cancer drugs Flashcards
What are the nitrogen mustards?
Nitrogen mustards:
- Mechloroethamine
- Cyclophosamide
- Ifofsamide
how do alkylating agents work and what are they?
akylating agents work by acetylating DNA (irreversible, covalent bond) and thus XL them and cause DNA damage. acts on both dividing and nondividing cells (cell cycle nonspecific)
- Nitrogen mustards
- Nitrosurea
- Triazenes
- Platinum analogs
TOX: BM TOX (NEUTROPENIA, THROMBOCYTOPENIA, ANEMIA)
mucosal tox, reproductive sys (male-sterility, females - amenorrhea), INC LEUKEMIA RISK, N+V
alkylating agent;;;nitrogen mustard:
mechloroethamine
TX: in combo with MOPP (Hodg), also used to tx cutaneous T-cell lymphoma
TOX: N+V, immunosupp (leucopenia, thrombocytopenia)
alkylating agent;;;nitrogen mustard
cyclophosamide and ifosfamide
TX: used in comb: CHOP (non-Hodg), CMF (BC), FAC (BC), FEC (BC): nonhodg, BC, ovarian, Lung, acute and chronic lymphocytic leukemia
-ifosfamide is converted in the P450 to active akylating agent, it is also used for sarcoma and testicular cancer
TOX: N+V, myelosuppression, HEMORRHAGIC CYSTITIS (b/c accumulation of acrolein (can be overcome by hydrating with MESNA)
alkylating agent;;;nitrosurea, list
- carmustine
2. lomustine
alkylating agent;;;nitrosurea
carmustine and lomustine
-both lipophilic
TX: brain tumors
TOX: renal tox, pul fibrosis, profound myelosuppression, severe N+V
alkylating agent;;;triazenes, list
- dacarbazine
2. temozolomide
alkylating agent;;;triazenes
Dacarbazine: IV, ABVD combo (Hodg, malig melanoma)
-prodrug, monoalkylators
Temozolomide: oral (good bioavailability), undergoes nonenzymatic conversion to methylhydrazine at physiological pH
-TX: malig gliomas, std tx in combo with radiation therapy
TOX: N+V, myelosuppression, FLU-LIKE SX (fever, fatigue)
alkylating agents;;;;platinum analogs
- cisplatin
- carboplatin
- oxaliplatin
platinum analogs
how they work
- inorganic platinum derivatives
- interacts with H20 to form the active cytotoxic form (+ charged, hydrated intermediate) –> covalently bind Gs in DNA –> intra and interstrand XLs
platinum analogs (what each of them tx)
- cisplatin - testicular, ovarian, cervical, bladder, HN, lung
TOX: renal, ototox, severe N+V, peripheral motor and sensory neuropathy at high doses, mild/mod myelosuppression - carboplatin: ovarian
TOX: mild/mod myelosuppression - oxaliplatin: gastric and colorectal (in combo with 5FU)
TOX: COLD-INDUCED PERIPHERAL NEUROPATHY, (NEUROPENIA?)
how do metabolites work and what are they?
- structural analogs of folic acid/purine/pyr bases, therefore inhibits enzymes required for puring/pyr nucleotide syn or compete with them for DNA/RNA syn
- inhibits S phase (Cell cycle specific drugs / DNA syn inhibitors)
- folate analogs
- pyrimidine analogs
- purine analogs
antimetabolite;;;folate analogs and what they do
- methotrexate = antifolate = folic acid antagonist
- blocks DHFR (DHFR normally converts dietary folate to tetrahydrofolate required for thymidine and purine biosynthesis)
- use leucovorine rescue (N5-formyl-THF) to bypass the toxicity on other cells (normal cells have more carriers for leucovorine –> dec side effects)
TX: childhood acute lymphoblastic leukemia (ALL), choriocarcinoma (malig trophoblastic tumor)
- {in combo therapy: burkitt’s lymphoma, breast, ovary, H+N, bladder carcinoma}
- cannot penetrate CNS, therefore intrathecal administration for meningeal dz.
- high concentrations tx osteosarcoma
TOX: BM (myelosuppression, spontaneous hemorrhage), GI tox (oral ulcers, stomatitis), renal (MTX crystalizes in urine and cause damage), liver (long term –> fibrosis/cirrhosis), defective oogenesis/spermatogenesis (abortions)
antimetabolite ;;; folate analogs
pemetrexed - considered a 2nd line therapy
-active form is polyglutamate form that inhibits THF-dependent enzymes (TS, DHFR)
TX: colon, pancreatic, mesothelioma, non SCLC, multitargeted folate analogs
antimetabolites ;;; pyrimidine analogs
- 5-FU
- capecitabine
- cytarabine (Ara-C)
- Gemcitabine
5FU
5-FU (pyr analog): a prodrug that req enzymatic conversion to become active: 5FdUMP (inhibits TS, prevents thymidine syn), 5FdUTP (incorp into RNA)
TX: IV bc GI tox, and rapid metabolic degradation in gut and liver
combos: breast, colorectal, gastric, HN, cervical, pancreatic
topical: TX BCC
TOX: HAND-FOOT SD, cardiac tox
antimetabolite;;;pyrimidine analogs; capecitabine
capecitabine: new oral form, prodrug -> converted to 5’d-FdU
TX: met BC and colorectal cancer
TOX: HAND-FOOT Sd (sensitivity to palms and soles), CARDIAC TOX (ACUTE CP), anemia, thrombocytopenia, anorexia, N, mucosal ulcerations, stomatitis, diarrhea
antimetabolite;;;pyrimidine analogs; cytarabine (ara-C)
Cytarabine (ara-C): S-phase specific pyrimidine antagonist
analog of 2-deoxycytidine but ribose is replaced by D-arabinose
1=deoxycytidine kinase
ara-C -1->ara-CMP –> ara-CTP (competes with dCTP for incorp into DNA by DNA poly –> premature DNA chain termination
MOST EFFECTIVE for acute myeloid leukemia (AML), useful for ALL, blast phase CML
TOX: severe myelosupp, GI tox
antimetabolite;;;pyrimidine analogs; gemcitabine
gemcitabine: difluoro analog of deoxycytidine (dFdC)
gemcitabine -p–> dFdCMP –> dFdCDP –| ribonucleotide reductase (therefore deplete deoxyribonucleotide pool for DNA syn)
gemcitabine –p–>dFdCMP–>dFdCTP —> gets into DNA therefore terminates DNA syn
similar to cytarabine in that it also inhib dna syn
diff from cytarabine in that it is active throughout the whole cycle
MORE effective than cytarabine against solid tumors
TX: 1st line tx for pancreatic carcinoma, effective against nonSCLC, ovarian, bladder, esophageal, HN cancers
TOX: myelosupp, FLU-LIKE Sd
what are the purine analogs
- 6-mecaptopurine
- prodrug, metabolized by hypoxanthine-guanine phosphoribosyl transferase (HGPRT)
6MP —HGPRT–> 6TIMP
6MP –XO–> 6thiouric acid (allopurinol inhib XO)
6TIMP:
1. inhib the feedback inhib of p-ribosylamine syn (generated from PRPP (precursor to IMP)
2. inhib IMP (IMP makes AMP and XMP (GMP))
3. thio-GMP–>RNA (inhib DNA/RNA syn)
what is 6mp used for and the tox, and mechanism of resistance
TX:
- maintain remission in pts with ALL (acute lymphoblastic leukemia)
- allopurinol + 6MP dec hyperuricemia in pts getting chemo. but since allopurinol inhib XO, 6MP builds up, therefore give lower dose of 6MP to avoid toxicities
TOX: BM supp, livetox with prolonged use
mechanism of resistance: dec HGPRT, dec drug tranport
how do dna intercalating agents work?
aka antitumor ab’s from soil microbe streptomyces
-binds DNA: inhib DNA/RNA/both syn, cause DNA strand breaks, interfere w/ cell replication
what are the DNA intercalating agents?
- Dactinomycin (aka Actinomycin D)
- Anthracyclines
- Bleomycin
DNA intercalating agent ;;; actinomycinD
actinomycin D:
intercalates btwn GCs in DNA –> interferes w/ RNA poly –> cannot transx, cause single strand breaks
TX: pediatric tumors: Wilm’s tumor, rhabdomyosarcoma, Erwing’s sarcoma, advanced choriosarcoma in women
TOX: N+V, anorexia, hematopoietic supp with PANCYTOPENIA (WBC, RBC, platelets)
what are the anthracyclines?
- daunorubicin
- doxyrubicin
- idarubicin
- epirubicin
they are all ANTIBIOTICS from streptomyces
ALL intercalate btwn DNA bps via HYDROXYL RADICALS
TOX: myelosupp, neutropenia, irrev dose-dep CARDIOTOXICITY (cardiomyopathy), stomatitis, GI disturbances, alopecia
daunorubicin and idarubicin
AML
idarubicin also used in combo with Ara-C for CML
doxorubicin
broad spectrum of use: sarcomas, breast and lung carcinomas, malignant lymphomas
epirubicin
met BC and gastric cancer
Bleomycin
- mix of 2 copper chelating peptides from streptomyces
- binds DNA and induces 1/ds DNA breaks after its oxidized and forms free radical
TX: testicular cancer (usually in combo with vinblastine / etoposide), SCC, lymphomas
TOX: min myelosupp and immunosupp
PUL TOX (PUL FIBROSIS)
CUTANEOUS TOX (hyperpig, hyperkeratosis, erythema)
hyperthermia, headache, N+V
how do microtubule inhibitors work? and what are two of them?
microtubules are formed from tubulins poly/depoly
vinca alkaloids and taxanes –| mitosis by causing M arrest by interfering with microtubule function
what are the vinca alkaloids? (they are natural plant alkaloids), how do resistance happen?
blocks tubulin POLYMERIZATION
- vinblastine: (w. bleomycin, cisplatin)
TX: met testicular tumors
part of ABVD for Hodg
TOX: myelosupp, N+V - vincristine: (w. glucocorticoids) –> childhood ALL
TX: hodg, nonhodg
TOX: dose limiting neurotoxicity (rel low tox in BM)
RESISTANCE:
via P-glycoprotein channels that pump the drug out
what are the taxanes? (also plant alkaloids)
- paclitaxel (taxol)
2. docetaxel (taxotere) (more potent), yew trees
what do the taxanes, paclitaxel and docetaxel, do?
prevent microtubule depoly (neccessary for chromo desegregation during mitosis), M phase arrest
TX: Met BC, ovarian, lung, HN tumors
docetaxel: hormone-refractory prostate cancer
TOX: neutropenia, peripheral neuropathy, hypersensitivity rxns
what are the topoisomerase inhibitors? and want do they do in general?
topoisomerases (1-ssDNA, 2-dsDNA) breaks and reseals DNA during replication to relieve torsional stress.
-the drugs inhib the topo by preventing DNA resealing
- epipodophyllotoxins
- camptothecin analogs (natural from chinese plant)
what are the epipodophyllotoxins?
- etoposide and teniposide
both are podophyllotoxin derivative; semisynthetic
both inhib topo2 –> DNA damage by stablizing the breaks induced by topo
etoposide: broad activity: testicular carcinoma, lung cancer, nonhodg
teniposide: ALL (Acute lymphoblastic leukemia)
TOX: dose-limiting myelosupp (neutropenia)
ORAL MUCOSITIS
what are the camptothecin analogs and what do they do?
irinotecan and topotecan: synthetic camptothecin analogs (inc activity, dec tox)
both inhib topo 1 –> accumulation of DNA breaks
irinotecan: adv colorectal cancer, good for lung, ovarian, cervical, brain
topotecan: ovarian and SCLC
TOX: SEVERE neutropenia, SEVERE diarrhea
