Onc Pharma Flashcards
Polyfunctional alkylating agents
Break H-bonding in DNA and then erroneously cross-link DNA, most mutagenic CTX
- Busulfan: CML / Myeloablation. SE: MS(Myelosuppression), Pulmonary fibrosis, hyperpigmentation.
- Mustards / Nitrosoureas (Carmustine, Lomustine, Semustine, Streptozocin): Require bioactivation and cross BBB, so used in brain tumors. SE: CNS toxicity
- Cyclophos / Ifos:
a. Cross-link at Guanine N7 site
b. Require bioactivation in liver via P450
c. Metabolized by kidneys into Acrolein –> cause uroepithelial necrosis —> Hemorrhagic cystitis –> prevented by Mesna. - Cis(renal)platin / Car(kan)boplatin
- Dacarbazine / Procarbazine
Amifostine
- Reduce the incidence of neutropenia-related fever and infection induced by alkylating agents 2. Decrease the cumulative nephrotoxicity associated with platinum-containing agents.
- Reduce the incidence of xerostomia by radiotherapy for head and neck cancer
Alkaloids
- Paclitaxel / Docetaxel: Prevent depolymerization in M phase and prevent Anaphase to occur. SE: Neuropathy.
- Vincristine / Vinblastine: bind b-tubulin and inhibit polymerization (M phase arrest). SE: Vinc; neuropathy. Vinblas; blasts bone marrow.
Topoisomerase II inhibitors
Etoposide / Tenoposide: Topoisomerase II inhibitors –> inc DNA degradation
(II sides)
Topoisomerase I inhibitors
Irinotecan / Topotecan: Topoisomerase I inhibitors –> inc DNA degradation.
(I CAN)
Antitumor Antibiotics
- Anthracyclins (Doxorubicin or Adriamycin/ Daunorubicin / Epirubicin / Idarubicin): generate free radicles –> interfere with DNA replication by breaking DNA —> Dilated cardiomyopathy –> CHF –> Dexrazoxane is used to prevent cardiotoxicity and is an iron chelating agent.
- Dactinomycin or Actinomycin D: intercalate in DNA grooves –> inhibit RNA polymerase attachment –> inhibit cell growth. Used in childhood tumors.
- Bleomycin / Mitomycin / Plicamycin: generate free radicles –> interfere with DNA replication by breaking DNA. The only one which is G2 specific. SE: Pulmonary fibrosis.
Antimetabolites (classification)
- Purine antagonists
- Pyrimidine antagonists
- Antifolic acid synthesis
- Amino acid synthesis antagonists.
- Purine antagonists
- Azathioprine / 6-Mercaptopurine (6MP) / 6-Thioguanine (6TG):
a. Purine (thiol) analogs –> Dec de novo purine synthesis.
b. Activated by HGPRT (Aza is converted to 6MP)
c. Is used to wean patients off steroids & to treat steroid-refractory chronic diseases.
d. Affect Liver and cause Myelosuppression. Aza and 6MP are metabolized by Xanthine oxidase; thus both have inc toxicity with Allopurinol or Febuxostat. - Cladribine (2CDA) / Fludarabine / Pentostatin:
a. Purine analogs —> break DNA strands and inhibit DNA polymerase
b. Rx for Hairy cell leukemia, SE: Nephro and Neurotoxicity
- Pyrimidine antagonists
- Fluorouracil (5-FU):
a. Pyrimidine analog bioactivated into 5-FUMP –> covalently i.e. irreversibly bonds with B9 (THF) –> this complex inhibits Thymi-dylate Synthase –> dec TMP –> dec DNA synthesis.
b. Myelosuppression which is not reversible by Leucovorin (Folinic acid), rather its cytotoxic effects are enhanced by folinic acid - Cytarabine (ARA-C) / Azacitidine:
a. pYrimidine analog –> inhibit DNA polymerase
b. SE: Pancytopenias
- Antifolic acid synthesis
Methotrexate (MTX):
a. B9 (DHF) analog —> competitively inhibits Dihydrofolate reductase —> dec THF production –> dec TMP production —> Dec DNA synthesis.
b. Myelosuppression which is reversible with Leucovorin (Folinic acid) i.e. Rescue. Hepatotoxicity, Pulmonary fibrosis, Mucositis
- Amino acid synthesis antagonists.
Azaserine
Log Kill / Fractional kill hypothesis
Defined chemo —> defined dose —> at defined day —> will kill a constant percentage or fraction of cancer cell population rather fix number.
1st order kinetics –> applied on tumors of high Ki67%, not on solid tumors
Rationale for chomo combination and to precent chemo resistance to develop
Drugs that don’t cause myelosuppression
Belo, Vinc , Cisplatin
Cytokines,
IL 2, IL 11, GCSF, GMSF,
a. Aldesleukin (IL-2) –> inc NK cells and lymphocyte diff –> Renal cell carcinoma and Metastatic melanoma
b. IL-11 –> inc platlet formation
c. Filgrastim GCSF —> granulocytes recovery
Which factor determines the upper limit of chemo tolerability
Bone marrow suppression
Tumor resistance is by
“Human Multiple Drug Resistance” (HMDR 1 gene) –> expression of P-Glycoprotein pump –> eflux chemo and develop resistance.
Hydroxyurea
inhibit Ribonucleotide reductase –> dec DNA synthesis.
Rx: CML, Sklemia (inc Hb F)
Bevacizumab
Avastin
a. inhibit VEGF –> inh Angiogenesis
b SE: hemorrhage, Abdominal pain
Erlotinib
EGFR tyrosine kinase inhibitor
Non-small cell lung carcinoma
Rituximab
monoclonal antibody against CD20 (on B cells, so is used in mostly non hodgkin’s).
SE: Inc risk of progressive multifocal leukoencephalopathy.
Selective Estrogen Receptors Modulators (SERM)
” SERMs are competitive partial agonists of the ER. So have a different effect on different tissues, and block the binding of Estrogen to the ER receptors.”
Clomifene / Tamoxifen / Raloxifene
a. all are estrogenic in bone,
b. but raloxifene is antiestrogenic in the uterus while tamoxifen is estrogenic in this location
c. Tamoxi is used for breast Rx and prevention. But inc the risk of endometrial cancer. SE: hot flashes.
d. Raloxi is used in osteoporosis prevention.
Trastuzumab (Herceptin)
Monoclonal antibody against “Humen Epidermal Growth Factor - 2 Receptor” HER-2 (c-erbB2), a tyrosine kinase receptor —> kill HER-2 neu positive cells in breast and gastric cancer by apoptosis.
SE: Cardiotoxicity.
Vemurafenib
Small molecule inhibitor of BRAF oncogene + melanoma in metastatic melanoma.
Breast Ca, pre & post menopausal Rx
Pre: ER+, PR+ cancer –> Taxoxifen
Post: ER+, PR+ cancer –> Aromatase inh —> Anastrazole
Denosumab: Rx for bone related events in metastatic breast cancer
