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MS 2 - Unit 1 > Pharmacology - Cancer II Lecture > Flashcards

Pharmacology - Cancer II Lecture Flashcards

1
Q

MOA - alkylating agents - all

A

Alkylating agents produce strong electrophiles through carbonium or ethyleneimoniun intermediates, which covalently bond via alkylation of nucleophilic moieties in DNA, for example the N7 position of guanine. • Compounds with the ability to transfer an alkyl group to DNA • Promote cross-linking of DNA strands resulting in DNA damage • Cell cycle non-specific agents- act on both proliferating and resting cells • Evolved from chemical warfare agents (mustard gas)

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2
Q

T/F: Alykalting agents are cell cycle non-specific

A

True

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3
Q

Important side effects - alkylating agents (in general)

A

• Dose-related bone marrow suppression (neutropenia, thrombocytopenia, anemia) • Mucosal toxicity (oral mucosal and GI ulceration) • Nausea and vomiting • Toxic effects on male and female reproductive system • Highly carcinogenic; increased risk of secondary leukemia

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4
Q

What are three reasons building up alykating agents can cause resistance in some patients?

A
  1. Decreased permeability or uptake 2. increased rates of catabolism 3. enhanced DNA repair 4. increased glutathione production, which inactivates the alkylating agent via conjugation
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5
Q

Class - Mechlorethamine (Mustargen)

A

Nitrogen mustard

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6
Q

Class - Cyclophosphamide (Cytoxan)

A

Nitrogen mustard

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7
Q

Class - Ifosfamide (Ifex)

A

Nitrogen mustard

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8
Q

MOA - Mechlorethamine (Mustargen)

A
  1. Alkylating agent 2. becomes active spontaneously in the body or through the liver enzymatically
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9
Q

What cancers is Mechlorethamine used to treat?

A
  1. Hodgkin’s disease 2. topically for cutaneous T-cell lymphoma used in MOPP for Hodgkin’s disease
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10
Q

What are the important side effects of Mechlorethamine?

A
  1. Nausea/emesis 2. Myelosuppression (Leucopenia, thrombocytopenia) 3. Sterility (why not used much anymore)
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11
Q

MOA - Cyclophosphamide (Cytoxan) and Ifosfamide

A
  1. Alkylating agent 2. conversion by hepatic cytochrome P450 to active form phosphoramide mustard
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12
Q

What cancers is Cyclophosphhamide used to treat?

A
  1. ALL alone or in combination 2. non-Hodgkin’s lymphoma 3. Breast, lung, ovarian cancers *most widely used alkylating agent* very broad clinical spectrum, component of many combination regimens (CHOP, CMF, FAC, FEC etc)
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13
Q

What are the important side effects of Cyclophosphamide and Ifosfamide?

A
  1. Hemorrhagic cystitis due to acrolein – fix with MESNA administration 2. Nausea/emesis 3. Myelosuppression
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14
Q

What cancers is Ifosfamide used to treat?

A
  1. Sarcoma 2. Testicular cancer
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15
Q

Class - Carmustine (Gliadel)

A

Nitrosoureas

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16
Q

Class - Lomustine (Ceenu)

A

Nitrosoureas

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17
Q

MOA - Carmustine (Gliadel)

A

Alkylating agent highly lipophilic

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18
Q

MOA - Lomustine (Ceenu)

A

Alkylating agent highly lipophilic

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19
Q

Carmustine and Lomustine are both used to treat what cancers?

A

Brain tumors (can cross BBB) and meningeal leukemias

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20
Q

What are the side effects of both Carmustine and Lomustine (the nitrosoureas)?

A
  1. Renal toxicity 2. Pulmonary fibrosis 3. Profound myelosuppression 4. Severe nausea and emesis
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21
Q

Class - Dacarbazine (DTIC)

A

Triazenes

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22
Q

Class - Procarbazine (Matulane)

A

Triazenes

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23
Q

Class - Temozolamide (Temodar)

A

Triazenes

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24
Q

Which drug of the triazenes is known to put patients most at risk for developing leukemia?

A

Procarbazine (Mutalane)

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25
Q

MOA - Dacarbazine (DTIC)

A
  1. Alkylating agent (monoalkylators) 2. prodrug activated by liver cytochromes
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26
Q

What cancers is Dacarbazine used to treat?

A
  1. Part of ABVD for Hodgkin’s disease 2. Malignant melanoma
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27
Q

How is Dacarbazine administered?

A

IV

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28
Q

What are the side effects of Dacarbazine?

A
  1. Nausea and emesis 2. Myelosuppression (neutropenia and thrombocytopenia) 3. Flu-like symptoms Same effects as Temozolamide
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29
Q

MOA - Procarbazine (Mutalane)

A
  1. Alkylating agent (monoalkylators) 2. forms free radicals (leukemia risk)
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30
Q

What cancers is Procarbazine used to treat?

A

Hodgkin’s lymphoma

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31
Q

MOA - Temozolamide (Temodar)

A
  1. Alkylating agent (monoalkylators) 2. nonenzymatic conversion to methylhydrazine at physiologic pH
32
Q

What cancers is Temozolamide used to treat?

A

Malignant gliomas

33
Q

What are the side effects of Temozolamide?

A
  1. Nausea and emesis 2. Myelosuppression (neutropenia and thrombocytopenia) 3. Flu-like symptoms Same effects as Dacarbazine
34
Q

Class - Cisplatin (Paraplatin)

A

Platinum analog

35
Q

Class - Oxaliplatin (Eloxatin)

A

Platinum analog

36
Q

MOA - Cisplatin (Paraplatin)

A
  • inorganic platinum derivatives; covalently bind to nucleophilic sites (e.g., N7 of guanine) on DNA; form intrastrand and interstrand cross-links
37
Q

What cancers is Carboplatin used to treat?

A

Ovarian cancer

38
Q

What is the major side effect of Carboplatin?

A

Myelosuppresion (thrombocytopenia)

39
Q

MOA - Oxaliplatin (Eloxatin)

A
  1. Alkylating agent *that does not form carbonium ion intermediate or formally alkylate DNA 2. Covalently binds nucleophilic sites on DNA (N7 position of guanine) 3. Converted to active cytotoxic forms by reacting with water to form positively charged, hydrated intermediates that cross link with DNA
40
Q

What cancers is Oxaliplatin used to treat?

A

Gastric and colorectal cancers in combination with 5-FU

41
Q

What are the side effects of Oxaliplatin?

A
  1. Peripheral sensory neuropathy (cold-induced) **main and unique** 2. Neutropenia
42
Q

Class - Methotrexate (Trexall)

A

Folate analog Inhibits purine and TMP synthesis

43
Q

Class - Pemetrexed (Alimta)

A

Folate analog

44
Q

MOA - Antimetabolites - all (in general)

A
  1. Structural analogs of folic acid or of the purine/pyrimidine bases found in DNA 2. Act in S-phase of cell cycle (cell-cycle specific) 3. Inhibit enzymes required for neucleotide synthesis or compete with endogenous nucleotides in DNA or RNA synthesis 1. Folate Analogs Methotrexate, Pemetrexed 2. Pyrimidine Analogs 5-Fluorouracil, Cytarabine, Gemcitabine 3. PurineAnalogs 6-Mercaptopurine
45
Q

MOA - Methotrexate (Trexall)

A

Antimetabolite Inhibits dihydrofolate reductase (DHFR), which converts dietary folate to tetrahydrofolate (THF) needed for thymidine synthesis and purine synthesis most widely used antimetabolite in cancer chemotherapy;

46
Q

How is Methotrexate administered?

A

Orally or intrathecally

47
Q

What cancers is Methotrexate used to treat?

A
  1. Childhood ALL and choriocarcinoma 2. Used in combinateion for Burkitt’s lymphoma and carcinomas of the breast, ovary, head and neck, and bladder 3. Administered intrathecally for meningeal leukemia and meningeal mestastases of tumors 4. Use in high dose for osteosarcoma
48
Q

What are the side effects of Methotrexate?

A
  1. Renal toxicity (MTX can crystallize in the urine and cause renal damage) 2. Hepatotoxicity (long-term use of MTX may lead to fibrosis or cirrhosis) 3. Reproductive complications 4. Myelosuppression, spontaneous hemorrhage 5. GI toxicity (ulceration, stomatitis)
49
Q

What can be used to alleviate the side effects of Methotrexate?

A

Leucovorin

50
Q

MOA - Pemetrexed (Alimta)

A

Antimetabolite a multi-targeted folate analog, which inhibits both DHFR and thymidylate synthase

51
Q

What cancers is Pemetrexed used to treat?

A

Mesothelioma Non-small cell lung cancer

52
Q

Class - 5-Fluorouracil (5-FU, Carac)

A

Pyramidine analog

53
Q

Class - Cytarabine (AraC, Depocyt)

A

Pyramidine analog

54
Q

Class - Gemcitabine (dFdC, Gemzar)

A

Pyramidine analog

55
Q

MOA - 5-Fluorouacil (5-FU, Carac)

A

Antimetabolite, a prodrug 1. Converted to active metabolites 2. 5-FdUMP inhibits TS 5-FdUMP inhibits thymidylate synthase and thus inhibits DNA synthesis.

56
Q

What cancers is 5-Fluoouracil used to treat?

A

used as a component of combo regimens for treatment of breast, colorectal, gastric, head and neck, cervical and pancreatic cancers used topically for basal cell carcinomas

57
Q

What are the side effects of 5-Fluorouracil?

A
  1. Hand-foot syndrome (erythema, sensitivity of palms and soles) 2. Cardiac toxicity (acute chest pain) 3. Anorexia, nausea 4. Mucosal ulcerations 5. Stomatitis 6. Dermatitis 7. Diarrhea 8. Thrombocytopenia 9. Anemia
58
Q

How is 5-Fluorouracil administered?

A

IV, bc of rapid degradation and metabolism in gut and liver

59
Q

MOA - Cytarabine (AraC, Depocyt)

A

Antimetabolite - analog of 2’-deoxycytidine (natural ribose is replaced by D-arabinose) - converted to Ara-CMP by deoxycytidine kinase - Ara-CMP is subsequently converted to Ara-CTP, which competes with dCTP for incorporation into DNA by DNA polymerase - when incorporated into DNA, Ara-CTP inhibits DNA synthesis

60
Q

What cancers is Cytarabine used to treat?

A
  1. Cytarabine is the most effective treatment for AML 2. ALL 3. Blast phase CML
61
Q

What are the side effects of Cytarabine?

A
  1. Severe myelosuppression 2. GI tract toxicity (stomatitis, diarrhea, ulceration)
62
Q

MOA - Gemcitabine (dFdC, Gemzar)

A

Antimetabolite 1. dFdCDP inhibits ribonucleotide reductase 2. dFdCTP incorporates into DNA and terminates DNA synthesis more effective in treating solid tumors than cytarabine

63
Q

What cancers is Gemcitabine used to treat?

A
  1. Pancreatic cancer - first line therapy
  2. Non-small call lung cancer
  3. Ovarian, bladder, esophageal, and head and neck cancers

***more effective in treating solid tumors than cytarabine

64
Q

What are the side effects of Gemcitabine?

A
  1. Myelosuppression ***major issue with this drug according to Dr. Lemke
  2. Flu-like symptoms
65
Q

Which drug is more effective against solid tumors, Gemcitabine or Cytarabine?

A

Gemcitabine is more effective against solid tumors.

66
Q

Class - 6-Mercaptopurine (Purinethol)

A

Purine analog

67
Q

MOA - 6-Mercaptopurine (Purinethol)

A

a pro-drug; requires enzymatic conversion to ribonucleotide by HGPRT 1. Metabolized to become 6-thionosinic acid (TIMP) 2. TIMP inhibits first step of de novo purine synthesis, and formation of AMP 3. TIMP converted to thio-guanine nucleotides, which inhibits DNA and RNA synthesis

68
Q

What cancers is 6-Mercaptopurine used to treat?

A

6-Mercaptopurine is used to maintain remission in acute ALL

69
Q

What are the side effects of 6-Mercaptopurine?

A
  1. prolonged use leads to hepatotoxicity 2. Myelosuppression Mechanism of Resistance - decreased expression of HGPRT - decreased drug transport
70
Q

What is a drug interaction that 6-Mercaptopurine has that increases toxicity?

A

6-Mercaptopurine interacts with allopurinol used to treat gout. 6-MP is converted to inactive metabolite (6-thiouric acid) by xanthine oxidase. Allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels. It is important to decrease the dose of 6-MP in patients receiving allopurinol to avoid accumulation of the drug and exacerbation of toxicities.

71
Q

Alkylating agents are cell cycle specific or non-specific?

A

CCNS Cell cycle-nonspecific (CCNS) drugs (e.g. alkylating agents) -kill both cycling and and noncycling tumor cells -effective against both low growth fraction tumors, such as solid tumors, as well as high growth fraction tumors

72
Q

Antimetabolites and vinca alkaloids are cell cycle specific or nonspecific?

A

Cell cycle-specific (CCS) drugs (e.g. antimetabolites, vinca alkaloids) -active in a specific phase of the cell cycle -effective against high growth fraction tumors (when a large proportion of tumor cells are proliferating) ; such as hematologic malignancies

73
Q

Name the major alkylating agents:

A

Mechlorethamine Cyclophosphamide Ifosfamide Temozolamide Carmustine Dacarbazine

74
Q

What cancers is Cisplatin used for?

A
  • Cisplatin has efficacy against a wide range of neoplasms; used for treatment of testicular, ovarian, bladder and lung carcinomas.
75
Q

What are the major toxicities of Cisplatin?

A

Ototoxicity Nephrotoxicity Peripheral neuropathy Myelosuppression Nausea and vomiting

76
Q

What is Leucovorin rescue?

A

Leucovorin (N-5 formyltetrahydrofolate) is administered to the patient several hours after an otherwise lethal dose of methotrexate. The rationale for this technique is that the malignant cells are killed selectively, while the normal cells are “rescued” by the folinic acid. One hypothesis is that tumor cells cannot uptake folinic acid (Leucovorin) whereas normal cells can uptake folinic acid and bypass the requirement of DHFR.

MS 2 - Unit 1 (12 decks)

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