Lec 1 & 2: Intro. to Cancer Pharmacology & Cancer Cytotoxic Agents Flashcards
Biological Dogma Applied to Cancer Therapeutics
Basic Cancer Terminology
1.) Oncology
2.) Cancer
3.) Neoplasm
1.) Oncology – the branch of medicine that deals with the prevention, diagnosis, and treatment of cancer. The study
of cancer biology.
.
2.) Cancer – a large group of diseases characterized by uncontrolled growth and spread of abnormal cells (American Cancer Society)…. Cancer – a malignant neoplasm (Pitot).
.
3.) Neoplasm (new growth) – a heritably altered, relatively autonomous growth of tissue. NOTE: DNA oriented
Basic Cancer Terminology
4.) Tumor
5.) Benign
6.) Malignant
4.) Tumor– any swelling or mass of tissue occupying a volume of space.
.
5.) Benign – having non-invasive and focal characteristics. Relatively differentiated…not necessary cancer- just cut it out
.
6.) Malignant – having dedifferentiated, invasive, and/or metastatic character.
Different Kinds of Cancer (part 1)
1.) Carcinomas are the most common types of cancer arising from the cells that cover external and internal body surfaces. Lung, breast, prostate, and colon are the most frequent cancers of this type in the US.
.
2.) Sarcomas are cancers arising from cells found in the supporting tissues of the body such as bone, cartilage, fat, connective tissue, and muscle.
.
3.) Lymphomas are cancers that arise in the lymph nodes and tissues of the body’s immune system. (hematologic malignment)
Different Kinds of Cancer (part 2)
4.) Leukemias are cancers of the immature blood cells that grow in the bone marrow and tend to accumulate in large numbers in the bloodstream. (hematologic malignment)
.
5.) Blastomas are cancers of primitive, incompletely differentiated cells resembling the precursor cells of the cancer.
.
6. ) Melanoma is a type of cancer originating from melanocytes. Melanocytes are melanin-producing cells derived from the neural crest and are located in the stratum germinativum of the epidermis.
2023 US Cancer Incidence and Mortality … just know general trend and the important part
Incidence: Breast (female) and prostate (male) cancer (2n for both is lung cancer)
.
Mortality: Lung for both!!! why? lungs are encased deeply with in body so you don’t really detect that something is wrong until it’s too late!
.
NOTE: if it’s a kidney cancer that has metas. to the lung it is NOT lung cancer it is still kidney!
Example of Normal Tissue Growth
NOTE: need to know the normal so you can know what’s not normal in cancer! Ex. squamous cell carcinoma is a carcinoma…melanoma is different!
Neoplasms and metastasize picture
Tumors (Neoplasms) Development
Development of a NEOPLASM - a localized neoplasm that has not invaded beyond certain boundaries (i.e., the basement membrane) may be considered a preneoplastic lesion. Examples include carcinoma in situ (CIS).
Early Events in Carcinogenesis:
Early Events in
Carcinogenesis:
1. Initiation
2. Promotion
3. Progression
.
.
.
1 – Invasion: Cancer cells invade surrounding tissues and blood vessels
.
2 – Metastasis: Cancer cells are transported by the circulatory system to distant sites
.
3 – Cancer cells reinvade & grow at a new location
Tumor Grading
Tumor Staging
Principles of Cancer Chemotherapy:
Anti-proliferation
Cancer cells do not divide faster, but more of them are actively dividing (higher growth fraction)….NOTE: cancer typically arise from one cell
Principles of Cancer Chemotherapy:
Differential sensitivity
Chemotherapy needs to be more cytotoxic to the neoplastic cells compared to normal cells
Principles of Cancer Chemotherapy:
Characteristics of cancer chemotherapies
- Goal is to rid body of neoplastic cells; in many cases, able to prevent growth of neoplastic cells, shrink the neoplasm, and increase survival
- Generally have a narrow therapeutic index (i.e., LD50/ED50)
- Palliation: alleviate symptoms of cancer and reduce life threatening toxicity in effort to improve quality of life
Factors Affecting Response to Chemotherapy (5 factors)
1.) Tumor Burden - larger tumors have lower growth fractions, less responsiveness, and greater propensity to metastasize
.
2.) Tumor Cell Heterogeneity - genetic changes to cells cause significant cellular variation
.
3.) Drug Resistance - inherited or acquired resistance to
chemotherapy
.
4.) Dose Intensity - intended chemotherapy doses may not be given due to toxicity
.
5.) Patient-specific factors - intended chemotherapy doses may not be given due to toxicity
General Principles – tumor growth considerations
The kinetics of tumor growth can be used to predict effective drug schedules; however, confounding variables include:
* tumor cells may lie dormant for variable or long periods of time (lie dormant: NOT dividing…this is NOT good! chemo agent usually target dividing cells!) -
* tumor cells not actively dividing are relatively immune to the conventional drugs
* tumor recurrence is often associated with drug resistance because drug exposure without apoptosis can select for or induce protective mechanisms
Some General Principles of the ‘Classical’ Antineoplastic Drugs (Compare with ‘New’ Antineoplastics)
* Most of the conventional antineoplastics directly or indirectly interfere with nucleic acid synthesis, and therefore:
act relatively non-specifically, causing toxicity to any replicating cell population, e.g., bone marrow, GI tract, hair follicles
are given in defined courses and combinations to limit toxicity, i.e., cannot be given continuously due to toxicity
are given with careful consideration of their limiting toxicities, e.g., bone marrow suppression
are given with careful consideration of drug interactions
are most effective when all or most malignant cells are dividing, and before accumulation of genomic diversity leading to resistance, i.e., early in the disease
General Principles – combination drugs
…Antineoplastic drugs are given in combination to:
- provide cytotoxic actions at multiple sites
- avoid the toxicity of high doses of single agents
- delay the emergence of resistance
- synchronize tumor cell growth for application of cell cycle specific agents at the appropriate time
General Principles – Chemotherapy Toxicities (star)
The Cell Cycle and Cancer Chemotherapy
Cell-Cycle Specific (CCS): Cancer Chemotherapy Cytotoxic Agents
- Drugs that inhibit or kill during a particular phase of the cell cycle
. - Schedule dependent – need to maintain a cytotoxic level for enough time to allow a tumor to cycle through
. - Are more effective against tumors with high growth fractions
Antimetabolites: 1.) Antifolates - general, examples, MOA, structure
- Structural analogs of folic acid
- Examples include methotrexate (amethopterin; Trexall®; Rhematrex®), trimetrexate (Neutrexin®), pemetrexed (Alimta®), pralatrexate (Folotyn®), and aminopterin… NOTE: Methotrexate is the most important prototype - what the rest of the drug will eventually turn into
- Folic acid is present in several forms; an active form is tetrahydrofolic acid (TFA)
- Involved in transfer of single carbon units as methyl groups
- Involved in purine and pyrimidine metabolism (i.e., synthesis)
.
RED MOA: Inhibit dihydrofolate reductase & antifolate activity – also, inhibition of 1 carbon transfers (methyl transfer rxn) associated with amino acid synthesis (i.e., serine and methionine)
Thymidylate Synthesis and Folate Metabolism as Targets
of Chemotherapy
Inhibit dihydrofolate reductase & antifolate activity… so no methyl transfer reaction! thus no serine and methionine amino acid!
Leucovorin Rescue
Leucovorin rescue = Rescue normal cells using
N5formylH4folate (i.e., leucovorin), which is used to reduce toxicity of antifolates. Leucovorin is a reduced folate derivative.
.
1.) Low dose methotrexate enters cells through folate transporters; high dose methotrexate enters cells through both passive uptake and folate transporters (can enter cells independent of folate transporters)
2.) Leucovorin is a reduced folate derivative that can be used to replenish folate pools in normal cells
—- Low doses of leucovorin enter the cell with intact folate transporters
—- Taken up by normal cells with folate transporters
3.) Bypasses the methotrexate blocked enzyme to replenish the folate pool
4.) Normal cells only have reduced folate (leucovorin) despite MTX inhibition of DHFR, tumor cells remain folate starved
5.) Use of leucovorin with 5-FU for colon cancer treatment – increased efficacy of 5-FU – binds TS more avidly when given with leucovorin
Antimetabolites: 2.) Purine Analogs - general, MOA
Antimetabolites: 5-fluorouracil (5-FU; Efudex®) - more info, MOA, uses
- Amidophosphoribosyltransferase (also GPAT) and orotate phosphribosyl transferase activity is required to form 5-fluor-2’-deoxyuridine-5’-phosphate (FdUMP) from 5-FU
- RED MOA - F-dUMP binds to thymidylate synthase and methylene-tetrahydrofolate to inhibit thymidylate synthase activity and block thymidine production.. -> Thymine starvation –> Inhibition of DNA synthesis
- 5-FU is also bioactivated to 5-FUTP and incorporated into RNA interfering with RNA processing (RNA stability and function)
- 5-FU has a short t½ (10-15 min) due to extensive metabolism
- Use: colorectal cancer; solid tumors (e.g., breast cancer, GI malignancies, hepatoma, head & neck cancer)
Antimetabolite: Capecitabine (Xeloda®) - more info, MOA, uses
- Capecitabine is a prodrug: requires carboxylesterase, cytidine deaminase, and thymidine phosphorylase activity to produce active form, 5-FU
- Hydrolysis to 5-FU by thymidine phosphorylase, present at higher levels in some tumors, leads to concentration in tumors
- Oral bioavailability – metabolic activation
- Cytotoxicity similar to 5-FU
.
NOTE: most of these agents have to be given IV! But capecitabine can be given orally!
Antimetabolites: Cytarabine (ara-C): literally just know everything about it lol
- S-phase specific
- Ara-C – ara for arabinose sugar
- Bioactivation to araCMP by deoxycytidine kinase; –> araCTP
- Inhibits DNA polymerase alpha and beta blocking DNA synthesis and DNA repair
- Short t½ due to extensive metabolism
- Not effective orally as it is metabolized to ara-uridine in the liver
- Use: hematologic malignancies; acute myelogenous leukemia & non-Hodgkin’s lymphoma (not active in solid tumors)
- Toxicity – myelosuppression, mucositis, N&V
Antimetabolites: Gemcitabine literally just know everything about it lol
- Structure and mechanism similar to ara-C
- Rapidly eliminated from the plasma; greater cellular accumulation
- Use: broader than ara-C, including solid tumors
Hydroxyurea… and antimetabolite? (unsure).. MOA/ how it works
Hydroxyurea Inhibits Ribonucleotide Reductase…Used in treatment of polycythemia vera, a myeloproliferative neoplasm (JAK2 mutation present), CML, & myeloid metaplasia
Taxanes vs Vinca alkaloids (general)
Antimitotic Agents: Vinca Alkaloids
From vinca rosea, the Periwinkle plant..MOA, examples, indications, structure, toxicity
1.) MOA ‐ bind to tubulin preventing the formation of
microtubules by inhibiting tubulin polymerization
2.) Examples and use:
— Vincristine (Oncovin®; Vincasar®) – hematologic cancers; some use in solid tumors
— Vinblastine (Velban®) – use in lymphomas and solid tumors
— Vinorelbine (Navelbine®): semisynthetic derivative of
vinblastine; use in NSCLC, breast, and ovarian cancer
3.) Note unique clinical activity of vinblastine versus
vincristine. Vincristine has higher affinity for axonal
microtubules, hence greater neurotoxicity.
4.) Toxicity – myelosuppression (less with vincristine),
neurotoxicity (greater with vincristine), N/V, and
alopecia (greater with vinblastine)
Antimitotic Agents: Taxanes…MOA, examples, indications, structure, toxicity, resistance
1.) MOA ‐ taxanes act by binding to microtubules to promote tubulin polymerization producing aberrant microtubular structures resulting in inhibition of mitosis and cell division.
.
2.) Examples:
—- Paclitaxel (Taxol®; Onxol®) – derived from the bark of the Pacific and European Yew tree.
—- Albumin‐bound paclitaxel (Abraxane®) – selective binding to specific albumin receptors present on some tumor cells
—- Docetaxel (Taxotere®) – semisynthetic taxane derived from the European Yew tree
—- Cabazitaxel (Jevtana®) – semisynthetic – poor substrate for P‐ glycoprotein
.
3.) Use: solid tumors (e.g., ovarian cancer, breast cancer, SCLC and NSCLC, head and neck cancer, prostate cancer, others)
.
4.) Resistance: P‐glycoprotein
.
5.) Toxicity – myelosuppression (dose‐limiting neutropenia and anemia), neurotoxicity (numbness and parathesia), ocular and visual disturbances, alopecia, asthenia, fatigue, weakness, allergic reaction, cardiac toxicity
CCS antibiotics
Antitumor antibiotics (G2 ‐ M phase) ‐ bleomycin (Blenoxane®) . . . what is it?, MOA, Uses/ indication, toxicity
- Bleomycin – a small peptide that binds DNA and chelates iron
- CCS antitumor antibiotic acting in G2 phase
- MOA: Bleomycin binds DNA; leads to the formation of free radicals that result in DNA strand breakage and inhibition of DNA synthesis
- Uses: Hodgkin’s and non-Hodgkin’s lymphomas, germ cell cancers, head and neck cancer, squamous cell carcinoma of the skin and cervix
- Toxicity: pulmonary, usually presenting as pneumonitis with cough – may be fatal
.
NOTE: Bleomycin does not interact with DNA via covalent bond…it reacts with the metal that’s adjacent to the DNA…causing release of free radicals and thus damaging DNA/ killing it
CCNS Antitumor Antibiotics: dactinomycin, mitomycin
1.) Mitomycin C (e.g., Mutamycin®)
– Requires bioactivation producing an alkylating agent that cross‐links DNA
– Useful under hypoxic conditions (solid tumors; large solid tumors)
– Toxicity: Hemolytic‐uremic syndrome, manifested as microangiopathic, hemolytic anemia, thrombocytopenia, and renal failure
.
2.) Dactinomycin (e.g., Cosmegen®)
– Actinomycin D
– Intercalates into DNA; blocks RNA and protein synthesis
– Induces single‐stranded breaks act on topoisomerase II
– Uses: Wilms tumor, rhabdomyosarcoma, germ cell
tumors, Ewing’s sarcoma
Alkylating Agents and Platinum Compounds (cross-link DNA)…general classes
NOTE: These directly binds to DNA = most will cause cross link!
Alkylating Agents: Nitrogen Mustards . . .5 examples
Alkylating Agents: Nitrosoureas and others
Platinum Coordinating Agents
Anthracyclines
NOTE: important to know that these tox side effect can cause cardio tox!!!
Miscellaneous Cancer Chemotherapies
