Anti-Cancer Drugs: Alkylating Agents

Question 1

Antimetabolites

Answer 1

Act on S phase of the cell cycle

Question 1

In which phase of cell growth/proliferation do non-cell-cycle-specific drugs act?

Answer 1

They work in both the cell cycle and in resting (G-0) cells

Question 1

Ifosfamide

Answer 1

An alkylating agent in the nitrogen mustard class It releases acrolein, which has adverse effects on the body

Question 1

Describe adverse effects of Cisplatin

Answer 1

Its dose-limiting toxicity is nephrotoxicity, which can be minimized with forced hydration and a administration of amifostine. It can also accumulate in the inner ear and cause ototoxicity, which leads to tinnitus and hearing loss Progressive peripheral, motor, and sensory neuropathy in the form of stocking-glove distribution Development of acute myeloid leukemia about 4 years after treatment

Question 2

Cisplatin

Answer 2

An alkylating agent in the platinum drug class Becomes active in aqueous solution, so no other activation required. Administered via IV MOA: Introduces intra-strand DNA links at N7 of guanine to interrupt DNA replication and transcription

Question 2

Describe the adverse effects of alkylating agents

Answer 2

If injected, they produce damage to blood vessels (called vesicant action); however, it can be given orally Can produce a rapidly-appearing congestive heart failure that does not produce long-term consequences if the person survives. Secondary malignancies and teratogenicity Lungs: fibrosis, dyspnea, cyanosis, pulmonary insufficiency

Question 3

Rasburicase

Answer 3

Used to treat toxicity of chemotherapy to the kidney by speeding the conversion of uric acid to allantoin. This prevent deposition of uric acid that could eventually precipitate in the renal tubules.

Question 4

Name two platinum drugs What type of drug is this?

Answer 4

CISPLATIN and carboplatin This is an alkylating agent

Question 4

Name a drug in the alkyl sulfate class and describe adverse effects

Answer 4

Busulfan, which is metabolized in the liver. Can be given orally or IV. Patients can develop veno-occlusive disease of the liver (a form of vascular damage in the liver that can be fatal but is reversed with defibrotide) and an Addison’s disease-like effect

Question 6

How to cure/treat a solid tumor

Answer 6

1) surgically excise it if in a convenient anatomical location (sometimes chemo is used in conjunction to get rid of any remaining post-surgical cells) 2) Chemotherapy by itself 3) Radiation by itself 4) Radiation with chemotherapy

Question 6

Discuss the mechanism of action of alkylating drugs

Answer 6

These guys transfer an alkyl moiety onto DNA, usually at the most approachable site of the N7 of guanine. Once the initial attachment is made, the drug can then attach a second alkyl moiety to the same strand (intra-strand linkage) or to the complementary strand (DNA cross-linking). These actions result in strand breakage through guanine excision and in miscoding.

Question 7

Defibrotide

Answer 7

Drug used to reverse veno-occlusive disease of the liver, which can occur after patient receives either Busulfan or BCNU (Carmustine) drugs

Question 8

Name a drug class that works on the S-phase of the cell cycle

Answer 8

Antimetabolites

Question 9

Describe adverse effects of ifosfamide

Answer 9

Altered mental status, coma, generalized seizures, cerebellar ataxia Renal failure - proximal tubules affected and difficulty in electrolyte resorption Urotoxicity and bladder tumors, resulting in severe hemorrhagic cystitis, requiring the patient to take Mesna, a drug, as well as receive hydration.

Question 10

Name a drug that works on the G2 phase of the cell cycle

Answer 10

Bleomycin

Question 11

Tumor Lysis Syndrome

Answer 11

A possible side effect of chemotherapy Occurs because when tumor cells lyse, they release their contents into the bloodstream; the contents then travel to the kidney, where organ damage can occur. Patients might experience volume depletion, tubular obstruction, uric acid deposition (which precipitates in renal tubules), and saturation of renal elimination, leading to increased K+ and P+ / decreased Ca2+. Treat with hydration and the drugs allopurinol (to reduce uric acid) or rasburicase (to speed conversion of uric acid to allantoin).

Question 12

Bleomycin

Answer 12

Works on the G2 phase of the cell cycle

Question 14

What do you call chemotherapy treatment that occurs prior to other procedures?

Answer 14

neo-adjuvant therapy

Question 15

Name a drug in the triazene class

Answer 15

Dacarbazine

Question 16

Brief overview of the cause of nausea and vomiting in cancer?

Answer 16

The stimulus for nausea and vomiting can arise: 1) from detection of the drug at the base of the fourth ventricle 2) from detection by the “chemo trigger zone” in the GI tract 3) from detection thru higher order cortical input, relaying the psychological aspects of impending chemotherapy.

Question 16

Mechlorethamine

Answer 16

An alkylating agent in the nitrogen mustard class

Question 17

Is there a use for cyclophosphamide outside of cancer treatment?

Answer 17

Yes, to prepare a patient for allogenic stem cell transplantation or to treat rheumatoid arthritis

Question 18

Name four drugs in the nitrogen mustard class. What type of drug is this?

Answer 18

cyclophosphamide (prototype), mechlorethamine, melphalan, and ifosfamide These are alkylating agents

Question 19

What are outcomes of drug administration?

Answer 19

1) Improvement, as seen via a decreed in tumor markers, a CAT/PET/MRI scan, improvement of organ, or improvement of quality of life. 2) Toxicity, as seen with secondary malignancies, organ toxicity, and sterility. 3) Tumor Lysis Syndrome: occurs because when tumor cells lyse, they release their contents into the bloodstream; the contents then travel to the kidney, where organ damage can occur. Patients might experience volume depletion, tubular obstruction, uric acid deposition, and saturation of renal elimination, leading to increased K+ and P+ / decreased Ca2+. Treat with hydration and the drugs allopurinol (to reduce uric acid) or rasburicase (to speed conversion of uric acid to allantoin).

Question 21

Podophyllotoxins

Answer 21

Act on the S and G2 phases of the cell cycle

Question 23

How do the newer cancer drugs differ from their older counterparts?

Answer 23

Older drugs aim to kill the tumor, whereas newer drugs are focused on mitigating growth (prevent angiogenesis, force terminal maturation, etc.); thus, cancer becomes a lifelong disease to manage. These drugs can cost 50K $ though.

Question 24

In general, what do cell-cycle-specific drugs do?

Answer 24

They act on a stage of the cell cycle. This means that only some cancer cells will be in that portion of the cycle at any given time.

Question 24

Describe the contents of a drug cocktail used to treat emesis

Answer 24

Serotonin antagonist, NK-1 antagonist, and a corticosteroid Methylprednisone and dexamethasone are also effective to treat emesis.

Question 25

Name a drug in the hydrazine class

Answer 25

Procarbazine

Question 27

Melphalan

Answer 27

An alkylating agent in the nitrogen mustard class Adverse effect: Lung fibrosis

Question 28

CCNU (Lomustine)

Answer 28

An alkylating agent in the nitrosoureas class Orally administered

Question 29

Allopurinol

Answer 29

Used to treat toxicity of chemotherapy to the kidney by reducing the amount of uric acid. This prevent deposition of uric acid that could eventually precipitate in the renal tubules.

Question 31

Cyclophosphamide

Answer 31

An alkylating agent in the nitrogen mustard class; it is the prototype It must be activated via conversion to a 4-hydroxy metabolite, which exists in equilibrium with aldophosphamide. Next, the drugs are delivered to normal and tumor tissue, and aldophosphamide is converted to cytotoxic forms of phosphoramide mustard and acrolein. A highly associated toxicity is the drug’s effect on the lungs, leading to dyspnea, pulmonary insufficiency, cyanosis, and fibrosis. In addition, the acrolein produced can cause hemorrhagic cystitis, requiring the patient to receive a drug called Mesna, as well as hydration.

Question 32

Location of proliferating cell populations upon which cancer drugs have an effect

Answer 32

1) Lining of the oral cavity and GI tract 2) Hair 3) Myelosuppression after about 10 days

Question 33

Mesna

Answer 33

Often given in concert with ifosfamide and cyclophosphamide, two drugs in the nitrogen mustard class of alkylating drugs that cause adverse effects in the kidney and bladder. There, it complexes with and inactivates acrolein. Can be given intravenously or orally.

Question 34

Procarbazine

Answer 34

An alkylating agent in the hydrazine class A highly reactive DNA methylator via CYP activation Causes chromatid breaks and translocations Resistance rapid when used alone Adverse effects: Hypertensive drug-drug reactions, as well as nausea and headache if taken with alcohol.

Question 35

Dacarbazine

Answer 35

An alkylating drug in the triazene class A DNA methylating agent that is resisted by cancer cells through the removal of methyl groups Must be metabolically activated

Question 36

Resistance Mechanisms to Drugs by Tumor

Answer 36

Many times, response to a drug is great - radical reduction of tumor….but what’s left is a population of tumor cells that are inherently resistant to tumor treatment Methods: 1) Increased capacity to repair DNA damage 2) produce large quantities of free radical scavenging agents 3) up-regulating P-glycoprotein, which can eject drug out of the tumor cell against concentration gradient

Question 37

Adverse effects of Decarbazine

Answer 37

Myelosuppression Chills, fever, and myalgias a few hrs after therapy

Question 38

Name two drugs in the nitrosoureas class What type of drug is this? Describe its phenotype

Answer 38

BCNU and CCNU These drugs are alkylating agents These drugs are lipophilic and non-ionized and therefore enter the CNS easily. Because they can cross the blood brain barrier, they are given to treat brain tumors.

Question 39

4 basic categories of anti-cancer drugs (based on mechanism of action)

Answer 39

1) drugs that interact with cell membrane receptors or their associated tyrosine kinase; drugs that block things like mTOR. 2) Interrupt cell division by blocking the essential activity of the mitotic spindle or by inhibiting DNA replication via topoisomerase activity 3) Those that have an effect on existing DNA via alkylation or free radical damage 4) Create false “building blocks” that inhibit the synthesis or function of DNA Note: DNA damaging agents = alkylating agents DNA synthesis inhibitors = antimetabolites

Question 41

BCNU (Carmustine)

Answer 41

An alkylating agent in the nitrosoureas class Can also carbamolyate proteins, preventing DNA repair. Parenteral administration Toxicity: convulsions, CNS dysfunction-encephalopathy and endocrine dysfunction; in addition, patients can develop veno-occlusive disease of the liver (a form of vascular damage in the liver that can be fatal) => reversed with drug defibrotide

Question 42

Toxicity: Cisplatin vs. Carboplatin

Answer 42

Toxic vs. Not as toxic; dose-limiting toxicity is peripheral neuropathy

Question 43

How to cure/treat blood cancers or metastases

Answer 43

1) chemotherapy is the main method 2) Targeted drugs if proven that tumor has specific epitope recognized by antibody (examples are hormonal agonists/antagonists for treatment of hormonally responsive breast and prostate tumors and targeted therapy at things like HER-2

Question 44

Name the five alkylating drug classes

Answer 44

Nitrogen mustards Alkyl sulfates Nitrosoureas Triazenes Hydrazines These drugs may all be alkylating drugs, but they cannot be used for just any tumor. Each drug in each drug class has a specific tumor for which it is used. In addition, the smallest structural changes in the drug can change its spectrum of anti-tumor activity.

Question 45

What do you call chemotherapy treatment that occurs after other treatment methods?

Answer 45

adjuvant therapy

Question 47

Name a drug that works on both the S-phase and the G2 phase of the cell cycle

Answer 47

Podophyllotoxins

Question 48

Amifostine

Answer 48

It is administered with cisplatin to reduce its cytotoxic effect. It generates a metabolite with free radical scavenging capabilities that can interact with the highly reactive cytotoxic moieties from cisplatin in the urine.

Question 49

Drugs and drug classes that are cell cycle specific

Answer 49

Antimetabolites Podophyllotoxins Bleomycin Vinca aklyloids Taxels

Question 50

Name two drug classes that work on the M phase of the cell cycle

Answer 50

Vinca alkyloids Taxels

Question 51

Taxels

Answer 51

Work on the M phase of the cell cycle

Question 52

Vinca alkyloids

Answer 52

Work on the M phase of the cell cycle