Cancer drugs Flashcards
(46 cards)
1
Q
Alkylating agent
A
- ability to transfer alkyl group to DNA. Promote cross-linking of DNA strands causing damage.
- cell cycle non-specific
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
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
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.
5
Q
4 subclasses of alkylating agents
A
- nitrogen mustards
- nitrosoureas
- triazenes
- platinum analogs
6
Q
nitrogen mustards
A
- bifunctional alkylating agents
- spontaneous conversion to active form in body OR enzymatically converted in liver
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)
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)
9
Q
use of cyclophosphamide
A
-cyclophosphaide is most widely used AA, singly or in combination for ALL/CLL/NHL/breast/lung/ovarian
10
Q
ifosfamide
A
- treats sarcoma and testicular cancer
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
12
Q
Nitrosoureas
A
- highly lipophilic
13
Q
Carmustine and Lomustine
A
-able to cross BBB– tx brain tumors
14
Q
Toxicity of Carmustine and Lomustine
A
- cause profound myelosuppression
- severe nausea and vomitting
- RENAL TOXICITY
- PULMONARY FIBROSIS
15
Q
Triazenes
A
-
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)
17
Q
Use of Dacarbazine
A
combination regimen (ABVD) for Hodgkin’s disease and malignant melanoma
18
Q
Use of Temozolomide
A
malignant gliomas– standard agent w/ radiation
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
Toxicity of Cisplatin
- 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
Toxicity of carboplatin
(less toxic and less reactive) Myelosuppression (thrombocytopenia)
27
Toxicity of Oxaliplatin
- PERIPHERAL SENSORY NEUROPATHY (cold-induced acute)
| - neutropenia
28
Antimetabolites
- 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
Methotrexate- MTX (folate analog)
- 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
Uses of Methotrexate
- 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
Toxicity of MTX
- 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
Mech of resistance to MTX
- reduced drug uptake by neoplastic cells
- inc. production of DHFR
- Dec. affinity of DHFR for MTX
33
Pemetrexed (folate analog)
- 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
5- fluorouracil (pyrimidine analog)
- 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
Use of 5-fluorouracil
- 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
Toxicity of 5-FU
- 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
Cytarabine (ara-C)- pyrimidine analog
- 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
Use of Ara-C
- MOST effective tx against AML
| - also ALL and CML
39
Toxicity of Ara-C
- severe myelosuppression
| - GI tract toxicity
40
Gemcitabine (analog of deoxycytidine)- pyrimidine analog
- 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
Use of Gemcitabine
- first line against pancreatic carcinoma
| - non-small cell lung cancer, ovaraian, bladder, esophageal, H&N
42
Toxicity of Gemcitabine
- myelosuppression
| - Flu-like symptoms
43
Mercaptopurine 6- MP (purine analog)
- 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
Use of Mercaptopurine
- 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
Toxicity from 6-MP
- bone marrow suppression
| - HEPATOXICITY with prolonged use
46
Mech of action of 6-MP
- dec. expression of HGPRT causes lower 6-MP activation
| - dec. drug transport
