Anti neoplastic drugs flashcards
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Transcript of Anti neoplastic drugs flashcards
Anti-Neoplastics
Antimetabolites◦Methotrexate◦5-FU◦Mercaptopurine◦Azathioprine
Alkylating Agents◦Cyclophosphamide◦Cisplatin◦Chlorambucil◦Carmustine
Cytotoxic Antibiotics◦Doxorubicin◦Dactinomycin◦Daunorubicin◦Bleomycin
Natural Products◦Vincristine◦Vinblastine◦Etoposide◦Paclitaxel
Hormones◦Tamoxifen◦Anastrazole◦Prednisone
Monoclonal Ab◦Trastuzumab◦Rituximab
Immunosuppressants◦Azathioprine◦Prednisolone◦Cyclosporine
Others◦Asparaginase◦Imatinib Mesylate◦Hydroxyurea
Drugs acting at Cell Cycle phases
S phase◦Methotrexate blocks dihydrofolate reductase◦5 – FU inhibits thymidylate synthase◦Mercaptopurine inhibits purine nucleotide
interconversions◦Hydroxyurea inhibits ribonucleotide reductase◦Pentostatin inhibits adenosine deaminase
Drugs acting at Cell Cycle phases
G2 phase◦ Bleomycin fragments DNA
M phase◦ Vincristine & Vinblastine binds tubulin & blocks MT
polymerization◦ Paclitaxel prevents MT depolymerization; promotes
polymerizationG1 phase
◦ Dactinomycin binds DNA & inhibits DNA-dependent RNA synthesis
Between S and G2◦ Etoposide interferes with topo II◦ Dactinomycin
What is an induction regime?
High dose of tx for a short period of time to reduce burden on cells
CCNS – Cell cycle nonspecific drugs
Used for cancers with low percentage of mitotic cells
Cyclophosphamide, busulphan, chlorambucil
Doxorubicin, daunorubicin, dactinomycinCisplatinRecruitment: initial use of CCNS drugs
achieves a significant log kill which causes more cells in Go to go into G1; then CCS drugs are given
Log – Kill concept
Drug/irradiation kills a constant proportion of cells in population, not fixed number of cancer cells
One log kill = 90% decrease in cell pop3 log kill = 99.9% decreaseSmaller tumor will have greater portion of
cells killed than larger tumor but they regrow quicker between cycles of therapy
Breast Cancer Combo
CyclophosphamideMethotrexate5-FU
Pancreatic Cancer Combo
DoxorubicinMethotrexate5-FU
Ovarian Cancer Combo
CisplatinPaclitaxel
Testicular Cancer Combo
CisplatinVinblastineBleomycin
Non Hodgkin’s Lymphoma Combo
CyclophosphamideDoxorubicinVincristinePrednisoneRituximab
Hodgkin’s Disease Combo
MechlorethamineVincristinePrednisoneProcarbazine
DoxorubicinBleomycinVinblastineDacarbazine
Drugs w/ features you must know
CytarabineCapecitabineCarmustineEtoposideTopotecanFulvestrantFlutamide &
FinasterideLeuprolide
RituximabHydroxyureaImatinib Mesylate
Cytarabine
AntimetaboliteDOC for AMLMoA: blocks DNA strand elongationNeurotoxic
Etoposide
Stabilizes the topo II – DNA complex causing dsDNA breaks during DNA replication
Dose limiting leukopeniaTreat first time and metastatic testicular
cancermay cause AML!!
Capecitabine
Oral prodrug converted to 5-FUMoA: inhibits thymidylate synthaseUseful for paclitaxel and doxorubicin –
resistant pts with colorectal or metastatic breast cancers
Carmustine
Alkylating agent; nitrosoureasMost alkylating agents taken up by active
transport but nitrosoureas taken up by passive transport
Liphopilic & passes BBB CNS ToxicityUsed for CNS cancers that are metastatic
malignant astrocytoma
Topotecan
Unique topo I inhibitor, preventing religation of bits of helices accumulation of single stranded breaks in DNA
Dose limiting neutropenia
Fulvestrant
Antiestrogen for hormone-sensitive tumors
Give to post-menopausal women who are resistant to tamoxifen
Flutamide & Finestiride
Flutamide is a nonsteroidal androgen antagonist which inhibits the translocation of steroid receptors to the nucleus
Finasteride is a 5-alpha reductase inhibitor which inhibits synthesis of dihydrotestosterone
Both used to treat prostate cancer
Leuprolide
GnRH analog which acts as a partial agonist at GnRH receptors
When administered in constant doses to maintain stable blood levels, it inhibits the release of LH and FSH
Used in tx of prostate cancer
Rituximab
This is an unconjugated chimeric (murine/human) antiCD20 monoclonal antibody which binds to the CD20 antigen on follicular B cells in Non Hodgkins lymphoma
Hydroxyurea
Inhibits ribonucleotide reductase ribonucleotides to deoxyribonucleotides
Used for myeloproliferative disorders
Imatinib Mesylate
Inhibits bcr-abl tyrosine kinase found in chronic myelocytic leukemia (CML)
Antimetabolites
Methotrexate (CCS works during S phase)
Uses◦Solid tumors such as choriocarcinoma◦Osteogenic sarcoma◦Acute Lymphoblastic Leukemia (ALL)◦Psoriasis◦Abortifacient
Looks like folate take up by cells readily
MoA of Methotrexate
Inhibits dihydrofolate ReductaseThis enzyme reduces folate to
tetrahydrofolate which is a one carbon unit carrier used in synthesis of purines and pyrimidines which are part of DNA and RNA cell replication
ANTIDOTE: Leucovorin folinic acid rescue◦Host cells are rescued while cancer cells die
Methotrexate Toxicity
NephrotoxicityMyelosuppression
◦Neutropenia, thrombocytopenia, mucositis, diarrhea, and GI ulceration (oral)
◦G-CSF can counteract leukopeniaPulmonary toxicity and hepatotoxicity
(long term)
Other Antimetabolites
Pyrimidine analogs◦5 – FU◦Capecitabine 5-FU◦Cytarabine
5 – FU◦MoA: inihibit thymidylate synthase◦Uses: colon, breast, rectal, gastric, pancreatic
cancer◦Capecitabine is same but one of the newest
drugs for pancreatic cancer
Toxicity of 5-FU and Antimetabolites
Anorexia, nauseaAlopeciaStomatitis and diarrheaMyelosuppression (less for capecitaine)Maculopapular rash
Resistance develops when thymidylate synthase becomes less sensitive to the drug
Purine Analogs
Azathioprine, MercaptopurineMoA: as nucleotides they inhibit
phosphoribosylpyrophosphate (PRPP) synthetase reduction in PRPP
They also inhibit PRPP amidotransferase reduction in phosphoribosylamine
Block de novo PURINE synthesis and salvage pathways
Toxicity:◦ Bone marrow suppression◦ Leukopenia◦ Hyperuricemia (Mercaptopurine)◦ Hepatotoxicity
Purine analogs
Pentostatin◦Uses: Hairy Cell Leukemia◦MoA: blocks adenosine deaminase
impairment of DNA replication and cell division◦Toxicity: Myelosuppression
Alkylating Agents
Cyclophosphamide (ifosphamide also)BusulphanCarmustine (nitrosoureas)
Cyclophosphamide
MoA: prodrug converted in liver to active nitrogen mustard (nephrotoxic) and acrolein (causes cystitis) interferes with transcription and translation and causes increased ADH secretion (water reabsorption leading to hyponatremia results)◦Drug is given with high water load
ANTIDOTE: MesnaADH antidote: Demeclocycline
Cyclophosphamide Use and Toxicity
Uses◦Hodgkin’s disease◦Lymphomas, myeloma◦Leukemia◦Ovarian & breast tumors
Toxicity◦Myelosuppression◦Permanent amenorrhea and azoospermia◦Renal and bladder toxicity (hemorrhagic cystitis &
hematuria)◦Alopecia◦Cardiotoxic at high doses
Busulphan
MoA: cross-links DNA strands by covalently bonding guanine residues prevents DNA replication & transcription
Use: CMLToxicity:
◦Busulphan Lung - pulmonary fibrosis◦Busulphan tan – hyper pigmentation
Temozolamide
Some success in treating malignant gliomas (multiforme glioblastoma thought to be incurable)
Cytotoxic Antibiotics
DoxorubicinDaunorubicinDactinomycinBleomycin
All CCNS mostly
Doxorubicin
MoA: ◦Intercalates DNA and is topo II block/poison◦Increases radicals◦Causes extravasation ulcers and
inflammationUSES:
◦Breast, ovarian, bladder tumors – Solid tumors◦Bronchogenic carcinoma◦Lymphoma and leukemia
Doxorubicin Toxicity
CardiomyopathyColors urine redStomatitisAlopeciaAnemia, leukemia
ANTIDOTE for radicals: Dimethyl SulphoxideANTIDOTE for cardiomyopathy: Dexrazoxane
Daunorubicin
Similar to doxorubicinUse: LEUKEMIA
Dactinomycin
MoA: binds DNA Helix prevents transcription of DNA by RNA polymerase
USES◦Rhabdomyosarcoma◦Wilm’s tumor in children◦Ewing’s Tumor◦Kaposi’s sarcoma
Toxicity: Pancytopenia
Bleomycin
MoA: fragments DNA via free radicals cells accumulate in G2 phase
USES◦Lymphomas◦SCC◦Testicular carcinoma◦Choriocarcinoma
Toxicity: Pulmonary Fibrosis, hyperpigmentation
Natural Products
Vinca alkaloids: Vincristine and VinblastineEpidophyllotoxins: EtoposideCamptothecins: TopotecanTaxanes: Paclitaxel
Vinca Alkaloids
MoA: bind tubulin and prevent MT assembly; act in M phase
Vincristine (Neurotoxic—peripheral neuropathy, loss of deep tendon reflexes)◦Use: Hodgkin’s disease, rhabdomyosarcoma,
lymphomas, leukemia, neuroblastomaVinblastine (reversibly myelotoxic)
◦Use: Hodgkin’s, testicular carcinomaResistance assoc/ MDR gene mutation
Epidophyllotoxins - ETOPOSIDE
MoA: stabilizes topo II-DNA complex dsDNA breaks
Specific for late S and early G2 phasesUses: testicular carcinoma (less toxic than
other natural products), Hodgkin’s diseaseToxicity:
◦Leukopenia; hepatic and renal toxicity at high dose
◦May cause AML!!!
Taxane - Paclitaxel
MoA: inhibit MT disassembly abnormal/dysfunctional spindles
Uses◦Advanced ovarian cancer w/ cisplatin◦Metastatic ovarian or breast cancer
Toxicity◦Hypersensitivity reactions◦Neutropenia◦Peripheral neuropathy & muscle pain
Hormonal Chemotherapy
EstrogensAntiestrogens
◦Tamoxifen◦Fulvestrant◦Anastrazole
AndrogensAntiandrogens
◦Flutamide◦Finasteride
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