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CMOD Week 8 > Anticancer Drugs 1 > Flashcards

Anticancer Drugs 1 Flashcards

1
Q

What are the four basic categories of anticancer drugs?

A

1) Targeted drugs- drugs that interact with one of a number of cell surface receptors or their associated tyrosine kinases or by blocking a downstream effector molecule for cell growth, mTOR.
2) action on mitotic spindle

3) Action on DNA
a) Existing DNA- alkylating agents/free radical damage

b) DNA synthesis inhibitors (antimetabolites)

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2
Q

What is the difference between the mechanisms of older drugs and newer ones, typically?

A

Whereas older drugs are designed to kill the tumor cell, many of the newer agents are designed not to kill the tumor, but to control its growth, thereby making the cancer a lifelong but manageable disease.

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3
Q

Most cytotoxic chemotherapy drugs have adverse effects upon rapidly proliferating cell populations. What are the common side effects?

A

Myesuppression (blood and bone marrow), hair loss, and GI pain

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4
Q

What is the (very) basic basis of vomiting?

A

the stimulus for nausea and vomiting can arise either from detection of the drug at the base of the fourth ventricle, by the so-called “chemo trigger zone” (where there is an absence in the BBB), within the gastrointestinal tract itself, and finally through higher order cortical input, relaying the psychological aspects of impending chemotherapy.

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5
Q

The most effective way of curing a patient of a solid tumor is to _____.

A

surgically excise it. Radiation is also used for tumors that cannot be removed because of difficult anatomical location.

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6
Q

If chemotherapy is used before the other modalities (surgery, radiation) it is called _____.

A

neo-adjuvant treatment. If used after, it is simply termed adjuvant

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7
Q

Chemotherapy is the main treatment modality in what cancers?

A

systemic disease, i.e. blood cancers or metastases

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8
Q

How is a patient’s response to cancer therapy evaluated?

A

CAT & PET scans and MRIs are used extensively, as are tumor specific markers. In some instances the resolution of associated symptoms, e.g., abdominal ascites, may be used as evidence of activity.

This can sometimes be used as justification for drug use in a patient with late stage disease, i.e., as a palliative treatment.

In contrast, the appearance of secondary malignancy, organ toxicity and sterility all indicate a failure of the regimen.

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9
Q

What is Tumor Lysis Syndrome (TLS)?

A

The intent of treatment is to kill the tumor, unfortunately when one does this the tumor cells lyse their contents into the bloodstream and thence they find their way to the kidney, where organ damage can occur. Patients receiving chemotherapy of large tumors or blood cancers receive prophylaxis of renal damage with the treatment indicated.

also see hypercalcemia and hyperkalemia leading to heart arrhythmia

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10
Q

How can renal function be protected in tumor patients with TLS?

A

The main culprit of TLS is uric acid, which forms from xanthine via xanthine oxidase. The drug Allopurinol (PO) targets xanthine oxidase

Also, a drug called Rasburicase (IV) can be used to speed the conversion of insoluble uric acid to soluble allantoin, which produces less renal damage

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11
Q

What are the main classes of alkylating agents used in cancer treatment?

A

Nitrogen mustards, alkyl sulfanotes, nitrsoureas, triazenes, hydrazines, and platinum drugs

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12
Q

What is a constant structural component of all alkylating drugs?

A

the chloroethyl function- the active part of the molecule. This is the part of the drug that actually attached to the DNA.

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13
Q

What is the alkylating drug Busulfan used to treat?

A

CML

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14
Q

What is unique about the structure of Busulfan?

A

the drug attaches to DNA via sulfur moieties, not via the choloethyl group

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15
Q

What is the alkylating drug cyclophosphamide used to treat?

A

ALL, non-Hodgkin lymphoma (NHL)

type of nitrogen mustard

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16
Q

How is cyclophosphamide activated?

A

In order to become an effective anticancer drug it must first be converted by hepatic microsomal enzymes to a 4-hydroxy metabolite which exists in equilibrium with another product, aldophosphamide. These active metabolites are delivered to tumor and normal tissue where non-enzymatic cleavage of aldophosphamide to the cytotoxic forms of phosphoramide mustard and acrolein occurs. The liver itself seems protected by further conversion of the 4-OH metabolite to a 4-keto, inactive product.

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17
Q

What are the members of the Bis(chlorophyl)amine alkylating agents?

A

cyclophosphamide, ifosfamide, mechloroethamine, melphalan, chlormabucil

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18
Q

How do alkylating agent produce their cytotoxic effect?

A

by transferring an alkyl moiety on to DNA.

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19
Q

What is the most common attach site on DNA by alkylating agents?

A

N7 of guanine. Once the initial attachment is made, the alkylating agent may go on to attach the second alkyl moiety to the same DNA strand (intrastrand linkage) or to the complementary strand (DNA cross-linking).

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20
Q

What is a common side effect of alkylating agents given via IV?

A

damage to the lining of the blood vessels (a vesicant action)

most intense is mechloroethamine

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21
Q

What is an alkylating agent that can be given orally, thus avoiding damage to blood vessel linings.

A

Cyclophosphamides

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22
Q

Common side effects of cyclophosphamide?

A

congestive heart failure (short term Cardiotoxicity)

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23
Q

What are some other side effects of the bis(chloroethyl)amine Alkylating agents?

A

CNS (especially ifosamide)- altered mental status, coma, seizures, ataxia

Lungs (especially cyclophosphamide, chlorambucil, and melphalan)- fibrosis, dyspnea, cyanosis, pulmonary insufficiency

Risk of secondary malignancy

Reproductive risks- 1/6 of malformed offspring

24
Q

Bladder damage via alkylating agents is common in which drugs? Why?

A

Cyclophosphamide and ifosfamide because they produce acrolein which can produce hemorrhagic cystitis

25
Q

Renal damage via cyclophosphamide and ifosfamide occur where specifically in the kidneys?

A

proximal tubules

26
Q

Specifically, what kind of renal damage do cyclophosphamide and ifosfamide cause?

A

difficulty in Ca2+ and Mg2+ reabsorption, glycosuria, and renal tubular acidosis

27
Q

How can the renal toxicity of cyclophosphamide and ifosfamide be avoided/treated?

A

good hydration and co-administration of a drug called Mesna

28
Q

How does Mesna work?

A

Mesna can be given intravenously and orally; it concentrates in the renal tubules and bladder where it complexes with and inactivates the troublesome acrolein product.

29
Q

What else is cyclophosphamide used for?

A

in prep for stem cell transplantation or in refractory ( after use of DMARDs) rheumatoid arthritic treatment.

30
Q

What are the main members of the alkyl sulfonate class of drugs?

A

Busulfan (busulfex)

31
Q

Does busulfan have to be activated to work?

A

No, rather it undergoes spontaneous hydrolysis in aqueous solution

32
Q

What are some toxicities associated with Busulfan?

A

Pulmonary fibrosis, GI damage, veno-occusive disease and an Addison’s disease like-effect

33
Q

What are the main members of the Nitrosoureas drug family?

A

Carmustine (BCNU) and lomustine (CCNU)

34
Q

What can BCNU do in addition to alkylation?

A

carbamoylate. This unusual adduct is attributed for the lack of cross resistance of BCNU with other alkylating agents.

35
Q

What is unique about BCNU and CCNU compared to other cytotoxic agents?

A

both carmustine and lomustine are highly lipophilic and non-ionized, these attributes rendering them capable of passing easily across the blood brain barrier. Therefore, they, along with temozolomide and vincristine, are often used to treat brain tumors.

36
Q

Which nitrosoureas drug has more widespread application?

A

BCNU- can treat astrocytoma, brain metastases, malignant glioma, medulloblastoma

while CCNU is only used to treat malignant glioma

37
Q

How are CCNU and BCNU administered?

A

CCNU- PO; BCNU- parenteral

38
Q

Whata re some BCNU CCNU toxicities?

A

thrombocytopenia and leukopenia, inj. site reactions, delayed pulmonary fibrosis

39
Q

Additional BCNU toxicities?

A

convulsions; endocrine dysfunction, CNS dysfunction-enceptahlopathy; hepatic veno-occlusion toxicity

40
Q

Where are BCNU and CCNU metabolized?

A

liver, extensive

41
Q

Veno-occlusive disease (of the liver) is common in which alkylating agents?

A

Busulfan and BCNU and strong alkylating agents

occurs 2-10 weeks after starting therapy- jaundice, ascites seen

42
Q

How is veno-occlusive disease treated?

A

defibrotide

43
Q

What are the members of the platinum compound family?

A

cisplastin and carboplatin

44
Q

Do platinum drugs need metabolic activation?

A

No, similar to busulifan they become spontaneously active in aqueous solution- IV only

45
Q

How do platinum compounds works?

A

They produce predominantly intra-strand DNA links which interrupts DNA replication and transcription by binding at N7 of guanine

46
Q

Unlike most cytotoxic drugs, whose dose-limiting toxicity is myelosuppression, the dose limiting toxicity of cisplatin is ______.

A

nephrotoxicity

47
Q

How can the nephrotoxicity of cisplatin be avoided?

A

by forced hydration and by the administration of a cytoprotective agent, amifostine

48
Q

What is another common side effect of cisplatin?

A

ototoxcitiy due to accumulation via copper transport (vertigo too), peripheral neuropathy, and progressive neuropathy

49
Q

Does carboplatin have as intense of side effects as cisplatin?

A

No, although similar side effects are seen. The dose-limiting toxicity is myelosuppression/ peripheral neuropathy

50
Q

What are two DNA methylating drugs?

A

Dacarbazine (DTIC) and Procarbazine (matulane)

51
Q

Do Procarbazine and DTIC require metabolic activation to work?

A

Yes

52
Q

Side effects of Procarbazine (DTIC has standard infusion reaction side effects)?

A

disulfram-like effect, weak MAO inhibitor

53
Q

Recall that the cell has processes for repairing DNA damage; these were discussed in your studies last fall. For this reason, not every cell receiving drug-induced damage goes on to apoptose. Given sufficient time, much of the damage can be repaired and the cell can reenter the cell cycle. Therefore, chemotherapy seeks to overwhelm the ability of the endogenous repair processes to restore the damage, thereby prompting the cell into the process of self- destruction.

A

Recall that the cell has processes for repairing DNA damage; these were discussed in your studies last fall. For this reason, not every cell receiving drug-induced damage goes on to apoptose. Given sufficient time, much of the damage can be repaired and the cell can reenter the cell cycle. Therefore, chemotherapy seeks to overwhelm the ability of the endogenous repair processes to restore the damage, thereby prompting the cell into the process of self- destruction.

54
Q

One of the major problems with chemotherapy is the fact that a tumor has inherent heterogeneity in its genetic composition. This heterogeneity superimposes on the heterogeneity inherent in an individual patients capacity for metabolism and elimination of the cytotoxic agent. Initial use of an anticancer drug is often met with success; the tumor burden is reduced but not completely eradicated. What remains from the initial treatment or treatments is a cell population that is inherently unresponsive to the cytotoxic agent. Amongst the many reasons for lack of response is the fact that these residual tumor cells have increased capacity to repair DNA damage, they are capable of producing large quantities of free radical scavenging agents or they have upregulated P- glycoprotein which, as you recall, is capable of extruding drug out of the tumor cell against the concentration gradient.

A

One of the major problems with chemotherapy is the fact that a tumor has inherent heterogeneity in its genetic composition. This heterogeneity superimposes on the heterogeneity inherent in an individual patients capacity for metabolism and elimination of the cytotoxic agent. Initial use of an anticancer drug is often met with success; the tumor burden is reduced but not completely eradicated. What remains from the initial treatment or treatments is a cell population that is inherently unresponsive to the cytotoxic agent. Amongst the many reasons for lack of response is the fact that these residual tumor cells have increased capacity to repair DNA damage, they are capable of producing large quantities of free radical scavenging agents or they have upregulated P- glycoprotein which, as you recall, is capable of extruding drug out of the tumor cell against the concentration gradient.

55
Q

Which alkylating agents are most likely to induce vomiting (emesis)?

A

cisplatin, mechlorethamine, Cyclophosphamide, carmustine, Dacarbazine

56
Q

What drugs can be given in a prophylactic cocktail to prevent nausea and vomiting (emesis) from the afore-mentioned drugs?

A

Most commonly, a serotonin antagonist, an NK-1 antagonist, and a corticosteroid.

CMOD Week 8 (10 decks)

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