Covalently binds to DNA (guanine), crosslinks bases of DNA
Agents affecting microtubule function
: Taxol, Vincristine, Vinblastine
M-phase
Taxol – binds to tubulin and hyperstabilizes polymerized microtubules so that mitotic spindle can’t break down
Vinca Alkaloids – bind to tubulin and block polymerization of microtubules so that mitotic spindle can’t break down
Vincristine – peripheral neuropathy
Vinblastine – myelosuppression (VinBlastine Blasts Bone marrow)
Antihormones
: Tamoxifen, Raloxifen
G1-phase
Mixed agnoist/antagonist that compete with endogenous hormones (estrogen, androgen) for receptors, clinically used in breast cancer, most effective in post-menopausal women, and may increase risk of endometrial carcinoma via partial agonist effects
Include cyclophosphamide, cisplatin, chlorambucil, nitrogen mustard, and nitrosoureas.
Exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell constituents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cell. They are most lethal for rapidly dividing cells. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to a secondary malignancy such as acute leukemia.
Cyclophosphamide
Most commonly used alkylating agent. Can be taken orally. Only is cytotoxic after generation of their alkylating species following hydroxylation of cytochrome p450.
Mechanism
: Cyclophosphamide – via P-450, gets hydroxylated to phosporamide mustard (cytotoxic step) and acrolein – causes cross-linking of DNA (cytotoxicity). Lecture’s way of putting it: 2 chloroethyl side groups undergo intramolecular cyclization to form highly reactive carbonium ion intermediates which alkylate purine bases, inducing DNA x-linking and other damages. Cell-cycle non-specific.
Resistance
: can occur from increased DNA repair, decreased drug permeability, and reaction with thiols.
Side Effects
: immediate: alopecia, nausea, vomiting, and diarrhea; long-term: bone marrow depression (leukocytosis), hemmorhagic cystitis and fibrosis of the bladder, SIADH, and neuropathy (decreased deep tendon reflexes).
Cisplatin
Severe toxicity, has synergistic effects with radiation and other chemotherapeutic agents.
Mechanism
: Similar to other alkylating agents. In the high Cl- milieu of plasma, cisplatin persists as a neutral species, which enters the cell and binds to the N7 of guanine of DNA, forming inter- and intra-strand crosslinks. The resulting cytotoxic lesion inhibits both DNA and RNA synthesis. Cytotoxicity can occur at any stage in the cell cycle but the cell is most vulnerable in G1 and S.
Resistance
: if cells have elevated glutathione or increased DNA repair, or metallothionein is induced.
Adverse effects
: nephrotoxic, neurotoxic, ototoxic. (Ameliorate these by aggressive hydration and diuresis.)
Tumor Antibiotics
include hydroxydaunomycin (adriamycin, doxorubicin) and bleomycin.
Mechanism
: Anthracycline antibiotics, three major activities that may vary with type of cell; all are maximal in S and G2
Intercalation in the DNA
: drugs insert nonspecifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA causing a local uncoiling, thus blocking DNA and RNA synthesis. Can interfere with the topoisomerase II- catalyzed breakage-reunion reaction of DNA strands to cause unreparable breaks.
Binding to cell membranes
: alters the function of transport processes coupled to phosphatidylinositol activation.
Generation of oxygen radicals through lipid peroxidation
: reduce molecular O2, producing superoxide ions and hydrogen peroxide that mediate single scission of DNA. Generally, those tissues with high amounts of glutathione peroxidase or superoxide dismutase are protected. Tumors and the heart are generally low in SOD – may explain cardiotoxicity of the drug.
Resistance
: increased efflux via the amplified transport P-glycoprotein. Cells rich in glutathione peroxidase are also resistant. Decreased cytochrome P-450 reductase, topoisomerase II and DNA repair may also play a role.
Adverse Effects
: irreversible, dose-dependent cardiotoxicity, apparantly a result of the generation of free radicals, is the most serious adverse reaction. Other effects include a transient bone marrow suppression, stomatitis, and GI tract disturbances. Alopecia is usually severe.
Antimicrotubule Agents
includes vincristine and taxol
Mechanism
: cycle-specific and phase-specific, because they block mitosis in metaphase. Bind to microtubular protein, tubulin, is GTP-dependent and blocks the ability of tubulin to form microtubules. Resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation.
Resistance
: Resistant cells have been shown to have enhanced binding of vinblastine to the P-glycoprotein, which is responsible for the efflux of vincristine and vinblastine and several other drugs. Alteration in tubulin structure may also affect the binding of the vinca alkaloids.
Adverse effects
: phlebitis or cellulitis, if the drugs extravasate during injection, as well as nausea, vomiting, diarrhea, and alopecia. Peripheral neuropathy and GI disturbances.
Natural Products
include vincristine, cyclosporin A, mitoxantrone, and taxol.
Cyclosporin A
Mechanism
: preferentially suppresses cell-mediated immune reactions, whereas humoral immunity is affected to a far lesser extent. Cyclosporin binds to cyclophilin complex and inhibits the dephophorylation of NFATc. The end-result is the decrease of IL-2, the main stimulus for the increase in the number of T-lymphocytes. It is used to prevent rejection of the kidney, liver, and cardiogenic allogenic transplants.
Adverse Effects
: nephrotoxicity, hepatotoxicity, infections and anaphylactic reactions. Others include hypertension, hyperkalemia, tremor, hirsuitism, glucose intolerance, and gum hyperplasia.
Mitoxantrone
– tumor antibiotic, not as cardiotoxic as hydroxydaunomycin; interferes with topoisomerase II.
Hormone (Adrenocortical Steroids)
includes prednisone and dexamethasone
Prednisone
Mechanism:
Prednisone is inactive and must be reduced to prednisolone by 11-B hydroxysteroid dehydrogenases. The steroid binds to a receptor that triggers the production of specific proteins. The specific mechanism for its lymphocytopenic action after interaction with DNA remains to be elucidated.
Resistance:
An absence of receptor protein or a mutation that lowers receptor affinity for the hormone confers resistance.
Semi-Synthetic
allopurinol (xanthine oxidase inhibitor) and etoposide (VP-16).
Etoposide
Mechanism
: analog of podophyllotoxin. Block cells in the late S-G2 phase of the cell cycle. Binding of the drugs to the enzyme-DNA complex results in the persistence of the transient cleavable form of the complex and thus renders it susceptible to irreversible double-strand breaks.
Resistance
: to topoisomerase inhibitors is conferred by either the presence of the multi-drug resistant P-glycoprotein, or mutation of the enzyme.
Adverse effects
: myelosuppression (primarily leukopenia) is the major toxicity. Alopecia, anaphylactic reactions, nausea, and vomiting. Hypotension may occur if the drug is injected rapidly.
Biological Modifiers
G-CSF, GM-CSF, erythropoietin
– all used to counteract the effects of chemotherapy, specifically to increase the amount of RBC’s and WBC’s.
Clinical Example: Lymphoma
CHOP regimen: Cyclophosphamide, Hydroxydaunomycin, Vincristine (Oncavin), Prednisone. Standard treatment for high-grade non-Hodgkin lymphoma, can also be used for low-grade.
Allopurinol (xanthine oxidase inhibitor) given to prevent tumor lysis syndrome. When tumor lyses, excess purines are released causing increased uric acid. This is especially important when treating high grade lymphomas.
