Fa Pharmacology 2009 - Oncology

Front 1

Methotrexate

Back 1

Mechanism:
- S-phase specific antimetabolity.
- Folic acid analog that inhibits dihydrofolate reductase, resulting in ↓dTMP and therefore ↓ DNA and protein synthesis.

Clinical Use:
- Leukemias, lymphomas, choriocarcinoma, sarcomas.
- Abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis.

Toxicity:
- Myelosuppression, which is reversible with leucovorin (folinic acid) "rescue."
- Macrovescicular fatty change in liver.
- Mucositis.

Front 2

5-Fluorouracil (5-FU)

Back 2

Mechanism:
- S-phase-specific antimetabolite.
- Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid --> inhibits thymidylate synthase --> ↓dTMP and same effects as MTX.

Clinical use:
- Colon cancer and other solid tumors, basal cell carcinoma (topical)
- Synergy with MTX.

Toxicity:
- Myelosuppression, which is NOT reversity with leucovorin;
- photosensitivity.
- Can "rescue" with thymidine.

Front 3

6-mercaptopurine (6-MP)

Back 3

Mechanism: Blocks de novo purine synthesis. Activated by HGPRTase.

Clinical use: Leukemias, lymphomas (not CLL or Hodgkin's).

Toxicity:
- Bone marrow, GI, liver.
- Metabolized by xanthine oxidase; thus ↑ toxicity with allopurinol.

Front 4

Cytarabine (ara-C)

Back 4

Mechanism: Inhibits DNA polymerase.

Clinical use: AML, ALL, high-grade non-Hodgkin's lymphoma

Toxicity: Leukopenia, thorombocytopenia, megaloblastic anemia.

Front 5

cyclophosphamide, ifosfamide

Back 5

Mechanism:
- Alkylating agents
- covalently x-link (interstrand) DNA at guanine N-7.
- require bioactivation by liver.

Clinical use:
- Non-Hodgkin's lymphoma, breast and ovarian carcinomas.
- immmunosuppresants.

Toxicity:
- myelosuppression.
- hemorrhagic cystitis (prevented w/ MESNA)

Front 6

Nitrosureas: carmustine, lomustine, semustine, streptozocin.

Back 6

Mechanism:
- Alkylate DNa.
- REquire bioactivation.
Cross BBB ---> CNS.

Clinical us; Brain tumors (including glioblastoma multiforme).

Toxicity: CNS toxicity (dizziness, ataxia).

Front 7

Cisplatin, carboplatin

Back 7

Mechanism: cross-link DNA.

Clinical use: Testicular, bladder, ovary, and lung carcinomas.

Toxicity: Nephrotoxicity and acoustic nerve damage

Treat Cisplatin Toxicity: Amifostine.

Front 8

Busulfan

Back 8

Mechanism: Alkylates DNA.

Clinical use: CML. Also used for ablating bone marrow in hematopoietic stem cell transplants.

Toxicity: Pulmonary fibrosis. hyperpigmentation.

Front 9

Doxorubicin (Adriamycin), daunorubicin.

Back 9

Mechanism: Generate free radicals and noncovalently intercalate in DNA (creating breaks in DNA strand to ↓ replication).

Clinical use: Part of the ABVD combination regiment for Hodgkin's lympomas; also for myelomas, sarcomas, and solid tumors (breast, ovary, lung).

toxicity:
- Dilated cardiomyopathy (prevent dexrazoxane - iron chelating agent),
- myelosuppression and marked alopecia.
- Toxic extravasation --> tissue necrosis.

Front 10

Dactinomycin (actinomycin D)

Back 10

Mechanism: Intercalates in DNA.

Clinical use: Wilms' tumor, Ewing's sarcoma, rhabdomyosarcoma.

toxicity: Myelosuppression

ACTinomycin D is used for childhood tumors (children ACT out).

Front 11

Bleomycin

Back 11

Mechanism: Induces formation of free radicals, which cause breaks in DNA strands.

Clinical use: Testicular cancer, Hodgkin's lymphoma (part of the ABVD regiment for Hogkin's)

Toxicity: Pulmonary fibrosis, skin changes, but minimal myelosuppression.

Front 12

Hydroxyurea

Back 12

mechanism: Inhibits Ribonucleotide Reducatase --> ↓ DNA synthesis (S-phase specific).

Clinical use: Melanoma, CML, sickle cell disease (↑ HbF).

Toxicity: Bone marrow suppression, GI upset.

Front 13

Etoposide (VP-16)

Back 13

Mechanism: G2-phase specific agent that inhibits topoisomerase II and ↑ DNA degradation.

Clinical use: small cell carcinoma of the lung and prostate, testicular carcinoma.

Front 14

Prednisone

Back 14

Mechanism: May trigger apoptosis. May even work on nondividing cells.

Clinical use:
- Most commonly used glucocorticoid in cancer chemotherapy.
- Used in CLL, Hogkin's lympohmas (part of the MOPP regiment).
- Also an immunosuppressnat used in autoimmune disease.

Toxicity:
- Cushing-like symptoms
- immunosuppression, cataracts, acne, osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis.

Front 15

Tamoxifen, raloxifene

Back 15

Mechanism: SERMs - receptor antagonists in breast, agonists in bone; block the binding of estrogen to estrogen receptor-positive cells.

Clinical use: Breast cancer. Also useful to prevent osteoporosis.

Toxicity:
- Tamoxifen may ↑ the risk of endometrial carcinoma via partial agonist effects; "hot flashes."
- Raloxifen does not cause endometrial carcinoma because it is an endometrial antagonist.

Front 16

Trastuzumab (Herceptin)

Back 16

Mechanism: Monoclonal antibody against HER-2 (erb-B2). Helpts kill breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity.

Clinical use: Metastatic breast cancer.

Toxicity: Cardiotoxicity.

Front 17

Imatinib (Gleevec)

Back 17

Mechanism: Philadelphia chromosome bcr-abl tyrosine kinase inhibitor.

Clinical use: CML, GI stromal tumors.

Toxicity: Fluid retention.

Front 18

Vincristine, Vinblastine

Back 18

Mechanism: M-phase specific alkaloids that bind to tubulin and block polymerization of microtubules --> Mitotic spindle cannot form.("Microtubules are the vines of your cells")

Clinical use: Part of the MOPP (Oncovin [vincristine=]) regiment for Hodgkins lymphoma
- Wilm's tumors
- choriocarcinoma.

Toxicity:
- Vincristine - neurotoxicity (areflexia, peripheral neuritis), paralytic ileus.
- VinBLASTine BLASTS Bone marrow (suppression).

Front 19

Paclitaxel, other taxols

Back 19

Mechanism: M-phase specifi agents that bind to tubulin and hyperstabilize polymerized microtubules so that mitotic spindle cannot break down (anaphase cannot occur).

Clinical use: Ovarian and breast carcinomas.

Toxicity: Myelosuppression and hypersensitivity.