Antineoplastic Agents Part I: Chemotherapy in general Flashcards
Top 4 cancer sites
- Breast cancer (female)
- Lung and bronchus
- Prostate
- Colon and Rectum
Alkylating Agents (list)
Nitrogen mustards:
- cyclophosphamide
- ifosfamide
Alkyl sulfonate:
- Busulfan
Platinum coordination complexes:
- Cisplatin
Natural Products (originally isolated from plants or bacteria, etc.)
Vinca alkaloids:
Vinblastine
Vincristine
Taxanes: Paclitaxel
Tpipodophyllotoxins: Etoposide
Antibiotics: Bleomycin, Doxorubicin
Enzymes: L-Asparaginase
Antimetabolites
Folic acid analogs: Methotrexate (MTX)
Pyramidine analogs: Fluorouracil
Purine analogs: mercaptopurine
Differentiating agents
Tretinoin
Biological response modifiers
Interferon-alfa
Interleukin-2
Immunomodulators
Thalidomide
Rescue agents
Leucovorin
Mesna
Protein tyrosine kinase inhibitors
Dasatinib
Erlotinib
Imatinib
Lapatinib
Proteasome inhibitor
Bortezomib
Remember it by “Borteasome”
Monoclonal Antibodies
Bevacizumab
Cetuximab
Rituximab
Trastuzumab
Agents used to minimize adverse effects
Filgrastim
Ondansetron
Ondansetron
Cancer Treatment Modalities
Chemotherapy
- Immunotherapy
- Targeted Therapies
- Vaccines
Radiation Therapy
Surgery
Transplantation
Combinations are the norm
Primary Induction Therapy
The main treatment that provides the best possible outcome
Also called first-line therapy
Neoadjuvant Therapy
Treatment given BEFORE primary induction therapy in order to improve outcome
E.g., Chemo or radiation to shrink a tumor before surgery
Adjuvant Therapy
Additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse
Biology of Cancer: The Cell Cycle
Cell cycle checkpoints control transitions between cell cycle stages
DNA damage?
Spindle assembly?
Favorable conditions?
Completed replication?
Failure to pass checkpoint: cell cycle is delayed or cells apoptose
Cycling Out of Control
In many forms of cancer, proteins or pathways involved in regulating the checkpoints between the phases of the cell cycle may be absent or mutated
For example: p53, CDKs
Aberrations in checkpoint regulation result in uncontrolled and unregulated cell proliferation
Cell cycle specific (dividing) vs. cell cycle nonspecific (regardless of whether they are dividing or not)
Cell cycle specific agents
Antimetabolites antitumor antibiotic-bleomycin Taxanes Vinca alkaloids Toppoisomerase inhibitors
Cell cycle nonspecific agents
Alkylating agents
anthracyclines
platinum analogs
Growth fraction
the ratio of proliferating cells to resting cells (G0)
Growth fraction is a determinant of responsiveness to chemotherapy Cells with high growth fraction: - Bone marrow - GI tract - Hair follicles - Sperm-forming cells
Growth Fraction and Therapeutic Response
The initial growth rate of most solid tumors is rapid but decreases over time
Burkitt lymphoma (high growth fraction; curable by chemotherapy) vs. colorectal carcinoma (low growth fraction; chemotherapy has minor activity)
Some disseminated tumors can be cured by single-agent chemotherapy
The growth fraction of solid tumors can be increased by reducing the tumor burden (i.e., surgery or radiation)
Log Cell Kill Hypothesis
A fraction (not an absolute number) of cells are killed
A three-log cell kill eliminates 99.9% of cells:
10^12 to 10^9 cells
10^6 to 10^3 cells
Therapeutic Balance: Efficacy vs. Toxicity
Challenge: provide dose that is therapeutic without being (too) toxic
Antineoplastic drugs harm both cancerous tissues and healthy tissues
Not all drug regimens are appropriate for all patients
Factors to consider: Renal and hepatic function Bone marrow reserve General performance status Concurrent medical problems Patient willingness
Primary resistance
An absence of response on the first drug exposure
Thought to be due to genomic instability
Acquired resistance
Develops in response to exposure to a given antineoplastic agent Often highly specific to a single drug, or class of drugs, and is usually due to an increased expression of one or more genes
Examples of single agent resistance pathways include:
decreased drug transport into cells
reduced drug affinity due to mutations or alterations of the drug target
increased expression of an enzyme that causes drug inactivation
increased expression of DNA repair enzymes for drugs that damage DNA
Multidrug resistance and ATP-dependent Transporters
ATP-dependent transporter gene amplification in neoplasms confers resistance to a broad range of agents used in cancer treatments
The P-glycoprotein is an ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells (MDR1 gene)
Anthracyclines, vinca alkaloids, etoposide, paclitaxel, and dactinomycin
Toxicity of Antineoplastic Agents
The lack of neoplastic specificity for chemotherapeutic drugs is a major limiting factor in the treatment of cancer
Rapidly proliferating normal tissues (tissues with high growth fractions) are the major sites of toxicity
bone marrow, gastrointestinal tract, hair follicles, buccal mucosa, sperm forming cells
Many antineoplastic agents are mutagens themselves and can give rise to neoplasms years after treatment (e.g., alkylating agents have caused AML and ALL)
Common Adverse Effects of Chemotherapy
Occur during therapy with nearly all classic antineoplastic agents:
Nausea Vomiting Fatigue Stomatitis Alopecia
Myelosuppression – can lead to impaired wound healing and predisposition to infection
Low sperm counts and azoospermia
Depressed development of children exposed to antineoplastic agents
Minimizing Adverse Effects of Chemotherapy
Choose the route of administration that minimizes systemic toxicity as much as possible
Pharmacologic agents that help decrease adverse effects:
- Hematopoietic agents for neutropenia, thrombocytopenia, and anemia (will discuss later in the course)
- Serotonin receptor antagonist (ondansetron) and other drugs for emetogenic effects
- Bisphosphonates to delay skeletal complications
Rest and recovery
