small molecule inhibitors of the VEGF Receptor
Microtubule Inhibitors
Block microtubule polymerization and inhibit mitosis
Can cause neurotoxicity and peripheral neuropathy because microtubules are important for transport of cargo along neurons
Induce resistance via MDR1
Imatinib, Dasatinib, Ponatinib
Small molecule inhibitors of BCR-Abl tyrosine kinase that causes CML
Effective single-agent therapy that causes long-lasting remission
Resistance is driven by mutations in BCR-Abl that prevent binding of the drug, but the drug can be modified to combat these mutations
Strategies to maximize efficacy of treatment and minimize side effects
- Combination Therapy
- Rationaly Designed Therapies
- Prophylaxis
- Intermittent therapy
- Optimization of dosing and route
- Support of bone marrow function
Cell Cycle Nonspecific Drug Classes
- DNA Intercalating/Damaging Agents
- Alkylating Agents
- Protein Synthesis Inhibitors
Inhibit mutant B-Raf kinase
Vemurafenib, Dabrafenib
MDR1
Multi-Drug Resistance 1 gene
Recognizes toxic compounds and pumps them out of the cell
Expression of MDR1 increases dramatically over course of treatment
Allows cell to develop resistance to chemotherapeutics such as Microtubule Inhibitors and Topoisomerase Inhibitors
MDR1 is non-selective, so resistance to one drug gives resistance to many other drugs
Trastuzumab
(What is it, and what are the side effects?)
Monoclonal antibody against HER2 receptor
Can cause heart toxicity when used with Doxorubicin
Anti-Angiogenesis Drugs
(Mechanism)
Target VEGF
Theoretically stop cancer by preventing blood supply to cancer
Purpose of combination therapy
Using multiple mechanisms makes cells less likely to develop resistance
Therapy is more effective because you are targeting multiple pathways
Fewer side effects because you can use less of each drug
Topoisomerase Inhibitors
Topoisomerase is required for DNA replication and mitosis
These drugs induce resistance via upregulation of MDR1
Panitumumab
Monoclonal antibody against Epidermal Growth Factor Receptor
Treats EGFr-expressing metastatic colorectal carcinoma
High dermatologic toxicity
Examples of Alkylating Agents
- Nitrogen Mustards
- Nitrosoureas
- Hydrazines
- Platinum Compounds
Drug that can cause cardiomyopathy due to free radical generation as well as red urine
Doxorubicin
Tamoxifen
Hormonal therapy that acts as an antagonist to estrogen receptor
Used to prevent estrogen-receptor positive breast cancers
Less effective in pre-menopausal women cause they have more estrogen
Estrogen Receptor Antagonist
Tamoxifen
Tumor lysis syndrome
Occurs when a chemotherapeutic drug is so effective that proteins from lysed tumor cells can cause kidney failure
If RAS is mutated, would targeting a growth factor receptor be effective?
NO; RAS is downstream of growth factor receptors and is operating independently if mutated
Vemurafenib, Dabrafenib
small molecule inhibitors of mutant B-Raf kinase
This mutation is present in most melanomas
Resistance may develop months later with elevated ERK signaling
Longest parts of cell cycle? Shortest?
G1 and S phase take up around 40% of the cell cycle each
M phase takes up only 2% of the cell cycle
Rationally Designed Therapy
Drugs that target causitive molecular abnormality of fundamental, universal cellular processes
Require precise knowledge of cause of disease
Include:
- Small molecule inhibitors
- Antibodies
Antibiotics
Intercalate into DNA, cause single strand DNA breaks, and prevent transcription
Toxicity associated with longterm use
Minimally myelosupressive and immunosuppressive
Alkylating Agents
Highly reactive compounds that crosslink DNA and proteins
Prevent DNA replication and transcription of RNA
High toxicity to bone marrow and intestinal mucosa
All are mutagenic/carcinogenic and can induce secondary leukemia
Cells mutant for p53 have intrinsic resistance
5-fluorouracil
Antimetabolite that inhibits synthesis of thyidine from uracil
Potent radiosensitizer ; useful for locally advanced and accessible tumors
Venetoclax
Used to treat CLL where there’s an overexpression of Bcl-2
It acts as a Bcl-2 antagonist in order to allow apoptosis
May lead to Tumor Lysis Syndrome
Antimetabolites
Analogs of molecules required for DNA Synthesis (amino acids and vitamins)
S Phase Specific
Most effective for rapidly proliferating tumors - all cause myelosuppression (decreased bone marrow)
Aromatase Inhibitors
Exemestane and Anastrozole
Block Aromatase, which is responsible for synthesis of estrogen
Cells with a p53 mutation have intrinsic resistance to what class of drugs?
Alkylating Agents
Rituximab
Monoclonal antibody that binds CD 20
Found on 90% of non-Hodgkin’s lymphomas
Can cause Tumor Lysis Syndrome
GnRH Analogs
Leuprolide, Goserelin
Block sex hormone synthesis in testes and ovaries
Bevacizumab
Humanized antibody to VEGF that prevents it from binding to receptors
PD-1
Receptor on T cell that reduces cytotoxic activity when stimulated
Support Therapy
Drugs designed to support bone marrow function, etc
These drugs enable patients to tolerate chemotherapy, but do not play any role in killing cancer
Nivolumab, Pembrolizumab
Binds PD-1 on T cell and prevent inhibitory signal, thus allowing T Cells to kill cancer cells via production of IL-2 and Interferon
Trametenib
Inhibit MEK1 and MEK2 (downstream substrates of B-Raf)
Used in combination with B-Raf inhibitors
Inhibits MEK1 and MEK2
Trametenib
Progestins
Megestrol
Inhibit pituitary release of gonadotropins and can stimulate apetite in patients with cachexia
Antiandrogens
Used to treat prostate cancer
Steroidal Antiandrogens - inhibit androgen binding to receptor (cyproterone)
Non-steroidal Antiandrogens - inhibit nuclear translocation of receptor (bicalutamide)
Basically they inhibit Androgen Receptor-dependent gene transcription
Doxorubicin and Daunorubicin
Members of Antibiotic class (DNA Damaging drugs)
Doxorubicin causes unusual cardiomyopathy due to free radical generation
Also causes Red Urine
Induces upregulation of MDR1 and has resistance
