Anticancer Drugs Flashcards
What makes a normal cell into an abnormal cell? (6 things)
1) Sustaining proliferative signal
2) Evading growth suppressors
3) Activating invasion and metastasis
4) Eliciting replicative immortality
5) Inducing angiogenesis
6) Resisting Cell Death
These are all targeted with anticancer drugs
What are the 4 things an anticancer drug can act on?
1) Action on DNA
2) Action on Mitotic Signal
3) “Targeted” drugs
4) Hormonal Agents
What two things do DNA drugs do?
1) Damage DNA
2) Inhibit synthesis or function
What kind of drugs damage DNA?
1) Cyclophosphamide by alkylation
2) Doxorubicin by free radical generation
What kind of drugs inhibit synthesis or function?
1) Antimetabolites like methotrexate
2) Topoisomerase inhibitors like etoposide
What kind of drugs act on mitotic spindle?
Microtubule inhibitors like vincristine
What are some targeted drugs?
MABs directed at surface cell receptors
NIBs directed at receptor tyr kin (inside cell below cell surface)
mTOR inhibitors (prevent 2nd phase of Tcell activation)
An ideal agent would be what?
100% selective, eradicating tumor and sparing the host; no drugs currently meet this criteria
Newer agents aim to? (5 things)
1) Force terminal maturation with no proliferative potential
2) Alter invasive/metastatic potential of tumors
3) Prevent angiogenesis and thereby tumor growth
4) Produce tumor radio-sensitization or radioprotection of bystander tissues
5) Peterub tumor - host metabolic and immunologic relationship
These 5 things combined make sure patient does not what?
Die due to treatment instead of disease
What is local therapy done with? and when is it effective?
Radiation or surgery; when metastasis has NOT occurred
What are the two types of chemotherapy?
Systemic adjuvant or neoadjuvant
What is chemotherapy used for? When?
For “de-bulking” and for locally advanced early-stage disease; given prior to surgery or after surgery to end or lessen cancer
What is systemic chemotherapy used for?
Disseminated disease (often only to improve quality of life)
What are hormonal agonists/antagonists used for?
Treatment of hormonally responsive breast and prostate tumors
What is an example of biological therapy?
HER-2/neu targeted agents
Can drugs induce both clinical improvement and significant toxicity?
Yes
Can there be a quality of life improvement without a longevity increase?
Yes
What are some toxicities?
Secondary malignancies, myelosuppression, N/V, alopecia, organ toxicity
What is Tumor Lysis Syndrome (TLS)?
It is a multifactorial process of volume depletion, tubular obstruction, and cytotoxic chemotherapy. When lysis of tumor cells release purine nucleic acids, K+ and P. Causes renal elimination to be saturated (high K and P, low Ca, and gout), uric acid is deposited along with calcium phosphate.
When is TLS seen?
With ALL, burkitts lymphoma, non-Hodgkin’s lymphoma, or solid tumors
What is management of TLS?
Done with hydration (drugs ppt on kidney tubules), acid/base correction, sodium bicarb to alkanlinize the urine; allopurinol to prevent uric acid (gout); rasburicase (recombinant urate oxidase) to degrade uric acid to water soluble allantoin for elimination
What is the normal pathway of Nucleotide Precursors to Uric Acid?
Nucleotide precursors –> Hypoxanthine –> Xanthine –> Uric Acid
What inhibits Xanthine Oxidase?
Allopurinol
What converse Uric acid to Allantoin for elimination?
Rasburicase
When to cell cycle non specific drugs work?
In both cell cycle and resting time
T or F. Cell cycle specific drugs are most effective in phases they are specified for?
Yeah, dummy. Targets appear in each phase
What drugs are specific for M phase?
Taxels and Vinca Alkyloids
What drugs are specific for S phase?
Antimetabolites and Podophyllotoxins
What drugs are specific for G2?
Podophyllotoxins and Bleomycin
What is chemotherapy damage sensed by?
p53 protein resultant from depolarizaton of mitochondrial membrane = release of cytochrome c = apoptosis
What do alkylating agents do?
Leave chemical moiety bound to DNA and destroys DNA topology
Give the 8 classes of alkylating agents and a prototype of each.
1) Nitrogen mustards - cyclophosphamide (Ifosfamide, mechlorethamine, melphalan)
2) Alkyl Sulfonates - Busulfan
3) Nitcosoureas - BCNU, CCNU
4) Aziridines - Thiotepa
5) Antibiotics - Mitomyocin C
6) Platinum Drugs - cisplatin (carboplatin, oxaliplatin)
7) Triazenes - Dacarbazine
8) Hydrazines - procarbazine
True or False. Even if drugs have similar structures they can still affect different cancers.
True
The active part of Bis(chlorotheyl)amine Alkylating agents is what?
Chloroacetylaldehyde
What are the Bic(chloroethyl)amine drugs?
Cyclophosphamide, isosfamide, merchlorethamine, melphalan, chlorambucil
What do Bic(chloroethyl)amine drugs do?
Transfer alkyl group to DNA
What are the targets of Bic(chloroethyl)amine drugs?
N7 Guanine»_space; N1, N3 adenine, N3 cytosine, O6 guanine
Do Bic(chloroethyl)amine drugs cause a ss or ds DNA modification?
Either
What does the strand breakage through guanine excision of Bic(chloroethyl)amine drugs lead to?
Miscoding
What phase cells are most suseptible to Bic(chloroethyl)amine drugs?
Replicating (late G1-S) are MOST; leads to G2 block
How does resistance occur to Bic(chloroethyl)amine drugs?
Decrease uptake, decrease activation, increase inactivation (conjugation) of reactive moiety (increase rate and capacity) or increase repair of DNA miscodes (then supply drug to overwhelm repair mech)
Bic(chloroethyl)amine has dose related toxicities and is especially toxic to what kind of cell populations?
Rapidly dividing, like bone marrow, GI (stomatitis, mucositis, diarrhea), Reproductive (oligospermia, amenorrhea), Alopecia
How does Bis(chloroethyl)amine cause CNS problems?
Ifosfamide (from chloroacetaldehyde) = altered mental status, coma, generalized seizures, cerebellar ataxia
All alkylating agents cause what kinds of problems?
Lung problems, specifically cyclophosphamide, chloambucil, melphalan; fibrosis, dyspnea, cyanosis, pulm insufficiency
Do Alkylating agents cause carcinogenicity?
Yes; leukemias and solid tumors
Do Alkylating agents cause Teratogenicity?
Yes; 1/6 chance of malformed offspring
Renal failure is common in what 2 Alkylating agents?
Cyclophosphamide and ifosfamide; also they are responsible for urotoxicity/bladder tumors - they release acrolein
What is MENSA?
An antidote to acrolein; toxic- binds it up
What does MENSA do?
It is a prophylactic chemoprotectant from hemmorhagic cystitis
Is cyclophosphamide an immunosuppressant?
YES; it prepares the body for stem cell transplantation; total body irradiation, busulfan, cyclophosphamide; also used for RA
What are the toxicities of the alkyl sulfonate: busulfan.
Myelosuppression at conventional doses, pulmonary fibrosis, amenorrhea and fetal malformation; rarely develop asthenia and hypotension (Resembles addisons)
What are the 2 nitrosoureas?
Carmustine - BCNU; Lomustine - CCNU
Are BCNU and CCNU alkylators?
Yes
What do carmustine decomposition products do?
Carbamolyate proteins - inhibit DNA repair
Do one or both protein adducts contribute to carmustine toxicity?
Both
Is cross resistance common between these 2?
No, because of second mechanism of action
Does BCNU and CCNU enter the CNS in measurable amounts?
Yes; highly lipophilic and nonionized at psyiologic pH
The two drugs that are known for causing hepatic toxicity?
Busulfan and BCNU
What leads to the hepatic toxicity from Busulfan and BCNU?
Hepatic veno-occlusive disease - often fatal, caused by strong alkylating agents and starts 2-10 weeks after starting therapy; due to endothelial intimal edema venular wall fragmanetation
What is Thiotepa (Thioplex)?
A polyfunctional aziridine alkylator formed by hydrolysis.
Is thiotepa lipophilic?
Yes; administered IV, IVe, IC
Is thiotepa neurotoxic?
Yes; coma and seizures at high doses
How is mitomycin C administered and are there reaction?
Injected; yes, hemolytic anemia (endothelial damage)
How does Cisplatin, carboplatin work?
Intrastrand DNA links, predominantly N7 of guanine (DNA replication and transcription interrupted)
Is Cisplatin nephrotoxic?
Yes; force hydration and chloride diuresis
What is a protective agent for Cisplatin nephrotoxicity?
Amifostine cytoprotective agent
Is Cisplatin orotoxic?
Yes (tinnitus)
Is Cisplatin a myelosuppressive agent?
Yes; mild to moderate with transient leukopenia and thrombocytopenia
True or False, Cisplatin leads to progressive peripheral, motor, and sensory neuropathy.
True
What are the 2 newer derivations to reduce toxicity of Cisplatin?
Carboplatin and Oxaliplatin
What is Dacarbazine?
A metabolically activated DNA methylating agent; resistance by removal of methyl groups from the O6 guanine bases by AGT
Procarbazine (matulane) (O6-guanine) is a highly reactive DNA methylator via CYP activation, what does it weakly inhibit?
It is a weak MAO inhibitor with Disulfiram-like actions - avoid alcohol
The O6 alkylguanine-DNA alkyltransferase (AGT) is what?
A suicide protein acceptor that inactivates the protein to repair DNA to original structure
What is the goal of Antimetabolites?
To not impact existing drugs but provide false building blocks for further synthesis
What are the Folic Acid Analogs?
Methotrexate and Pemetrexed
What are the Pyrimidine Analogs?
Fluorouracil (5-FU), Capecitabine, Cytarabine, Gemcitabine
What are the purine analogs and related inhibitors?
6-mercaptopurine, thioguanine, pentostatin, Cladribine, Fludarabine
What is the mechanism of action of Methotrexate?
It is a Dihydrofolate reductase inhibitor; it denies availability of the THF cofactor for RNA/DNA synthesis
Are analogs actively uptaken by cells?
Yes, poor passage of BBB
If polyglutamated inside the cell are they trapped?
Yes
What is Pemetrexed?
GART inhibitor for mesothelioma
What is Trimetrexate?
Designed for BBB penetration for pneumocystis carinii
What is polyglutamation?
The process that traps drug in the cell
What are toxicities of Methotrexate?
GI, N/V, abdominal distress, Bone marrow, anemia, lymphoproliferative disorders, weak acid; ppts in tubules, pneumonitis, anemia in RA or psoriasis
Is 5-fluorouracil; 5-FU toxic?
You betcha
What does FdUMP do?
DNA synth inhib by thmineless death
What does FdUTP do?
Incorporated into DNA inhibition of synthesis and function
What does FUTP do?
Interference with mRNA translation
What are the toxicities of 5-FU?
Hand-foot syndrome - peripheral neuropathy
Does Leucovorin increase formation of TS complex?
Yes
What does increased formation of TS complex do?
Enhanced responsiveness to 5-FU
What is Capecitabine?
Oral agent that is similar in toxicity to 5-FU, Hand-foot happens more frequently, it is converted to 5-FU
What does chronic use of Capecitabine lead to?
Erasing of fingerprints.
