Cancer Chemotherapy Flashcards
First anticancer drug
Mustine (nitrogen mustard) for Hodgkin’s lymphoma
how do cancer cells alter host cells with regards to control mechanisms for proliferation and differentiation
- shorter, accelerated cell cycle
- excessive proliferation
- higher activity of nucleic acid and protein synthesis
- altered cell to cell communication
- invasive (disrupt normal healthy tissue)
- migrate to distinct sites (metastasis)
what do cancer cells use for nutrients and metabolic pathways?
the same nutrients and metabolic pathways as the host cell.
most common cancer in men age 15-35
metastatic testicular cancer. thus the importance of testicular palpation by patient
testicular cancer chemotherapy
1 round BEP (Bleomycin, Etoposide, Platinol)
3 rounds VIP (Vinblastin, Ifostamide, Platinol)
Mitomycin C
cross links DNA, bifunctional alkylation
Cytosine arabinoside, hydroxyurea, 6-MP, MTX, 5-FU
Blocks DNA synthesis
Etoposide
inhibits TOPOISOMERASE II DNA DEGREDATION
Vincristine, Vinblastine, Taxanes
block MITOTIC SPINDLE FORMATION
Mechanism of alkylating agents
Nitrogen mustards and Nitrosources. impair cell function by forming covalent bonds with the AMINO, CARBOXYL, SULFHYDRYL, and PHOSPHATE groups. the electron rich nitrogen at the N7 position in Guanine is particularly susceptible.
ACTIVE EVEN FOR THE RESTING CELLS IN GO
Nitrogen Mustards Mechanism of action
CHLOROETHYL SIDE CHAIN undergoes an intermollecular CYCLINIZATION (Sn1) and forms CARBONIUM ION intermediate or transition complex to become strongly electrophillic. Nucleophillic attack of unstable AZIRIDINE RING by electron donor
Effects of alkylation of the 7 nitrogen of Guanine residues in DNA (3)
- guanine residues are more acidic and enol tautomer is favored. it can mispair with thymine residues during DNA synth, leading to substitution of A-T pair for G-C pair
- causes opening of IMIDAZOLE RING or depurination by excision of guanine residue
- with bifunctional alkylating agents, the second 2-choloethyl side chain can undergo intermolecular cyclinization and alkylate a second guanine reside, resulting in cross linking of two nucleic acids or linking NA to protein
Nitrogen Mustards clinical use and adverse effects
used in combo with other drugs for lymphomas and leukemias.
adverse: teratogenic, immunosuppressive, carcinogenic
Mechlorethamine (mustargen, Mustine)
nitrogen based analog of mustard gas that was derived from chemical warfare research. first nitrogen mustard used and most reactive. primarily used in combination chemotherapy regiment MOPP (Mechlorethamine+Oncovin (vincristine)+Procarbazine+Prednisone) for treatment of HODGKIN’S DISEASE.
ADVERSE: more toxic to proliferating cells= bone marrow depression, infertility, and GI toxicity
Cyclophosphamide (cytoxin, Neosar)
Nitrogen mustard. Bioactivation: PRODRUG converted to PHOSPHORAMIDE MUSTARD and ACROLEIN by P450. DNA cross link of N7 Guanine.
CLINICAL USE: non-neoplastic disease, NON-HODGKIN LYMPHOMA, maintenence therapy of ACUTE LYMPHOID LEUKEMIA, breast cancer as adjuvent, carcinoid, neuroblastome
ADVERSE: bone marrow depression, ALOPECIA, GI, hemorrhagic cystitis
IFOSFAMIDE (ifex)
Nitrogen Mustard. analog of cyclophosphamide. activated in liver by ring hydroxylation.
USE: multidrug regimen to treat GERM LINE TESTICULAR CANCER, pediatric and adult sarcomas, and many cancers like cervical, lung, bone, ovarian, and breast
ADVERSE: similar toxicity to cyclophosphamide but greater PLATELET SUPPRESSION and severe urothelial damage and internal bleeding when not used with MESNA
Nitrosources mechanism of action
spontaneous degradation to form 2-chloroethyl carbonium ion and linerate organic isocyanates that attach carbanoyl groups to lyseine residues of proteins (cross linking DNA strands, break DNA strands, and carbamoylate proteins)
ADVERSE: highly carcinogenic and mutagenic; profound, cumulative myelosuppression; renal failure; alopecia; hepatotoxicity; pulmonary toxicity (Bosulfan)
Lomustine (CeeNU) and Semustine (MeCCNU)
Nitrosources. effective orally.
USE: important in treatment of BRAIN CANCER (highly lipophillic, crosses BBB). GI neoplasm and alternate drug for Hodgkin’s disease
Streptozotocin
Nitrosource. water soluble, not effective orally. methylates DNA and RNA and is particularly toxic to PANCREATIC ISLET CELLS.
USE: insulinoma (pancreatic islet cell carcimnoma and carcinoid, excessive insulin secretion), metastatic cancer of pancreatic islet cells
Busulfan
only listed alkyl sulfonate (sul=sul). selectively myelosuppression inhibiting granulocytopoeisis.
USE: Chronic Myelogenous Leukemia (CML) and other myeloproliferative diseases.
ADVERSE: myelosuppression. “BUSULFAN LUNG”: rare but fatal pulmonary fibrosis.
Antimetabolites
structurally similar to endogenous molecules in synthesis of DNA and RNA. act as enzyme inhibitors and are transferred by the enzymes to fake product. effect is to slow down the synthesis of nucleic acids (S PHASE SPECIFIC)
3 general categories:
purine analogs, pyrimidine analogs, folic acid analogs
Purine antagonists
inhibit purine ring formation (NT interconversion) (6-MP, 6-thioguanine)
Pyrimidine antagonists
inhibits pyrimidine synthesis (Pala Azaribine)
5-FLUOROURACIL (5-FU): inhibits dTMP synthesis
Folate antagonists
inhibit dehydrofolate reduction and blocks purine and TMP synthesis (MTX)
Cytarabine
antimetabolite. cytosine arabinoside. inhibits DNA synthesis.
6-mercaptopurine, 6-MP
purine antagonist. S phase specific. structural analog to adenine that is activated by HGPRT conversion to a nucleotide (6-TIMP). this inhibits the conversion of IMP to adenine and guanine and blocks the final step of synthesis or purines.
USE: maintenence in acute lymphoid leukemia in children.
ADVERSE: bone marrow suppression, immunosuppression, GI, hepatotoxicity
RESISTANCE: decreased activation (lack of HGPRTase) and increased breakdown of 6-TIMP by alk phos
6-thioguanine
purine antagonist. S phase specific. enzymatic (HGPRT) conversion to nucleoside (6-TGMP) which is incorporated into DNA as dTGTP.
USE: leukemias, particularly valuable in treating acute granulocytic leukemia when given with cytanabine
ADVERSE: bone marrow suppression, mild nausea
RESISTANCE: decreased conversion of the drug.
Methotrexate (MTX)
folic acid analog. inhibits DIHYDROFOLATE REDUCTASE, which decreases dTMP leading to decreased DNA and protein synthesis
Methotrexate Use
leukemias
lymphomas
choriocarcinoma
sarcomas
methotrexate toxicity
myelosuppression, which is reversible with leucovorin
macrovesicular fatty changes in liver
mucositis
teratogenic
5-Fluorouracil
pyrimadine analog, bioactivated to 5d-dUMP, which covalently complexes folic acid. this complex inhibits THYMIDYLATE SYNTHASE, which will decrease dTMP, leading to decreased DNA and protein synthesis
5-Fluorouracil use
colon cancer
blast cell carcinoma
5-Fluorouracil toxicity
myelsuppression, which is reverse with leucovorin
overdose- rescue with thymidine
photosensitivity
Dactinomycin
intercalates DNA
Doxorubicin (adriamycin), daunorubicon
generate free radical. noncovalently intercalate DNA, causing breaks in DNA and decreased replication.
USE: solid tumors, leukemias, lymphomas
Doxorubicin (adriamycin), daunorubicon toxicity
cardiotoxicity
myelosuppression
alopecia
Bleomycin
induces free radical formation, which causes breaks in DNA strands
Bleomycin use
testicular cancer
hodgkins lymphoma
Vincristine, Vinblastine
Alkaloids that bind to tubulin in M phase and block polymerization of microtubules so that mitotic spindle cannot form. used in solid tumors and leukemia
vincristine toxicity
neurotoxicity (areflexia, peripheral neuritis)
paralytic ileus
vinblastine toxicity
BLASTs bone marrow
Cisplatan, carboplatin
cross link DNA. used in testicular, ovary, and lung carcinoma
Cisplatan, carboplatin toxicity
nephrotoxicity
acoustic nerve damage
Hydroxyurea mechanism
inhibits RIBONUCLEOTIDE REDUCTASE, which leads to decreased DNA synthesis.
Hydroxyurea use and toxicity
used in melanoma, CML, and sickle cell
causes bone marrow suppression and GI irritation
Tamoxifen, raloxifene
SERMs receptor antagonist in breast and agonist in bones. block binding of estrogen to estrogen receptor positive cells.
Herceptin
monoclonal antibody against HER-2, a tyrosine kinase. helps kill breast cancer cells that overexpress HER-2. can cause cardiotoxicity
Imatinib (Gleevec)
philadelphia chromosome bcr-abl tyrosine kinase inhibitor. used in CML and GI stromal tumors
Rituximab
monoclonal antibody against CD20. used in Non hodgkins lymphoma and RA with methotrexate
