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CMOD/PCM- Block 2 > Pharm: Anticancer Drugs 1 & 2 > Flashcards

Pharm: Anticancer Drugs 1 & 2 Flashcards

1
Q

Describe the 4 basic groups of anticancer drugs.

A
  1. Hormonal agents
  2. Targeted Drugs (mAbs directed at cell surface receptors, NIBs directed at associated RTKs, mTOR inhibitors)
  3. Action on mitotic spindle
  4. Action on DNA
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2
Q

When you think DNA damaging agents, think:

A

Alkylating agents

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3
Q

When you think DNA synthesis inhibitors, think:

A

Antimetabolites

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4
Q

Are there currently any anticancer agents that are 100% selective for tumor cells and spare the good host cells entirely?

A

No.

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5
Q

Whereas older drugs’ aim was to kill the tumor cell, many of the newer agents are designed not to kill the tumor, but to:

A

control growth, thereby making the cancer a lifelong but manageable disease

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6
Q

What is the major problem with new cancer drugs over the conventional type?

A

They are prohibitively expensive

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7
Q

What are the 5 aims of newer anticancer drugs?

A

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-sensitive or radioprotection of bystander tissues
5- Perturb tumor-host metabolic and immunologic relationship.

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8
Q

What causes nausea and vomiting in chemotherapy pts?

A

Detection of the drug at the base of the fourth ventricle, by so called “chemo trigger zone), within the gastrointestinal tract itself, and finally through higher order cortical output, relaying the psychological aspects of impending chemotherapy.

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9
Q

What are the rapidly proliferating host cell (noncancerous) populations most adversely affected by chemotherapy?

A

Myelosuppression (delayed ~ 10 day toxicity)
Lining of oral cavity and GI tract
Hair

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10
Q

What is the most effective way of curing a pt of a solid tumor?

A

surgical removal (excision)

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11
Q

What is the treatment name for chemotherapy used before other treatment modalities such as surgery or radiation?

A

neo-adjuvant treatment

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12
Q

If chemotherapy is used after treatments such as surgery or radiation, it is called _______ treatment.

A

adjuvant treatment

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13
Q

What is the main treatment for systemic diseases such as blood cancers or metastases?

A

chemotherapy

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14
Q

What treatment modalities are effective when metastasis has not occurred?

A

radiation or surgery

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15
Q

T/F: systemic chemotherapy for disseminated disease is often only palliative with temporary improvement in quality of life.

A

True

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16
Q

Give a quick list of toxicities due to cancer therapy (chemo or radio).

A

Secondary malignancies, organ toxicity, sterility

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17
Q

Explain tumor lysis syndrome and explain in what types of cancers it is most common.

A

When therapy causes tumor cell lysis, they leak their contents into the circulation, ending up in the kidney, causing damage.
Seen with some cancers of the blood or solid tumors.

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18
Q

What are the biochemical changes to the blood in tumor lysis syndrome?

A

lysis of tumor cells releases purine nucleic acids, K+ & P
Renal elimination saturated by ^K+, ^P, v Ca2+, & gout.
Uric acid deposited, along with calcium phosphate.

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19
Q

How do you manage tumor lysis syndrome?

A

hydration, acid/base correction, sodium bicarbonate to alkalinize urine; specific drugs to reduce potential for precipitation

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20
Q

What drug can reduce the production of uric acid in tumor lysis syndrome?

A

allopurinol

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21
Q

Regarding treatment for tumor lysis syndrome:
What drug speeds the conversion of uric acid to allantoin, a more soluble product that produces less renal damage (no gout)?

A

Rasburicase

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22
Q

Allopurinol blocks the conversion of hypoxanthine to _________ and (previous blank) to __________ to prevent gout resulting from tumor lysis syndrome.

A

xanthine; uric acid

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23
Q

Regarding cell cycle specific drugs:

Vinca alkaloids/Taxols are specific to what phase of the cell cycle?

A

M phase (anti-microtubule)

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24
Q

Regarding cell cycle specific drugs:

Antimetabolites are specific to what phase of the cell cycle?

A

S - inhibit DNA synthesis

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25
Q

Regarding cell cycle specific drugs:

Podophyllotoxins are specific to what phase of the cell cycle?

A

S phase and G2- inhibits repair of break after topoisomerase splits dsDNA. Causes damage to DNA

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26
Q

Regarding cell cycle specific drugs:

Bleomycin is specific to what phase of the cell cycle?

A

G2 phase- induces DNA strand breaks

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27
Q

List the alkylating anticancer drugs.

A

Major agents are capitalized:
CYCLOPHOSPHAMIDE, BCNU, CCNU, CISPLATIN, MECHLORETHAMINE, MELPHALAN, Busulfan, Dacarbazine, Procarbazine, Ifosfamide, Carboplatin

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28
Q

Can every cytotoxic agent be used against every type of tumor, regardless of what organ it is in?

A

No

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29
Q

Cyclophosphamide is not active until:

A

It has been converted by hepatic microsomal enzymes to a 4-hydroxy metabolite which exists in equilibrium with aldophosphamide. These metabolites are delivered to tissues where they undergo further non-enzymatic cleavage to their cytotoxic forms, phosphoramide mustard and acrolein.

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30
Q

How do alkylating anticancer agents work, basically?

A

Transfer alkyl group to DNA» ssDNA or dsDNA cross-linking resulting in miscoding; strand breakage through guanine excision.

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31
Q

Alkylating agents trap the cell in this cell cycle phase:

A

G2, act in S phase

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32
Q

Why are alkylating agents best not given IV?

A

They cause blood vessels to blister (esp. mechlorethamine_

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33
Q

What is an unusual cardiovascular ADE of cyclophosphamide?

A

congestive heart failure with rapid onset (<2 wks), due to transmural hemorrhage
more common with high doses administered over short interval

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34
Q

In addition to alkylating anticancer agents being bad for your CV system, they also produce these negative side effects:

A
  • CNS: ifosfamide- altered mental status, coma, generalized seizures, cerebellar ataxia
  • Lungs: all alkylating agents» fibrosis, dyspnea, cyanosis, pulmonary insufficiency
  • 2ndary malignancies, leukemias, and solid tumors
  • Tetratogenicity; 1/6 chance of malformed offspring
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35
Q

A metabolite of the alkylating agent cyclophosphamide, acrolein, has these ADEs on the bladder:

A

severe hemorrhagic cystitis

prevented by good hydration and co-admin of Mesna (drug)

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36
Q

This alkylating anticancer agent can cause renal failure characterized by difficulty in Ca2+ and Mg2+ reabsorption, glycosuria, and renal tubular acidosis.

A

Cyclophosphamide

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37
Q

What is Mesna, when is it administered, and how does it work?

A

Mesna is a prophylactic chemoprotectant from hemorrhagic cystitis caused by alkylating anticancer agents. It is administered concurrently with alkylating agents to prevent damage to the bladder.
Complexes with and inactivates the toxic metabolite of cyclophosphamide, acrolein.

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38
Q

In addition to cyclophosphamide being used in chemotherapy for cancer, it is also used for/to treat:

A

Preparation for allogenic stem cell transplantation

Rheumatoid arthritis (RA)
-reserved for pts who have clearly failed DMARDs and anti-cytokine therapy
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39
Q

Does busulfan require metabolic precessing for activity?

What are the ADEs of busulfan use?

A

No, undergoes spontaneous hydrolysis in aqueous solutions.
Pulmonary fibrosis, GI mucosal damage, Veno-occlusive disease of the liver, impotence, sterility, amenorrhea & fetal malformation

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40
Q

What class of alkylating agents do we find busulfan in?

A

alkyl sulfonates

41
Q

What class of alkylating agents do we find cyclophosphamide and ifosfamide in?

A

Bis(chloroethyl)amine alkylating agents

42
Q

carmustine adn lomustine, often referred to as BCNU and CCNU, are two examples of what class of alkylating agents?

A

Nitrosoureas

43
Q

BCNU is special among the alkylating agents, because it not only alkylates but also:

A

can also carbamoylate, conferring a lack of cross resistance with other alkylating agents

44
Q

What characteristics of both BCNU and CCNU render them capable of passing easily across the BBB, therefore making them useful in treating brain tumors?

A

highly lipophilic and non-ionized

45
Q

List the unusual toxicities attributed to notrosoureases BCNU and CCNU

A

CCNU:
Nausea/vomiting, delayed thrombocytopenia & leukopenia, inj. site reactions
RARELY: pulmonary fibrosis/infiltrates; may be delayed by years
BCNU: convulsions; CNS dysfunction-encephalopathy
Endocrine dysfunction with brain irradiation

46
Q

Remind me, which alkylating agents are associated with veno-occlusive disease?

A

Busulfan and BCNU (carmustine)

47
Q

Veno-occlusive disease commonly leads to failure of this organ in particular by this mchanism:

A

liver; intimal edema and venular wall fragmentation

48
Q

How do the platinum compounds work as anticancer agents?

A

They are alkylating agents. produce intra-strand DNA links which interrupts DNA replication and transcription. p53 induces apoptosis when sees errors in coding.

49
Q

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

A

nephrotoxicity

50
Q

How can the nephrotoxicity of cisplatin be minimized?

A

Forced hydration and admin of cytoprotective amifostine.

51
Q

What is the major dose-limiting toxicity of cisplatin?

A

renal insufficiency
Ototoxicity (tinnitus and high-freq hearing loss [yes, opposites])
Peripheral neuropathy
mild to moderate myelosuppression, with transient leukopenia and thrombocytopenia

52
Q

What neurological symptoms are cisplatin associated with?

A

progressive peripheral, motor and sensory neuropathy

53
Q

The cousin to cisplatin ______, has similar but less severe ADEs. Dose-limiting toxicity is:

A

carboplatin; myelosuppression (majority of patients will suffer to varying degrees from thrombocytopenia, neutropenia, leukopenia or anemia)

54
Q

This drug, administered with cisplatin, produces cytoprotective effects through the generation of a metabolite with free radical scavenging capabilities.

A

Amifostine

55
Q

What are the benefits to treating with carboplatin over cisplatin?

A

Much less reactive, decreases nausea, neuro-, oto, & nephrotoxicity compared to cisplatin.

56
Q

Like cyclophosphamide that requires metabolic activation to produce its active moiety, _________, a methylating agent (alkylating agent, still) is used to treat cancer.

A

Dacarbazine (DTIC)

57
Q

What are the ADEs of Dacarbazine (DTIC)

A

myeosuppression, leukopenia and thrombocytopenia, usually mild-moderate.
Nausea/vomiting common 1-3 hrs post-therapy
Chills, fever, malaise, myalgias

58
Q

A second methylating agent, __________, also requires metabolic activation.

A

Procarbazine

59
Q

Describe the ADEs of Procarbazine, a methylating anticancer agent.

A

Weak MAO inhibitor- hypertensive drug-drug rxns
Disulfram-like actions, N/V when consuming EtOH
Potent immunosupressive & male infertility agent

60
Q

List the cancer resistance mechanisms to alkylating and methylating agents.

A

Increased DNA repair
Thiol trapping agents (free radical scavengers)
Decreased drug accumulation (eflux)

61
Q

List the antiemetic triad most commonly used to prevent acute emesis (vomiting) in pts on chemo.

A

a serotonin antagonist
an NK-1 antagonist (neurokinin-1)
a corticosteroid (methylprednisolone & dexamethasone_

62
Q

What alkylating agents and methylating agents carry the highest likelyhood (>90) of causing N/V in pts?

A

cisplatin, mechlorethamine, cyclophosphamide (>1500mg/m2), carmustine (BCNU), Dacarbazine (DTIC)

63
Q

Mercaptopurine, Thioguanine, and Fludarabine are ____ analogs.

A

purine

64
Q

Fluorouracil, Capecitabine, Cytarabine, and Gemcitabine are_____analogs.

A

pyrimidine

65
Q

Methotrexate has 2 MOAs. Can you name all two?

A
  1. folic acid analog -‐‑ inhibits thymidylate synthase, can’t make thymidine
  2. dihydrofolate reductase inhibitor -‐‑ can’t make nucleotides; in fact MTX has a 1000-‐‑fold greater affinity for DHFR than folate. Who knew.
66
Q

By inhibiting DHFR, what effect does methotrexate have on what molecules?

A

because DHFR catalyzes conversion of DHF (FH2) to THF (FH4), and THF is needed for nucleotide synthesis, MTX interrupts nucleotide synthesis and subsequently DNA & RNA synthesis

67
Q

What’s the big deal -‐‑ if methotrexate wants to inhibit folic acid, who gives a shit?

A

YOUR DNA, that’s who gives a shit. if folic acid is inhibited, then dUMP can’t be converted to dTMP which means you have no thymidine to use for DNA synthesis. so if you have a cancer, you will want methotrexate to impersonate folic acid and put a stop to the replicating madness.

68
Q

How does MTX become “trapped” inside the cell?

A

it gets polyglutamated -‐‑ but don’t worry, it can still inhibit its targets

69
Q

What effects of MTX lead to an accumulation of adenosine, and what effect does the accumulation have?

A

MTX also inhibits 2 early enzymes in the purine synthesis pathway: GARFT and AICARFT; these enzymes result in the accumulation of adenosine which is thought to be the anti-‐‑inflammatory basis of the drug’s utility in treating RA

70
Q

What is Leucovorin “rescue”?

A

administration of leucovorin will reverse the effects of MTX because it can be readily converted to THF and act as a DHF-independent folate cofactor and allow nucleotide synthesis

71
Q

What is Leucovorin used to treat?

A
  • overdose of MTX (that is, when MTX is given in high enough amounts to produce bone marrow toxicity - also known as slash which ends up causing megaloblastic anemia [an anemia resulting from inhibition of DNA synthesis in RBC production])
  • together with 5-FU treats colorectal cancer
72
Q

Pyrimethamine, used in the treatment of malaria, is a ____ inhibitor.

A

THF

73
Q

What are the unique resistance mechanisms cells can have against MTX?

A
  • decreased polyglutamation

- alteration of DHFR structure

74
Q

What are the unique toxicities associated with MTX?

A

gastrointestinal (diarrhea) and pulmonary effects, primarily infiltrates (pneumontis) and fibrosis; can also lead to bone marrow, anemia, lymphoproliferative disorders

75
Q

What drugs are at risk of interfering with MTX and how?

A

because MTX is eliminated in the urine, any drugs that interfere with renal excretion (such as NSAIDs) can reduce MTX clearance and potentially increase drug associated toxicity

76
Q

5-Fluorouracil (5-FU) is converted to what within the cell and inhibits what?

A

converted to 5’-FdUMP, which inhibits thymidylate synthase/thymine synthesis; leads to “thymineless death” of the cell

77
Q

What is the major unique side effect of 5-FU?

A

hand and foot syndrome, especially when used with longer duration infusions

78
Q

What is hand and foot syndrome?

A

condition of swelling, redness, and sometimes pain and blistering/callusing that occurs on the bottom of the hands and feet; happens when drugs get out of capillaries and damage the tissue

79
Q

What drugs is hand and foot syndrome associated with?

A

5-FU; capecitabine; cytarabine

80
Q

Why might Leucovorin be given with 5-FU?

A

it increases the formation of the TS complex which will enhance the response to 5-FU because it drives the incorporation of fluorouracil

81
Q

Capecitabine is essentially a pro- drug for ____, being metabolically converted to the active form intracellularly. Therefore, it can be administered ____.

A

fluorouracil; orally

82
Q

Capecitabine is used to treat which cancers, and has what toxicity profile?

A
  • metastatic breast and colorectal cancer

- hand and foot syndrome (more frequently than 5-FU), diarrhea, myelosuppression

83
Q

Cytarabine requires IC activation to what?

A

Ara-CTP

84
Q

Of all the antimetabolites, cytarabine is most specific for what?

A

the S phase of the cell cycle

85
Q

What is the MOA of cytarabine?

A

Let’s start with a bonus fact: cytarabine, also known as cytosine arabinoside, has arabinose sugar instead of deoxyribose sugar; so it’s similar enough to be incorporated as cytosine but prevents base stacking because the sugar is different; tumors are unable to remove the Ara-CTP and get termination of chain elongation –> multiple, shortened DNA strands

86
Q

What are the unique side effects of cytarabine?

A

leukopenia, thrombocytopenia, anemia, stomatitis, elevated hepatic enzyme levels, and a form of pulmonary edema (linked more to experimental high-dose therapy)

87
Q

Gemcitabine is a ____ analog that is converted into the active ____ and ____ nucleotide forms intracellularly.

A

deoxycytidine; diphosphate and triphosphate

88
Q

Mercaptopurine and its cousin thioguanine are activated by ____. and converted to what?

A

HGPRTases; toxic nucleotides that inhibit several enzymes involved in purine metabolism

89
Q

There are 3 pathways by which mercaptopurine can be metabolized. What drug inhibits one of these pathways and what effect does that have?

A

allopurinol - inhibits conversion of 6-mercaptopurine to 6-thiouric acid; this inhibition leads to increased mercaptopurine toxicity

90
Q

What is the effect of genetic polymorphisms on TPMT?

A

since TPMT is an enzyme that metabolizes mercaptopurine, polymorphisms result in a TPMT enzyme that has either high, intermediate, or low activity - this affects the rate at which mercaptopurine is metabolized and its subsequent toxicity

91
Q

What is the toxicity profile unique to mercaptopurine?

A
  • slow onset bone marrow depression

- jaundice, increased hepatic enzymes

92
Q

Because thioguanine is not metabolized via the ____ pathway, it has no conflict with allopurinol.

A

6-thiouric acid

93
Q

Hydroxyurea is a scavenger that captures the transient ____ ____ necessary for the conversion of ribonucleotides to ____, thereby preventing this final synthetic step and inhibiting cell division.

A

free radical; deoxyribonucleotides

94
Q

What are the toxicities unique to hydroxyurea?

A

maculopapular rash, dermatomyositis-like skin changes, peripheral erythema, facial erythema, skin cancer, skin ulceration and skin darkening

95
Q

What major toxicity will you associate with each of the following:

  1. capecitabine/cytarabine
  2. mercaptopurine/thioguanine
  3. methotrexate
  4. 5-FU
  5. hydroxyurea
A
  1. hand and foot syndrome
  2. pharmacogenetic dosing
  3. GI toxicity, renal precipitation
  4. hand and foot syndrome, GI toxicity
  5. desquamative interstitial pneumonitis, skin toxicities
96
Q

Decreased activation is a resistance mechanism against what drugs?

A

mercaptopurine, thioguanine, gemcitabine, cytarabine, 5-FU

97
Q

Increased inactivation is a resistance mechanisms against what drugs?

A

most purine and pyrimidine antimetabolites

98
Q

Decreased accumulation is a resistance mechanisms against what drugs?

A

P-gp and reduced polyglutamation of methotrexate

99
Q

Changes in target enzymes is a resistance mechanisms against what drugs?

A

methotrexate (DHFR)

CMOD/PCM- Block 2 (41 decks)

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