Transcript Anticancer Drugs - Acupuncture and Massage College

Anticancer Drugs
Felix Hernandez, M.D.
Alkylating Agents
• The first anticancer agents developed
• Chemically related to mustard gas used in WW1
• Are more effective in treating slow-growing tumors
because they are cell-cycle nonspecific
– Alkylating agent induced damage to cancer cells
accumulates even during non-active portions of the cell
cycle.
• All alkylating agents are toxic to hematologic cells,
therefore myelosuppression is a predictable side effect
• The drugs used to treat CNS cancers are used because
they cross the BBB not because they are better agents
Alkylating Agents
• Chlorambucil
– Phase: non specific
– MOA: crosslinks DNA by binding to both strands
– Resistance: decreased cellular uptake and increased repair of drug
induced DNA damage
– Side Effects: bone marrow suppression, drug is carcinogenic and may
be teratogenic
– Indications: Chronic Lymphocytic Leukemia (CLL), Ovarian Carcinoma
• Cyclophosphamide
– Phase: non specfic
– MOA: metabolized to phosphoramide mustard which is a DNA
alkylating agent
– Resistance: same
– Side Effects: hemorrhagic cystitis, BM suppression, cardiotoxicity
• Administer Mensa to prevent hemorrhagic cystitis (binds to the toxic
metabolite)
– Indications: breast, testicular and other solid tumors, leukemia,
lymphoma, neuroblastoma and immunosuppression
Alkylating Agents
• Carmustine
– Phase: non specific
– MOA: inhibit DNA synthesis by DNA alkylation and protein
carbamoylation
– Resistance: Same
– Side Effects: bone marrow suppression, pulmonary toxicity
– Indications: CNS tumors, lymphomas, Hodgkin’s, melanoma
• Cisplastin
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Phase: non specific
MOA: crosslinks DNA
Resistance: Same
Side Effects: renal toxicity, BM suppression, ototoxicity
• Use Amifostine to bind the toxic metabolites and decrease the
nephrotoxicity
– Indications: testicular, ovarian, lung, bladder cancer,
neuroblastoma, brain tumors, and osteosarcoma
Antimetabolites
• Are cell cycle specific agents
• Prevent the synthesis of nucleotides or inhibit
enzymes by mimicking nucleotides
• Methotrexate
• Mercaptopurine
• 5-Fluorouracil (5-FU)
Antimetabolites
• Methotrexate
– Phase: S-phase. It also arrests some cells in G1 phase
and stop them from entering S-phase
– MOA: blocks folate reduction by inhibiting
dihydrofolate reductase.
– Resistance: decreased uptake, increased production of
dihydrofolate reductase, altered forms of DHFR
– Side Effects: BM suppression, GI ulcers, nephrotoxicity,
hepatotoxicity
• Give leucovorin with it to rescue folate in noncancerous cells
– Indications: Acute Lymphocytic Leukemia (ALL),
osteogenic sarcoma, breast, head neck, small cell
lung, psoriasis, and RA
Antimetabolites
• Mercaptopurine
– Phase: S-phase
– MOA: metabolized to 6-mercaptopurine ribose
phosphate (6MPRP), a false negative feedback
inhibitor
– Resistance: increased alkaline phosphatase which
degrades 6MPRP, decreased sensitivity to
feedback inhibition
– Side Effects: BM suppression, hepatotoxicity
– Indications: Acute leukemia
Antimetabolites
• 5-Fluorouracil (5-FU)
– Phase: S/G1 phase-specific
– MOA: metabolized to fluoro-UMP which incorporates
into RNA. Is also metabolized to fluoro-dUMP which
inhibits thymidylate synthetase
• Prodrugs are Floxuridine and Capecitabine
– Resistance: decreased phosphorylation of the prodrug
to active form, increased or altered target enzyme
– Side Effects: anorexia, ulcers, BM suppression,
dermatitis, photo-sensitivity
– Indications: Many solid tumors, topically for
superficial tumors of the skin, Floxuridine for GI
adenocarcinoma and Capecitabine for breast CA
Antibiotic Cancer Agents
• Are isolated from the fungal species
Streptomyces
• Dactinomycin
– Phase: S-phase
– MOA: intercalates between guanine bases of DNA.
Also decreases RNA synthesis by blocking DNAdependent RNA synthesis
– Resistance: Decreased drug uptake
– Side Effects: hypersensitivity, BM suppression,
ulcers, acne, injection site necrosis
– Indications: Wilm’s tumor, Ewing Sarcoma,
testicular tumors
Antibiotic Cancer Agents
• Doxorubicin (Adriamycin), Daunorubicin
(Daunomycin)
– Phase: S-phase
– MOA: Intercalates into DNA and decreases DNA and
RNA synthesis, causes single and double strand breaks
– Resistance: decreased drug uptake, increased drug
efflux
– Side Effects: irreversible cardiomyopathy which leads
to CHF, ECG changes (benign), leukopenia
• Give Dexrazone to reduce the cardiomyopathy
– Indications: Doxorubicin  sarcomas, multiple
myeloma, acute leukemias, testicular, breast, gastric,
bladder, and throat CA. Daunorubicin  Acute
leukemias
Antibiotic Cancer Agents
• Bleomycin
– Phase: G2/M-Phase-Specific
– MOA: Bithiazole rings intercalate into DNA
strands. The drugs also oxidizes iron creating free
radicals which damage DNA
– Side Effects: pulmonary fibrosis, pneumonitis,
ulceration, increased skin pigmentation
– Indications: testicular cancer, lymphomas, SCC of
the head, neck, skin and genitalia.
• Is also used as a sclerosing agent for malignant pleural
effusion
Mitosis Inhibitors
• Vincristine, Vinblastine
– Phase: M-phase
– MOA: binds tubulin and depolymerizes
microtubules
– Resistance: decreased drug uptake and retention
– Side Effects: autonomic, peripheral and motor
neuropathy, no BM Suppression
– Indications:
• Vincrsitine: ALL, Hodgkin’s
• Vinblastine: Lymphomas
– Isolated from the periwinkle plant
Mitosis Inhibitors
• Paclitaxel
– Phase: M-phase specific
– MOA: stabalizes microtubules and prevents the
depolymerize microtubules which is essential for mitosis
– Side Effects: peripheral neuropathy, BM suppression,
myalgias
– Indications: metastatic ovarian carcinoma, breast CA
– Isolated from the bark of western yew
• Etoposide
– Phase: G2-phase-specific
– MOA: interferes with topoisomerase which causes DNA
strand breaks
– Side Effects: BM suppression
– Indications: testicular and lung cancers
Others
• Hydroxyurea
– Phase: S-phase-specific
– MOA: inhibits ribonucleotide reductases therefor
blocking deoxyribonucleotide formation (DNA
nucleotides)
– Side Effects: BM suppression
– Indications: chronic granulocytic leukemia
• Topotecan
– Phase: Non specific
– MOA: interacts with topoisomerase I and results in
DNA breaks during replication
– Side Effects: BM suppression, severe diarrhea
– Indications: lung and ovarian CA
Monoclonal Antibodies
• Rituxamab
– MOA: binds CD20 antigen on B-cells found in Bcell lymphomas and it exerts its cytotoxicity
– Side Effects: chills, rigors (infusion related)
– Indications: B-cell lymphomas
• Trastuzumab
– MOA: binds to HER2 protein and inhibits the
growth of tumor cells
• HER2 is overexpressed in 20-30% of breast CA
– Side Effects: same as Rituxamab
– Indications: Breast CA
Hormones
• Tamoxifen
– MOA: Estrogen receptor antagonist that prevents
endogenous estrogens from stimulating tumor growth
– Indications: estrogen-receptor positive breast CA in
postmenopausal women
– Side Effects: increased risk of uterine CA in treated women
• Aromatase Inhibitor
– MOA: inhibits aromatase, the enzyme responsible for
estrogen production in the ovaries
– Indications: advanced breast CA
• Flutamide
– MOA: testosterone receptors antagonist
– Indications: to inhibit the transient side effects caused by
initial Leuprolide induced LH and FSH secretion
Hormones
• Leuprolide
– MOA: GNRH analog which desensitizes GNRH
receptors in the pituitary causing a decreased
release of gonadotropin. Results in a decrease in
sex hormone release
– Indications: advanced prostate CA
– Side Effects: initially stimulates a transient release
of FSH and LH
Immune Mediators
• Interferon
– MOA: enhances the activity of cytotoxic-T, NK
cells, and macrophages. Inhibits the proliferation
of tumor cells.
– Indications: Hairy cell leukemia, Kaposi’s Sarcoma
• Misc.
– Tretinoin
• MOA: analog of retinoic acid (vitamin A) and induces
maturation in acute promyelocytic leukemia cells and
neuroblastoma.
• Side Effects: retinoic acid syndrome (fever, dyspnea,
pulmonary infiltrates and effusions, fluid retention)
Hematopoetic Agents
• Epoetin Alpha (Epogen)
– MOA: recombinant human erythropoetin that
stimulates erythropoiesis
– Indications: anemia associated with CRF,
correcting AZT (Zidovudine) induced anemia, and
chemotherapy induced anemia
– Requires several weeks of therapy before a change
in H/H is seen. It doesn’t replace transfusion for
acute treatments
– Contraindicated in patients with uncontrolled HTN
because it can exacerbate the HTN with the rise in
hematocrit
Hematopoetic Agents
• Filgrastim (G-CSF)
– MOA: recombinant granulocyte colony stimulating
factor which induces the synthesis of neutrophils
– Indications: replenishment of neutrophils in patients
treated with myelosuppressive drugs
– Side Effects: medullary bone pain due to rapid cell
proliferation in the BM
• Sargramostim (GM-CSF)
– MOA: recombinant granulocyte-macrophage colony
stimulating factor. Induces the maturation
granulocytes and macrophages but nor erythrocytes
or megakaryocytes,
– Indications: accelerate BM replenishment following
BM transplantation
– Side Effects: Medullary bone pain