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Pharmacology Unit 1 > Cancer drugs > Flashcards

Cancer drugs Flashcards

1
Q

Alkylating agent

A
  • ability to transfer alkyl group to DNA. Promote cross-linking of DNA strands causing damage.
  • cell cycle non-specific
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2
Q

Mech of action of alkylating agents

A
  • produce strong electrophiles through carbonium and ethyleneimonium ion intermediates, these covalently bind with nucloephilic sites on DNA.
  • Major site of alkylation in DNA= N7 of guanine
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3
Q

toxicity of alkylating agents

A
  • bone marrow- neutropenia, thrombocytopenia, anemia
  • mucosal- oral mucosal ulceration, intestinal denudation
  • nausea/vomitting
  • repro- amenorrhea in women and male sterility
  • increased risk of leukemia later in life
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4
Q

resistance to alkylating agents

A
  • dec. permeability or uptake of drugs
  • inc. rates of metabolism from active to inactive
  • inc. DNA repair mechanisms
  • -inc. glutathione which inactivates alkylating agents through conjugation.
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5
Q

4 subclasses of alkylating agents

A
  • nitrogen mustards
  • nitrosoureas
  • triazenes
  • platinum analogs
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6
Q

nitrogen mustards

A
  • bifunctional alkylating agents

- spontaneous conversion to active form in body OR enzymatically converted in liver

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7
Q

mechlorethamine

A

Use: -tx of Hodgkin’s disease (component of MOPP)
-topically for cutaneous T-cell lymphoma
Toxicity:- severe nausea and vomitting
- myelosuppression (leuco/thrombocytopenia)

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8
Q

cyclophosphamide and ifosfamide

A
  • prodrugs that need to be activated by cyt p450 in liver
  • active metabolite is phosphoramide mustard
  • taken orally and relatively long plasma life (unlike other AAs)
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9
Q

use of cyclophosphamide

A

-cyclophosphaide is most widely used AA, singly or in combination for ALL/CLL/NHL/breast/lung/ovarian

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10
Q

ifosfamide

A
  • treats sarcoma and testicular cancer
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11
Q

toxicity with cyclophosphamide and ifosfamide

A
  • nausea/vomitting/myelosuppression
  • HEMORRHAGIC CYSTITIS- local irritation of bladder due to toxic drug metabolite acrolein in urine. Hydration and MESNA will overcome
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12
Q

Nitrosoureas

A
  • highly lipophilic
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13
Q

Carmustine and Lomustine

A

-able to cross BBB– tx brain tumors

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14
Q

Toxicity of Carmustine and Lomustine

A
  • cause profound myelosuppression
  • severe nausea and vomitting
  • RENAL TOXICITY
  • PULMONARY FIBROSIS
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15
Q

Triazenes

A

-

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16
Q

Dacarbazine and Temozolomide

A
  • dacarbazine is prodrug and needs activation by cytochromes in liver (IV)
  • temozolomide undergoes nonenzymatic conversion to methylhydrazine at physio pH (taken orally, excellent bioavail)
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17
Q

Use of Dacarbazine

A

combination regimen (ABVD) for Hodgkin’s disease and malignant melanoma

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18
Q

Use of Temozolomide

A

malignant gliomas– standard agent w/ radiation

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19
Q

Toxicity of Dacarbazine and Temozolomide

A
  • nausea and vomitting
  • myelosuppression
  • flu like symptoms (fever, fatigue) during ttx
20
Q

Platinum analogs

A

only inorganic substance

21
Q

Cisplatin, Carboplatin, Oxaliplatin

A

bind to nucleophilic sites on DNA. Activated by reacting with water to form positively charged, hydrated intermediates that react with DNA guanine and form cross links

22
Q

Use of Cisplatin

A

wide range- genitourinary and head/neck

- used in combination regimens

23
Q

Use of carboplatin

A

ovarian cancer

24
Q

use of Oxaliplatin

A

gastric and colorectal cancer

25
Q

Toxicity of Cisplatin

A
  • RENAL TOXICITY (RENAL TUBULAR DAMAGE/NECROSIS) is the dose limiting toxicity
  • OTOTOXICITY with hearing loss
  • nausea/vomitting/myelosuppression
  • Peripheral motor and sensory NEUROPATHY at high doses
26
Q

Toxicity of carboplatin

A

(less toxic and less reactive) Myelosuppression (thrombocytopenia)

27
Q

Toxicity of Oxaliplatin

A
  • PERIPHERAL SENSORY NEUROPATHY (cold-induced acute)

- neutropenia

28
Q

Antimetabolites

A
  • structural analogs of folic acid or the purine or pyrimidine bases found in DNA.
  • inhibit enzymes in nucleotide synthesis or compete with them in DNA/RNA synthesis.
  • Specific to S phase
29
Q

Methotrexate- MTX (folate analog)

A
  • most widely used antimetabolite
  • folate antagonist that inhibits DHFR (converts folate to THF used in thymidine and purine synthesis)
  • TO RESCUE NORMAL CELLS- we use Leucovorin so the cell cycle can continue
30
Q

Uses of Methotrexate

A
  • treats childhood ALL, choriocarcinoma, breast/head and neck cancer
  • combination therapy regimens for Burkitt’s lymphoma adn carcinomas of breast, ovary, H&N, bladder
  • Can’t penetrate CNS– intrathecally for meningeal leukemia or any kind of meningeal metastases
  • High dose MTX used for osteosarcoma
31
Q

Toxicity of MTX

A
  • Bone marrow- myelosuppression, spontaneous hemorrhage
  • GI- oral ulceration, stomatitis
  • RENAL TOXICITY- at high doses, MTX can crystallize in the urine and cause renal damage
  • HEPATOTOXICITY- long term can lead to fibrosis or cirrhosis
  • Genital- defective oogenesis or spermatogenesis, abortion
32
Q

Mech of resistance to MTX

A
  • reduced drug uptake by neoplastic cells
  • inc. production of DHFR
  • Dec. affinity of DHFR for MTX
33
Q

Pemetrexed (folate analog)

A
  • rapidly metabolized to active polyglutamate that inhibits several THF dependent enzymes including DHFR and thymidylate synthase.
  • activity against colon cancer, mesothelioma, non-small lung cancer and pancreatic cancer.
34
Q

5- fluorouracil (pyrimidine analog)

A
  • prodrug requiring enzymatic activation to 5-FdUMP and 5-FdUTP to exert cytotoxic activity
  • 5-FdUMP inhibits thymidylate synthetase and prevents the synthesis of thymidine.
  • 5-FdUTP incorporated into RNA by RNA polymerase adn interferes with RNA function.
35
Q

Use of 5-fluorouracil

A
  • given IV due to severe toxicity to GI tract and rapid metabolic degradation in gut and liver.
  • used in combination therapy for treatment of breast, colorectal, gastric, H&N, cervical and pancreatic cancer
  • topical application to treat basal cell carcinoma
  • Capecitabine- newer, orally effective form. It is a prodrug which is converted to 5-dFdU and used for breast and colorectal cancer.
36
Q

Toxicity of 5-FU

A
  • anorexia and nausea
  • mucosal ulcerations, stomatitis, diarrhoea
  • thrombocytopenia and anemia
  • HAND FOOT SYNDROME- erythema, sensitivity of palms and soles can occur
  • Cardiac- acute chest pain
37
Q

Cytarabine (ara-C)- pyrimidine analog

A
  • analog of 2- deoxycytidine in which the natural ribose is replaced by D-arabinose
  • s- phase specific
  • Ara-C is converted into a bunch of things that eventually get incorporated into DNA and result in chain termination
38
Q

Use of Ara-C

A
  • MOST effective tx against AML

- also ALL and CML

39
Q

Toxicity of Ara-C

A
  • severe myelosuppression

- GI tract toxicity

40
Q

Gemcitabine (analog of deoxycytidine)- pyrimidine analog

A
  • not cell cycle specific
  • more effective against solid tumors than cytrabine
  • 2 ways in which DNA synthesis is inhibited- inhibition of enzyme ribonucleotide reductase so no deoxyribonucleotide pools for DNA synthesis, DNA syntesis termination
41
Q

Use of Gemcitabine

A
  • first line against pancreatic carcinoma

- non-small cell lung cancer, ovaraian, bladder, esophageal, H&N

42
Q

Toxicity of Gemcitabine

A
  • myelosuppression

- Flu-like symptoms

43
Q

Mercaptopurine 6- MP (purine analog)

A
  • lowers purine levels so RNA and DNA can’t be made

- Prodrug that is activated by HGPRT to TIMP that is incorporated into DNA/RNA inhibiting synthesis.

44
Q

Use of Mercaptopurine

A
  • primarily to maintain remission in ALL patients
  • ** ALLOPURINOL is used to reduce hyperuricemia in cancer pts receiving chemo. It inhibits xanthine oxidase adn thereby elevates plasma levels of mercaptopurine. therefore its imp to adjust the dose of 6-MP to avoid accumulation and toxicity
45
Q

Toxicity from 6-MP

A
  • bone marrow suppression

- HEPATOXICITY with prolonged use

46
Q

Mech of action of 6-MP

A
  • dec. expression of HGPRT causes lower 6-MP activation

- dec. drug transport

Pharmacology Unit 1 (1 decks)

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