ANTICANCER DRUGS Cancer development influences ENVIRONMENTAL Herpes Simplex 2 (Cervical & penile), Epstein barr (non-hodg lymph), HPV ( kaposi sarcoma, cervical), H. pylori ( stomach, lymphoma). INFECTIVE DIETARY abestos (lung), Benzene, Formaldehyde (nose, throat, trach), Vinyl chloride (sarcoma & leukemia), Arsenic (lung & skin), UV rays (skin) animal fat (colon, rectum, uterus, prostate, ovary), Heterocyclic amines (stomach, colon, rectum, pancreas, breast), alcohol (mouth, throat, esophagus, liver, breast) Proto-oncogenes: normal genes involved in cell differentation and division, regulating apoptosis. Oncogene: mutation of proto-oncogene effecting cellular growth proteins and triggers unregulated cell divisions. Cancer: group of disease with abnormal cell growth that is out of control and can spread to other areas of the body. Most cases- DNA damage in the cell. Antioncogenes: o some inherited, others protect others. develop. Tumor-suppressor (TS) signal cells to Cell Cycle—nonspecific & cell cycle— stop multiplying, specific Anticancer Drugs stopping the action oCell Cycle: of the oncogene. gap I (G1), Synthesis (S), gap 2 (G2), mitosis (M), gap 0 (G0) G0 = dormant phase, cells remain here and leave the cell cycle or return to the cell for replication. Cells in this stage are not as sensitive to antineoplastic drugs. If found defective apoptosis occurs. G1 = postmitotic gap, produces RNA, protein, and enzymes for DNA synthesis (15-18 hours). o o S phase = DNA components are synthesized, and the cells have doubled (10-20 hours). G2 = premeiotic gap, where the cell continues to grow and ensure it is not defective (3 hours). M phase = mitosis, cell growth is stopped and the cell divides into two daughter cells (1 hour). Anticancer drugs stop/slow growth of cancer cells by interfering cell replication. Cell Cycle-Nonspecific drugs (CCNS): act during any phase of cell cycle. Includes most alkylating drugs, antitumor abx, and hormones. View chart below Cell cycle-specific (CCS)L exert influence during specific phases of the cell cycle. Most effective against rapidly growing cancer cells. Includes antimetabolites, some alkylating agents and vinca alkaloids. Growth Factor: % of actively dividing cells decreases as the tumor enlarges, doubling time increases Doubling time: time it takes for tumor to x2 its size. Anticancer drugs are most effective against neoplastic cells with a high growth fraction (leukemia, lymphomas). Solid tumors respond less to anticancer drugs and are more responsive to highdose chemotherapy. This is d/t most of the growth occurring during G0 phase, having low growth fraction. Adequate vascularization is needed for anticancer drugs to be effective. More effective against small fast-growing tumors. Cancer Chemotherapy CANCER CHEMOTHERAPY -Effect health cells and cancer cells. -Side effects d/t the toxicity of the drugs on the healthy cells-but can heal themselves. -Typically given to those with systemic cancer, cancer that has spread, or is too large to be removed. -Typically given IV, but can be oral, IM, Subcut, IP, Intraventricular, intrapleural, intravesicular, intraarterial, and topical -Adjuvant therapy = surgery first followed by chemotherapy. -Neoadjuvant therapy = pre-surgery to shrink tumor. -Palliative therapy =used to improve quality of life. -Combined therapy is common, two drugs seem to be more effective than one. Typically, a CCNS and a CCS drug. -S/E & A/E: A/E on hair and skin cells. Can affect Gi tract, mucous membranes, bone marrow, reproductive systems. ALKYLATING DRUGS ANTIMETABOLITES ANTITUMOR ANTIBIOTICS PLANT ALKALOIDS IMMUNOMODULATORS TARGETED THERAPIES LIPSOMAL CHEMOTHERAPY HORMONES & HORMONAL AGONISTS HORMONES & HORMONAL ANTAGONISTS Myelosuppression (decrease in bone marrow), decreasing WBC, RBC, platelets. -damage cell’s DNA by cross-linking DNA strands, abdnorm. Base pairing, or broken DNA strands. Prevents reproduction of cancer cells. -drugs belong to CCNS category and kill in all phases of cell cycle. -used to treat leukemia, lymphoma, multiple myeloma, sarcoma and solid tumors of breast, ovary, uterus, lung, bladder, and stomach. (Kills many cancer types) -5 classes (1) nitrogen mustards-cyclophosphamides, (2) nitrosoureas-cross blood brain barrier-great for brain CA Tx, (3) alkyl sulfonates, (4) triazines, (5) ethylenimines -A/E & S/E: low RBC (anemia), Low WBC (leukopenia), low platelets (thrombocytopenia), anorexia, N/V/D, mucositis (stomatitis), alopecia, fatigue, infertility. -resemble natural substances. Building blocks but also substances that break down and recycle organic compounds in the body. -most classified as CCS drugs and exert effect in S phase of cell cycle. -Few have cytotoxic effects in multiple cell cycle phases. -Classified by the substance they interfere folate, pyrimidine, purine analogues, ribonucleotide reductase inhibs. -A/E & S/E: NSAIDs, penicillin’s, proton pump inhibs, probenecid, and acidic foods and drink -similar to natural abx. Do not treat infections but do interfere with DNA replication and RNA transcription. -effect all phases of the cell cycle (nonspecific) except Bleomycin’s (G2) phase. -anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin) and others (actinomycin D, bleomycin, mitomycin C, mitoxantrone). -Tx leukemias and solid tumors. -Rxns: alopecia, N/V, myelosuppression. Can cause vesication (blistering of tissue) -derived from plants (periwinkle) -block cell division in M phase. -Vinca alkaloids (periwinkle) and taxanes (yew tree) are considered antimicrotubule compounds, which disrupt and interfere with mitosis causing apoptosis. -A/E & S/E: leukopenia, hypersensitivity, alopecia, constipation, nausea. BIOLOGIC RESPONSE MODULATORS MISC. CHEMOTHERAPY AGENTS VACCINES ALKALYTING DRUG - Cyclophosphamide: can cause tissue necrosis if infiltrated, can be oral or IV, pt needs to be well hydrated. -PHARMAKOKINETICS: Oral- Gi absorbs well. Metabolized and activated by liver. Less than 25% eliminated by kidney. -PHARMAKODYNAMICS: a antineoplastic drug that can be used alone or with other drugs. Peak time avg. 1 hour. Anthracycline can induce toxicity if taken with cyclophosphamides. Also, RXN with aspirin, allopurinol, phenobarbital, warfarin, thiazide diuretics, and some psych medications. -SIDE EFFECTS & ADVERSE RXNS: hemorrhagic cystitis, cardiomyopathy, increase skin pigmentation or nail beds. ANTIMETABOLITE DRUG -Fluorouracil (5-FU): like uracil in DNA but has fluoride in it. Used for Breast CA, colorectal, GI, head and neck CA. Typically given IV for solid tumors, topical for basal cell carcinoma. -PHARMACOKINETICS: cross BBB, distributes throughout body tissues. Mostly catabolized in liver. -PHARMACODYNAMICS: concerts into many metabolites, inhibiting normal cell growth, interfering with the cell's RNA and DNA. -SIDE EFFECTS & ADVERSE RXNS: N/V/D. febrile, neutropenia, weight loss, pain, impaired wound healing, nephrotoxicity, bone marrow suppression, low blood counts. ANTITUMOR ABX: -anthracyclines: doxorubicin an antitumor antibiotic antineoplastic used to treat solid and hematogenous tumors. Often used in combination therapy. IV administration requires close monitoring for cardiotoxicity. Assess cardiac fxn before administering. -PHARMACOKINETICS: administered IV, does not cross BBB-very bound to dNA. Does not cross placenta but does pass through breast milk. Metabolized by liver. -PHARMACODYNAMICS: Normal regimen for breast, lung, gastric and ovarian cancers. -S/E. A/R: urine becomes pinkish or light red. Can cause cardiotoxicity, CHF, myelosuppression, abnormal ECG. -Vincristine: developed from periwinkle plant. Increases cellular retention. Neurotoxicity limits doses. Used to tx leukemias, breast carcinoma, NHL, multiple myeloma, soft tissue and osteogenic saromas, and brain tumors. -PHARMACOKINETICS: given parenterally. Distributes through tissues. Binds to RBCs and Platelets. Metabolized by liver as metabolites. -PHARMACODYNAMICS: cytotoxic-interferes with microtubules in M phase. Inhibits RNA, DNA and protein synthesis. Inhibits glycolysis. Does not cross blood brain barrier. -S/E & A/R: neurotoxicity, sensory loss, paresthesia, difficulty waking, muscle wasting, bronchospasms, optic atrophy. Avoid taking with calcium channel blockers, amiodarone, statin drugs, proton pump inhibitors, grapefruit juice.