What are the three super categories of classic antineoplastic drugs?
- Alkylating Agents
- Natural Products
What are the 6 subcategories of alkylating agents?
- Nitrogen Mustards
- Methylhydrazine derivative
- Alkyl sulfonate
- Platinum Coordination complexes
What are the 6 sub categories of natural product antineoplastics?
- Vinca alkaloids
What are the three subcategories of antimetabolite antineoplastic drugs?
- Folic acid analogues
- pyrimidine analogs
- purine analogs
What are the nitrogen mustard antineoplastics on our drug list?
5 with 2 BOLD
What is the one (non-nbold) methlhydrazine derivative on the drug list?
What is the alkyl sulfonate antineoplastic drug that is on our drug list?
What are the three nitrosoureas on our drug list?
What are the two (non-bold) triazenes?
What are the three platinum coordination complexes on our drug list?
What are the three vinca alkaloids on the drug list? (2 bold)
What are the two taxanes? (one bold)
What are the two Epipodophyllotoxins on our drug list?
What are the two camptothecins on our list? (no bold)
What are the seven antibiotics for neoplasms on our drug list?
- •Dactinomycin (actinomycin D)
- •Mitomycin C
What are the two enzyme drugs on our list? (one bold)
What are the two folic acid analogs? (one bold)
- Methotrexate (MTX)
What are the 6 pyrimidine analogs on our list? (one BOLD)
- Cytarabine (cytosine arabinoside)
- Fluorouracil (5-fluorouracil; 5-FU)
What are the 5 purine analogs? (one bold)
- Mercaptopurine (6-MP)
What is "primary induction therapy"?
•The main treatment that provides the best possible outcome
•Also called first-line therapy
What is neoadjuvant therapy?
Give an example
•Treatment given BEFORE primary induction therapy in order to improve outcome
•E.g., Chemo or radiation to shrink a tumor before surgery
What is adjuvant therapy?
•Additional therapy given CONCOMITANTLY or AFTER primary induction therapy in order to reduce the probability of relapse
What occurs in G1?
Synthesis of components needed for DNA synthesis
What occurs in S phase?
Synthesis of DNA
What occurs in G2?
Synthesis of components needed for mitosis
What happens in M phase?
What happens in G0?
Resting phase of cell cycle
Where are the four cell cycle checkpoints?
- G1 to S
- End of S
- G2 to M
- End of M
Why is the cell cycle stuff important for this topic?
Many antineoplastics are either cell cycle specific or cell cycle non-specific
What are the 7 categories of drugs that are cell cycle specific?
- Antitumor antibiotic - Bleomycin
- Vinca alkaloids
- topoisomerase I inhibitors
- Topoisomerase II inhibitors
What phase of the cell cycle do antimetabolits work on?
What phase of the cell cycle does bleomycin work on?
What cell cycle phase do taxanes work on?
What cell cycle phase do vinca alkaloids work on?
What phase do topoisomerase I inhibitors work on?
What cell cycle phase do Topoisomerase II inhibitors work on?
What are the 4 categories of cell cycle nonspecific agents?
- Alkylating agents
- antitumor antibiotics (except bleomycin)
- platinum analogs
What is "growth fraction"?
Ratio of proliferating cells to resting cells
What is growth fraction a determinant of?
Responsiveness to chemotherapy
What are 4 examples of cells with high growth fractions?
- •Bone marrow
- •GI tract
- •Hair follicles
- •Sperm-forming cells
What is the smallest detectible tumor mass and cell count?
One billion cells
How does Burkitt lymphoma respond to chemotherapy?
Burkitt lymphoma is an example of a high growth fraction neaplasm, and is thus cureable by chemotherapy.
How does colorectal carcinoma, a low growth fraction neoplasm, respond to chemotherapy?
Poorly, as is typical of low growth fraction neoplasms
How can the growth fraction of solid tumors be increaseD?
Reduction of the tumor burden by surgery or radiation
What percent of cells does a three-log kill eliminate?
Efficacy vs toxicity must be carefully considered in antineoplastic therapy. What are five example of factors to consider?
•Renal and hepatic function
•Bone marrow reserve
•General performance status
•Concurrent medical problems
Describe what is meant by "primary resistance".
What is this thought to be due to?
•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
What are four examples of single agent resistance pathways?
- •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
What is the important example of a method by which multidrug resistance occurs?
What gene is associated with this?
•The P-glycoprotein is an ATP-dependent efflux pump that actively pumps antineoplastic agents out of cells
What are five drugs that are especially prone to ATP-dependent transport resistance?
- vinca alkaloids
What is the major limiting factor in tx of cancer with chemo?
Lack of specificity, hits cells we would prefer they not
What are the major tissue sites of chemo toxicity?
•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 antineoplastics are themselves mutagenic and can give rise to secondary neoplasms years after therapy. What is an example of this?
Alkylating agents have been shown to cause AML and ALL
What are five common adverse effects that occur during therapy with nearly all classic antineoplastic agents?
What are three other common adverse effects of the classic antineoplastic agents?
•Myelosuppression – can lead to impaired wound healing and predisposition to infection
•Low sperm counts and azoospermia
•Depressed development of children exposed to antineoplastic agents
In chemotherapy it is important to take steps that limit adverse effects. One way to do this by selecting a route of administration that limits toxicity.
What are some pharmacological agents for reducing toxicity?
Oh, also have the patient rest and recover.
•Hematopoietic agents for neutropenia, thrombocytopenia, and anemia
•Serotonin receptor antagonist (ondansetron) and other drugs for emetogenic effects
•Bisphosphonates to delay skeletal complications
Which nitrogen mustard is the most widely used alkylatin agent and one of the most emetogenic agents?
What is the MOA for alkylating agents?
Form covalent linkages with DNA
Cyclophosphamide is a prodrug that is degraded to 4-hydroxycyclophosphamide and aldophosphamide. Aldophosphamide is further degraded to a toxic metabolite.
What is this metabolite and what is it known for causing?
•Acrolein: causes hemorrhagic cystitis
What is used as prophylaxis for the acrolein induced cystitis?
Mesna - inactivates acrolein
Systemic toxicities d/t alkylating agents are dose related. What can happen at the site of injection?
Direct vesicant effects and tissue damage. (Oral admin is the ticket)
Many alkylating agents produce acute toxicity, such as nausea and vomiting within 30-60 minutes. This can be pretreated with serotonin antagonists.
What are some examples of delayed toxicities from alkylating agents.
- bone marrow suppression with leukopenia
- mucosal ulceration
- intestinal denudation
What is one specific delayed toxicity for cyclophosphamide?
What are two delayed toxicities specific to cisplatin?
renal tubular damage
What is a specific delayed toxicity associated with busulfan?
What are the three major types of antimetabolites? What is one bolded drug from each category?
1.Folic acid analogs (methotrexate)
2.Pyrimidine analogs (5-Fluorouracil)
3.Purine analogs (6-mercaptopurine)
What is the MOA for the antimetabolites?
Structural analogs to compounds necessary for cell proliferation that block or subvert pathways that are involved in or lead to cell replication.
So, based on their MOA, what part of the cell cycle do the antimetabolites work at?
What is the specific MOA of methotrexate?
Inhibits dihydrofolate reductase (DHFR)
What are three indications for use of methotrexate?
Describe the dosing as high or low for each.
•Cancer - High dose
•Rheumatoid arthritis - Low dose
•Psoriasis - Low dose
In the event of an accidentaly methotrexate overdose, how would you treat the patient?
Leucovorin - allows reduced folate to bypass the DHFR
What is the prototype pyrimidine structural analog?
5-FU is a prodrug, what are the active components, and what do they do? 3
- FdUMP - covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate.
- FdUTP - incorporated into DNA
- FUTP - incorporated into RNA
What is the purine structural analog?
What are the MOA of 6-Mercaptopurine (6-MP)?
•Inhibition of several enzymes of de novo purine nucleotide synthesis
•Incorporates into DNA and RNA
Biotransformation of 6-MP includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase via first pass effect.
What medication must we use caution with when considering using 6-MP?
How does this change the dosing for oral and IV 6-MP?
- Allopurinol - commonly used to prevent hyperuricemia d/t tumor cell lysis, will result in increased levels of 6-MP, since it is a xanthine oxidase inhibitor.
- Must reduce the oral 6-MP dose by 50 - 75% when taking with allopurinol.
- IV dosing is unaffected since not subject to first pass metabolism. (xanthine oxidase is in the liver)
The antimetabolite drugs have relatively little acute toxicity after initial dose, and are cell cycle specific, working on the S-phase.
What are the three common routes of administration?
When would you want to do an intrathecal administration of methotrexate?
When there is invasion of the CNS by neoplasm
In addition to diarrhea, nausea, and vomiting, what are 5 more ADR's caused by the antimetabolites?
What are the prototype vinca alkaloids?
Vinblastine and Vincristine
What are two general ADRs of the vinca alkaloids?
Vincristine has some additional ADRs beyond the alopecia and myelosuppression of the vinca alkaloids. What are these?
- numbness and tingling of the extremities
- loss of DTRs
- motor weakness
- autonomic dysfunction
As mentioned previously the vinca alkaloids are associated with myelosuppression. Which one of the two prototypes is this more common with?
Vinblastine more than vincristine
What is the mechanism of action for the vinca alkaloids?
Bind to •β-tubulin and inhibit microtubule assembly
Are vinka alkaloids cell cycle specific?
Yes. They inhibit mitosis (M phase)
What is the MOA for taxanes?
Bind to β-tubulin and stabilize microtubule assembly
Based on their MOA, are taxanes cell cycle specific?
Yes, they work on the M-phase
What ADRs are associated with paclitaxel? 2
- Hypersensitivity reactions in hands and toes
- Change in taste
What is the MOA of the camptothecins?
Inhibition of type I topoisomerase
What does type I topoisomerase do?
cuts one strand of dsDNA, relaxes the strand and reanneals it.
What does Topoisomerase II do?
Cuts BOTH strands of dsDNA simultaneously to wind and unwinds DNA supercoils.
What are two inhibitors of type II topoisomerase?
Epidophyllotoxins - etoposide
Anthracycline antibiotics - doxorubicin
Are the topoisomerase inhibitors cell cycle specific?
Yes, except for anthracyclines which are CCNA.
They are primarily S phase, but also G1 and G2
What are the four major antineoplastic antibiotics?
- anthracyclines - doxorubicin
What are the main effects of the antitumor antibiotics?
mainly on DNA
All the antineoplastic antibiotics are products of various species of what bacterial genus?
What are the MOA of doxorubicin?
- Inhibit topoisomerase II
- Intercalate DNA
- Oxygen free radicals cause single and double strand DNA breaks
Based on the MOA of doxorubicin, is it cell cycle specific?
Cell cycle nonspecific - but cycling cells are more susceptible.
What ADRs are associated with doxorubicin?
- significant cardiotoxicity d/t free radical production
- cumulative cardiac dmg leads to arrhythmias and heart failure
What is the MOA of bleomycin?
Free radical production leading to single and double stranded DNA breaks
Is bleomycin cell cycle specific?
yes - G2 arrest
What are the ADRs associated with Bleomycin?
- minimal myelosuppression
- significant pulmonary toxicity (usually presents as pneumonitis with cough, dyspnea and dry inspiratory crackles.
What is the prototype antineoplastic enzyme drug?
What is the MOA for L-asparaginase?
hydrolyzes circulating L-asparagine into aspartic acid and ammonia, effectively inhibiting protein synthesis
So, cells can synthesize their own amino acids, why then is L-asparaginase useful?
Acute lymphoblastic leukemia (ALL) cells lack the enzyme asparagine synthetase and thus require an exogenous source of L-asparagine.
Is L-asparaginase cell cycle specific?
Yes - G1
What are the acute ADRs associated with L-asparaginase?
- Acute hypersensitivty reaction
What are the delayed toxicities associated with L-asparaginase?
- Increased risk of clotting and bleeding
- CNS toxicity
What are the categories of miscellaneous antineoplastic agents?
- Substituted Urea
- Differentiating agents
- Biological response modifiers
- protein tyrosine kinase inhibitors
- mTOR inhibitors
- proteosome inhibitors
- monoclonal antibodies
The BCR-ABL fusion protein results from the t(9:22) translocation and is found in 95% of patients with CML. What is the main drug we use on this?
What is the MOA of Imatinib?
- A small molecule inhibitor of the ABL tyrosine kinase
- Can also inhibit the RTKs - PDGFR and c-KIT
When mutated, overexpressed, or structurally altered, tyrosine kinases can become potent oncoproteins. Aberrant tyrosine kinase activity can occur in receptor tyrosine kinases or cytoplasmic kinases, and has been identified in many human neoplasms.
What do we use to target the extracellular RTK?
How about the cytoplasmic kinases?
Extracellular - mabs
Intracellular - nibs
What is the MOA of erlotinib and gefitinib?
Inhibit epidermal growth factor receptor (EGFR), an RTK
What toxicities are erlotinib and gefitinib known for?
Dermatologic toxicities - acneform rash
What epidermal growth factor receptor is expressed on 25-30% of breast cancers?
What drug do we use to inhibit HER2/neu?
What ADR is associated with Trastuzumab?
What does this mean for us in clinical practice?
Cardiovascular complications including decreased LVEF and heart failure.
Must get baseline CV measurements prior to treatment, and monitor heart function periodically through therapy.
Bevacizumab is used in tx of colorectal and lung cancers. What is its target and what does it down regulate?
VEGF - This antibody is against the ligand rather than the receptor.
Cetuximab is used in tx of colorectal, lung, pancreatic and breast cancers. What is its target?
EGFR - tyrosine kinase
Rituximab is used in tx of non-hogkin's lymphoma, what is its target antigen? What is that antigens function?
CD20 - proliferation and differentiation
In acute promyelocytic leukemia granulocytic maturation is inhibited by the t(15;17) translocation which creates the fusion protein PML-RARα. What drug do we use to treat this?
Tretinoin (all-trans-retinoic acid ATRA)
What is the MOA of Tretinoin?
•binds to the PML-RARα fusion protein and antagonizes the inhibitory effect on the transcription of target genes
•Within 1-2 days the neoplastic promyelocytes begin to differentiate into neutrophils, which rapidly die
What are the ADRs of Tretinoin?
•Vitamin A toxicity and retinoic acid syndrome are common adverse effects
Biological response modifiers are asgents that stimulate or suppress the immune system to help the body fight cancer. What are the two bio response molecules we discussed?
What is the MOA of Interferon?
Inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase phagocytic activity of macrophages, augment cytotoxicity of lymphocytes for target cells.
ADR's of interferon?
bone marrow depression
MOA for Interleukin-2?
Increase cytocoxic killing by T cells and NK cells
What is the major toxicity associated with IL-2?
Capillary leak syndrome