Anticancer Drugs Flashcards
General MOA of antimetabolites
Target pathways related to nucleotide and nucleic acid synthesis
Cell-cycle specific –> S-phase
Methotrexate MOA
Antimetabolite -
Folate analog that competitively inhibits dihydrofolate reductase –> decreased synthesis of dTMP and purine nucleotides –> decreased DNA synthesis –> cell death
Undergoes conversion to a series of polyglutamates. Process is catalysed by folypolyglutamate synthase (FPGS). They increase the inhibitory potency of MTX for additional sites, including, thymidylate synthase and enzymes of de novo purine biosynthetic pathway
Methotrexate PK
After high doses, MTX undergoes hydroxylation at the 7 position –> hydroxylated derivative is less hydrosoluble and may lead to crystalluria.
Renal excretion occurs through a combination of glomerular filtration and tubular secretion so the concurrent use of drugs that reduce renal blood flow (e.g. NSAIDs), that are nephrotoxic (e.g. cisplatin) or that are weak organic acids (e.g. aspirin or piperacillin) can delay drug excretion and lead to severe myelosuppression. Particular caution must be exercised in patients with renal insufficiency.
Methotrexate AE
Myelosuppression - reversible with leucovorin ‘rescue’
Hepatic fibrosis and cirrhosis
Pneumonitis - characterised by patchy inflammatory infiltrates that regress upon discontinuation of drug
Renal Damage - uncommon. Complication of high dose MTX if clearance is inadequate.
Neurologic Toxicities - with intrathecal administration as it does not normally cross BBB
Teratogenic - due to folate deficiency (neural tube defects) therefore contraindicated in pregnancy
Leucovorin
N5-formyl-THF
Antidote to drugs that decrease levels of folic acid (e.g.: MTX) to rescue the bone marrow
Provides normal tissues with the reduced folate, so it circumvents the inhibitor of dihydrofolate reductase
6-mercaptopurine MOA
Antimetabolite
Thio analog of hypoxanthine. Is a prodrug which is converted to Thio-IMP by the salvage pathway enzyme HGPRT:
1) Inhibits the first step of the de novo purine ring biosynthesis
2) Blocks formation of AMP and GMP from IMP
3) Formation of dysfunctional RNA and DNA by incorporation of guanylate analogs
6-mercaptopurine and 6-thioguanine resistance
Patients with Lesch-Nyhan Syndrome will be unresponsive to these drugs as they are prodrugs that need to be converted to their active metabolite by HGPRT.
6-mercaptopurine PK
Metabolised in liver to thiouric acid by xanthine oxidase and excreted by kidneys.
Because allopurinol, a xanthine oxidase inhibitor, is frequently administered to cancer patients receiving chemotherapy to reduce hyperuricemia, it is important to decrease the dose of 6-MP to avoid accumulation of the drug
Also metabolised by enzyme thiopurine methyltransferase (TPMT) –> patients who have weak activity of TPMT are at increased risk for severe toxicities such as myelosuppression
6-mercaptopurine AE
Nausea, vomiting, diarrhoea
Myelosuppression
Hepatotoxicity
6-thioguanine MOA
Converted to nucleotide TGMP by enzyme HGPRT which then:
1) Inhibits purine synthesis and phosphorylation of GMP to GTP
2) Can be incorporated into RNA and DNA
Allopurinol foes not potentiate 6-TG action because very little is metabolised to thiouric acid (unlike 6-MP)
6-thioguanine Indication
Acute nonlymphocytic leukemias
6-thioguanine AE
Nausea, vomiting, diarrhoea
Bone marrow suppression
Hepatotoxicity
6-thioguanine PK
Also metabolised by enzyme thiopurine methyltransferase (TPMT) –> patients who have weak activity of TPMT are at increased risk for severe toxicities such as myelosuppression
5-Flurouracil
Antimetabolite: pyrimidine analog
Converted to 5-FdUMP –> inhibits thymidylate synthase (conversion of dUMP to dTMP) –> DNA synthesis is inhibited –> Known as ‘thymineless death’
Also converted to 5-FUTP –> incorporates into RNA –> interferes with RNA processing and function
5-Flurouracil PK
Mainly metabolised by dihydropyrimidine dehydrogenase (DPD)
DPD deficiency seen in up to 5% of cancer patients –> may experience severe toxicity such as myelosuppression, neurotoxicity and life-threatening diarrhea
5-Fluorouracil/Leucovorin Use and MOA
Combination used as chemotherapy for colorectal cancer
5FU inhibits thmidylate synthase by forming a ternary complex (enzyme, substrate (5-FdUMP) + cofactor (N5, N10-methylene-THF/leucovorin)
Increasing levels of N5, N10-methylene-THF potentiates activity of 5FU.
5-Fluorouracil AE
Myelosupression
Hand-food syndrome: an erythematous desquamation of the palms and soles is seen after extended infusions as 5FU accumulates in the merocrine glands
Capecitabine MOA
Antimetabolite. Pyrimidine analog
Orally available prodrug of 5FU
Inhibits thymidylate synthase (conversion of dUMP to dTMP) –> DNA synthesis is inhibited –> Known as ‘thymineless death’
Capecitabine AE
Same as 5FU:
Myelosupression (less than with 5FU)
Hand-foot syndrome: an erythematous desquamation of the palms and soles is seen after extended infusions as 5FU accumulates in the merocrine glands
Cytarabine MOA
Antimetabolite. Pyrimidine analog of deoxycytidine.
Sequentially phosphorylated to the triphosphate –> incorporated into DNA –> incorporated residue inhibits DNA polymerase
Cytarabine PK
Not effective orally because of its deamination to the noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa. –> Given IV.
Does not enter CNS. May be injected IT.
Cytarabine AE
Severe myelosuppression
Hepatic dysfunction
High doses or IT –> seizures or altered mental states
Antitumor antibiotics general MOA
Bind to DNA through intercalation between bases and block synthesis or new RNA or DNA, cause strand breakage and Interfere with cell replication
Anthracyclines (doxorubicin and daunorubicin) and Bleomycin
Anthracyclines MOA
Doxorubicin (one of the most widely used anticancer drugs) and daunorubicin: have closely related chemical structures
Are cell cycle nonspecific
1) Inhibition of topoisomerase II
2) Intercalation in DNA –> blockade of DNA and RNA synthesis and strand breakage
3) Binding to cell membranes to alter fluidity and ion transport
4) Generation of free radicals through iron-dependent, enzyme-mediated process
Anthracyclines AE
Myelosuppression - main dose-limiting toxicity
Cardiotoxicity (chronic form)
- dose-dependent, dilated cardiomyopathy associated with heart failure
- due to free radicals
- Iron-chelating agent dexrazoxane can reduce cardiotoxicity
All anthracyclines can produce “radiation recall reaction” with erythema and desquamation of the skin observed at sites of prior radiation therapy.
Other adverse effects are stomatitis, gastrointestinal disturbances, alopecia.
Dexrazoxan
Minimizes adverse events due to anthracycline toxicity (daxorubicin)
Iron-chelating agent that reduces cardiotoxicity
Bleomycin MOA
Antitumor antibiotic - mixture of glycopeptides
Cell-cycle specific - arrests cells in G2 phase
DNA-bleomycin-Fe2+ complex undergoes oxidation to bleomycin-Fe3+ –> liberated electrons react with O2 to form free radicals (superoxide, hydroxyl radicals) –> DNA strand breakage
Bleomycin AE
Pulmonary toxicity - pneumonitis and pulmonary fibrosis (bleomycin is inactivated by bleomycin hydrolase which is not found in the lungs and skin)
Very little myelosuppression
Alkylating agents general MOA
Exert cytotoxic effects via transfer of their alkyl groups to various cellular components
Alkylation of DNA leads to cell death. Can occur on a single strand or on both strands through corse-linking. Most alkylating agents are bifunctional
Cell cycle non-specific but cells are most susceptible to alkylation in late G1 and S phases of the cell cycle, and arrest in G2
Alkylating agents general toxicities
Occur mainly in rapidly growing tissues like bone marrow, GI tract and gonads
Nausea and vomiting are common: The emetic effects are of CNS origin and can be reduced by pre-treatment with 5-HT3 receptor antagonists like ondansetron or granisetron.
Are mutagenic and carcinogenic
Mechlorethamine MOA
Nitrogen mustard - alkylating agent –> causes DNA strand breakage
Very unstable - solutions must be made up just prior to administeration –> only given IV
Mechlorethamine AE
Powerful vesicant = causes painful blisters
Severe nausea and vomiting
Severe myelosuppression
Alopecia
Immunosuppression
Cyclophosphamide MOA
Prodrug: activated to 4OH-cycylophosphamide by CYP2B
Most widely used alkykating agent (a nitrogen mustard) –> alkylation of DNA –> strand breakage –> cell death
Cyclophosphamide AE
Hemorrhagic cystitis due to acrolein a toxic metabolite of cyclophosphamide –> prevented with adequate fluid intake (IV hydration) and mesna (reacts with acrolein in bladder)
Myelosuppression
Sterility
Nausea, vomiting, alopecia
Melphelan MOA
Nitrogen mustard - bifunctional alkylating agent
Melphelan AE
Myelosuppression
Carmustine and Lomustine MOA
Nitrosoureas - alkylating agent
Require biotransformation, which occurs by non-enzymatic decomposition to alkylating and carbamoylating derivatives
Very lipophilic - cross the BBB –> useful in treatment of brain tumours
Busulfan MOA
Alkylating agent
Busulfan AE
Myelosuppression is main toxicity
May cause pulmonary fibrosis
Dacarbazine MOA
Alkylating agent
Acts as methylating agent after activation in the liver
Given IV
Dacarbazine AE
Nausea and vomiting
Mild to moderate myelosuppression
Procarbazine MOA
Converted by liver P450 enzymes to alkylating metabolites
Methylate DNA –> DNA, RNA and protein synthesis are inhibited
Procarbazine AE
Bone marrow depression
Weak MOA inhibitor -> hypertensive reactions may result if given with sympathomimetic agents or tyramine-containing foods
Disulfiram-like reactions –> Antabuse –> given to chronic alcoholics as it produces hangover life symptoms as soon as alcohol is taken. It inhibits alcohol dehydrogenase
Mutagenic and teratogenic
Platinum coordination complexes general MOA
Cisplatin
Carboplatin
Do not alkylate DNA.
Covalently find to DNA and share many pharmacological properties with alkylating agents –> Inhibit DNA synthesis and bind DNA through formation of cross-links
Given IV
Cisplatin AE
Myelosuppression: mild-to-moderate
Ototoxicity
Peripheral neuropathy
Nephrotoxicity - reduced by hydration and diuresis and with amifostine
Amifostine MOA
Cytoprotective agent used to reduce the renal toxicity associated with cisplatin
Carboplatin AE
Relatively well tolerated, with less nausea, neurotoxicity, ototoxicity and
nephrotoxicity than cisplatin.
Dose-limiting toxicity is myelosuppression
Vinca alkaloids MOA
Vincristine
Vinblastine
Microtubule inhibitors –> bind to b-tubulin and inhibit its ability to polymerise with a-tubulin –> cannot form microtubules –> cannot form mitotic spindle –> mitotic arrest in metaphase –> cell division stops –> cells die by apoptosis
Cell cycle specific - M-phase
Microtubules also have other functions in the cells such as axonal transport, phagocytosis and movement therefore inhibiting microtubules will lead to adverse affects
Vincristine AE
Peripheral neuropathy
Mild bone marrow depression
Alopecia
Vinblastine AE
Myelosuppression is dose-limiting
Peripheral neuropathy
Alopecia
Taxanes MOA
Paclitaxel
Docetaxel
Micrtobule inhibitors –> taxanes bind to b-tubulin subunit of microtubules –> promote microtubule polymerization –> prevent their depolymerisation –> arrests cells in mitosis and leads to apoptosis
Paclitaxel AE
Hypersensitivity –> reduced by premedication with dexamethasone, diphenhydramine and an H2 blocker
Myelosuppression
Peripheral neuropathy
Alopecia
Docetaxel AE
Myelosuppression - dose-limiting
Peripheral neuropathy - not as frequently as paclitaxel
Fluid retention - pretreatment with dexamethasone is required to prevent this
Alopecia
Mucositis
Etoposide MOA
Epipodophyllotoxin
Inhibits topoisomerase II –> breaks DNA on both strands –> DNA damage through strand breakage
Blocks cells in late S-G2 phase
Topotecan and Irinotecan MOA
Camptothecins
Inhibit topoisomerase I –> which normally breaks DNA on one strand to relieve supercoils –> inhibition results in DNA damage
S phase specific
Irinotecan AE
Myelosuppression
Diarrhea
- Early diarrhea occurs within 24 hours after administration, is believed to be due to cholinergic activity, and can be treated with atropine.
- Late diarrhea occurs 2–10 days after treatment, and can be life-threatening, leading to significant electrolyte imbalance and dehydration.
- Late diarrhea should be treated with loperamide.
Prednisone MOA
Glucocorticoid
Are lymphocytic –> suppress mitosis in lymphocytes
Used to treat acute leukemias and malignant lymphomas
Especially effective in the management of autoimmune hemolytic anemia and thrombocytopenia associated with chronic lymphocytic leukemia. This is due to the fact that they increase the number of platelets and red blood cells.
Tomoxifen MOA
SERMs –> bind to estrogen receptors and act as agonists or antagonists depending on the tissue
Antagonist on breast tissue –> used for receptor positive breast cancer
Agonist in non breast tissue
- a partial agonist in the endometrium so by giving this drug, estrogen will lead to hyperplasia of the endometrium which can potentially lead to endometrial cancer
- agonist on bone –> can prevent bone resorption
Tomoxifen AE
Hot flashes
Nausea
Fluid retention
Tamoxifen increases incidence of endometrial cancer
Roloxifene MOA
SERMs –> bind to estrogen receptors and act as agonists or antagonists depending on the tissue
Antagonist in uterus and breast
Agonist on bone –> promotes oestrogen effects in bone to inhibit resorption
Used for prevention of postmenopausal osteoporosis and prophylaxis of breast cancer in high risk postmenopausal women
Roloxifene AE
Hot flashes
Fluid retention
Fulvestrant MOA
SERDs –> no estrogen receptor (ER) agonist activity
Binds to ER –> inhibits its dimerisation and increases its degradation –> ER-mediated transcription is abolished
Aromatase Inhibitors Indication
Aromatase converts androstenedione to estrone
In postmenopausal women, this conversion is the primary source of circulating estrogen
Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer
Anastrazole and Letrozole MOA
Non-steriodal
Reversible competitive inhibitors of aromatase
Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer
Exemestane MOA
Steroidal
Irreversible inhibitor of aromatase
Aromatase inhibitors are standard of care for adjuvant treatment of postmenopausal women with hormone receptor-postive breast cancer
Androgen Inhibitors Indication
Two types - GnRH agonists and androgen receptor blockers
Therapy of prostate cancer - use of GnRH agonists along or in combination with androgen receptors blocker
Goserelin and Leuprolide MOA
GnRH agonists
GnRH release from hypothalamus is usually pulsatile
When given continuously or as a depot, GnRH agonists cause an initial surge in LH and FSH levels followed by inhibiton of gonodotropin release –> testosterone levels fall to 10% of their initial values after a month
Initial surge can be counteracted with administration of flutamide for 2-4 weeks
Goserelin and Leuprolide AE
Impotence
Hot flashes
Testicular atrophy
Flutamide MOA
Synthetic, nonsteroidal, androgen receptor blocker
Metabolised to an active metabolite that acts as a competitive agonist at the androgen receptor –> prevents its translocation to nucleus
Imatinib
Inhibitor of Bcr-Abl tyrosine kinase
9:22 translocation - used to treat chronic myelogenous leukemia
Transtuzumab
Monoclonal antibody against ErbB2 tyrosine kinase
Causes cardiotoxicity - but it is reversible
Transtuzumab
Monoclonal antibody against ErbB2 tyrosine kinase
Causes cardiotoxicity - but it is reversible
Flutamide AE
Gynecomastia
Hot flushes
Liver dysfunction
Asparaginase MOA
Most normal tissues synthesise L-aparagine in amount sufficient for protein synthesis
Neoplastic tissue require exogenous course of asparagine
Asparaginase hydrolyses serum asparagine to aspartate and ammonia–> deprives tumor cells of asparagine needed for protein synthesis –> cell death
Asparaginase AE
Hypersensitivity
Decrease in clotting factors: There is an imbalance between coagulation and anticoagulation –> coagulation wins so patients have more thrombotic events than bleeding events
Liver abnormalities
Pancreatitis –> it can activate pancreatic enzymes
Seizures/coma due to ammonia toxicity
Hydroxyurea MOA
Inhibits ribonucleotide reductase –> deletion of deoxynucleoside triphosphate pools –> inhibits DNA synthesis
Kills cells in S phase
Given orally
Hydroxyurea AE
Myelosuppression is major toxicity
At high doses megaloblastosis unresponsive to vitamin B12 may appear
GI symptoms, including nausea, vomiting and diarrhea are common with high doses
Interferon a Indication
Hairy cell leukemias, chronic myelogenous leukemias, malignant melanoma and Kaposi’s sarcoma
Interferon a MOA
IFNa can stimulate NK cells to attack malignant cells
Tumor cells can evade the immune system by not producing HLA. IFNa can also increase HLA expression in tumor cells so that the immune cells can attack the cancer cells
Interferon a AE
Depression
Fever with chills
Leukopenia, thrombocytopenia.
Fatigue, malaise, anorexia, weight loss, alopecia
Transient elevation of liver enzymes.
