Anti-Cancer Drugs: Alkylating Agents Flashcards Preview

Block 2 Pharmacology > Anti-Cancer Drugs: Alkylating Agents > Flashcards

Flashcards in Anti-Cancer Drugs: Alkylating Agents Deck (52):
1

Antimetabolites

Act on S phase of the cell cycle

1

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

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

1

Ifosfamide

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

1

Describe adverse effects of Cisplatin

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

2

Cisplatin

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

2

Describe the adverse effects of alkylating agents

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

3

Rasburicase

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.

4

Name two platinum drugs What type of drug is this?

CISPLATIN and carboplatin This is an alkylating agent

4

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

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

6

How to cure/treat a solid tumor

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

6

Discuss the mechanism of action of alkylating drugs

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.

7

Defibrotide

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

8

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

Antimetabolites

9

Describe adverse effects of ifosfamide

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.

10

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

Bleomycin

11

Tumor Lysis Syndrome

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).

12

Bleomycin

Works on the G2 phase of the cell cycle

14

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

neo-adjuvant therapy

15

Name a drug in the triazene class

Dacarbazine

16

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

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.

16

Mechlorethamine

An alkylating agent in the nitrogen mustard class

17

Is there a use for cyclophosphamide outside of cancer treatment?

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

18

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

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

19

What are outcomes of drug administration?

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).

21

Podophyllotoxins

Act on the S and G2 phases of the cell cycle

23

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

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.

24

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

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.

24

Describe the contents of a drug cocktail used to treat emesis

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

25

Name a drug in the hydrazine class

Procarbazine

27

Melphalan

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

28

CCNU (Lomustine)

An alkylating agent in the nitrosoureas class Orally administered

29

Allopurinol

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.

31

Cyclophosphamide

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.

32

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

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

33

Mesna

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.

34

Procarbazine

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.

35

Dacarbazine

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

36

Resistance Mechanisms to Drugs by Tumor

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

37

Adverse effects of Decarbazine

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

38

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

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.

39

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

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

41

BCNU (Carmustine)

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

42

Toxicity: Cisplatin vs. Carboplatin

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

43

How to cure/treat blood cancers or metastases

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

44

Name the five alkylating drug classes

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.

45

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

adjuvant therapy

47

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

Podophyllotoxins

48

Amifostine

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.

49

Drugs and drug classes that are cell cycle specific

Antimetabolites Podophyllotoxins Bleomycin Vinca aklyloids Taxels

50

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

Vinca alkyloids Taxels

51

Taxels

Work on the M phase of the cell cycle

52

Vinca alkyloids

Work on the M phase of the cell cycle