Cancer drugs Flashcards
Alkylating agent
- ability to transfer alkyl group to DNA. Promote cross-linking of DNA strands causing damage.
- cell cycle non-specific
Mech of action of alkylating agents
- 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
toxicity of alkylating agents
- 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
resistance to alkylating agents
- 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.
4 subclasses of alkylating agents
- nitrogen mustards
- nitrosoureas
- triazenes
- platinum analogs
nitrogen mustards
- bifunctional alkylating agents
- spontaneous conversion to active form in body OR enzymatically converted in liver
mechlorethamine
Use: -tx of Hodgkin’s disease (component of MOPP)
-topically for cutaneous T-cell lymphoma
Toxicity:- severe nausea and vomitting
- myelosuppression (leuco/thrombocytopenia)
cyclophosphamide and ifosfamide
- 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)
use of cyclophosphamide
-cyclophosphaide is most widely used AA, singly or in combination for ALL/CLL/NHL/breast/lung/ovarian
ifosfamide
- treats sarcoma and testicular cancer
toxicity with cyclophosphamide and ifosfamide
- nausea/vomitting/myelosuppression
- HEMORRHAGIC CYSTITIS- local irritation of bladder due to toxic drug metabolite acrolein in urine. Hydration and MESNA will overcome
Nitrosoureas
- highly lipophilic
Carmustine and Lomustine
-able to cross BBB– tx brain tumors
Toxicity of Carmustine and Lomustine
- cause profound myelosuppression
- severe nausea and vomitting
- RENAL TOXICITY
- PULMONARY FIBROSIS
Triazenes
-
Dacarbazine and Temozolomide
- dacarbazine is prodrug and needs activation by cytochromes in liver (IV)
- temozolomide undergoes nonenzymatic conversion to methylhydrazine at physio pH (taken orally, excellent bioavail)
Use of Dacarbazine
combination regimen (ABVD) for Hodgkin’s disease and malignant melanoma
Use of Temozolomide
malignant gliomas– standard agent w/ radiation
Toxicity of Dacarbazine and Temozolomide
- nausea and vomitting
- myelosuppression
- flu like symptoms (fever, fatigue) during ttx
Platinum analogs
only inorganic substance
Cisplatin, Carboplatin, Oxaliplatin
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
Use of Cisplatin
wide range- genitourinary and head/neck
- used in combination regimens
Use of carboplatin
ovarian cancer
use of Oxaliplatin
gastric and colorectal cancer
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
Toxicity of carboplatin
(less toxic and less reactive) Myelosuppression (thrombocytopenia)
Toxicity of Oxaliplatin
- PERIPHERAL SENSORY NEUROPATHY (cold-induced acute)
- neutropenia
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
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
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
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
Mech of resistance to MTX
- reduced drug uptake by neoplastic cells
- inc. production of DHFR
- Dec. affinity of DHFR for MTX
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.
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.
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.
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
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
Use of Ara-C
- MOST effective tx against AML
- also ALL and CML
Toxicity of Ara-C
- severe myelosuppression
- GI tract toxicity
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
Use of Gemcitabine
- first line against pancreatic carcinoma
- non-small cell lung cancer, ovaraian, bladder, esophageal, H&N
Toxicity of Gemcitabine
- myelosuppression
- Flu-like symptoms
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.
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
Toxicity from 6-MP
- bone marrow suppression
- HEPATOXICITY with prolonged use
Mech of action of 6-MP
- dec. expression of HGPRT causes lower 6-MP activation
- dec. drug transport
