Antineoplastic Drugs PDF

Antineoplastic Drugs Process ○ Alteration in genetic material ○ Expression of oncogenes ○ Inhibitions of tumor suppressor genes ○ Uncontrolled cellular growth aka cancer Metastasis ○ Neoplastic cells often invade previously unaffected or...

Antineoplastic Drugs Process ○ Alteration in genetic material ○ Expression of oncogenes ○ Inhibitions of tumor suppressor genes ○ Uncontrolled cellular growth aka cancer Metastasis ○ Neoplastic cells often invade previously unaffected organs ○ Process called metastasis ○ Dependent on angiogenesis, the formation of new blood vessels to support metastatic invasion and growth Categorizing drugs ○ Antineoplastic drugs are divided into 2 broad categories.. Cytotoxic agents – non-specifically inhibit DNA replication and mitosis Targeted anticancer drugs – inhibit specific proteins invo;ved in tumor cell growth Immunomodulators ○ Immunomodulators – drugs that alter activity of immune system ○ These drugs are divided into 2 major categories… Immunosuppressants Immunostimulants ○ Some drugs can both inhibit and stimulate the immune system ○ A number of mAb preparations are used as immunosuppressants to treat RA Treating cancer ○ Anti-neoplastic drugs are used to treat hematologic cancers that can't be surgically resected (e.g., leukemia, lymphoma) ○ Also used in combi with surgery and/or radiation to treat solid tumors Even if solid tumor can be surgically removed, chemo may be used to eliminate micrometastases Slows or prevent recurrence of malignant growth ○ If tumors are inoperable, chemo is often palliative R-CHOP ○ Rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone Choosing drugs ○ Drug selection based on clinical trials ○ Treatment varies depending on type and stage of cancer ○ First-line drugs used for initial treatment whereas other drugs usually used for relapses ○ Regimens are constantly evolving Role of cell cycle ○ Cytotoxic antineoplastic drugs can be classified as either… Cell cycle-specific agents Cell cycle nonspecific agents Innate resistance ○ Innate resistance – initial exposure to drugs dose not produce a response  ○ Can be because of mutations in cancer cell genome ○ Mutations in tumor suppressor genes are found in >50% of all malignancies ○ Linked to treatment failure with both RT and chemo drugs Acquired resistance ○ Acquired resistance – results from genomic mutations or abnormal gene expression as cancer cells continue to evolve ○ Mechanisms include (1) induction of drug efflux pumps (2) decreased affinity or over-expression of target enzymes and (3) decreased drug activation or increased drug inactivation ○ Other mechanisms to exist Myelosuppression ○ Usually results in leukopenia (low WBC) and thrombocytopenia (decreased PLT), but anemia (low Hb) can occur ○ Leukopenia can predispose patient to serious infections while thrombocytopenia can lead to bleeding ○ Leukopenia is usually delayed because time is required to clear circulating cells before this becomes evident Organ system toxicity ○ Some antineoplastic drugs have characteristic organ system toxicities that are unrelated to inhibiting cell division… Doxorubicin (Adriamycin) causes cardiotoxicity Cyclophosphamide, ifosfamide causes hemorrhagic cystitis Cisplatin causes renal toxicity Bleomycin (Blenoxane®) causes pulmonary toxicity Vincristine, paclitaxel (Taxol®) cause neurotoxicity Cytotoxic agents ○ Folate antagonists (e.g., MTX) ○ Purine analogues (e.g., mercaptopurine) ○ Pyrimidine analogues (e.g., fluorouracil) ○ Ribonucleotide reductase inhibitors (e.g., hydroxyurea) DNA alkylating drugs (e.g., cisplatin) ○ DNA intercalating drugs (e.g., doxorubicin, bleomycin) DNA topoisomerase inhibitors (e.g., etoposide) ○ Mitotic inhibitors (e.g., paclitaxel, vincristine) MTX ○ MTX first used to induce remission in kids with acute childhood leukemia 50 years ago ○ Most-widely used anti-metabolite in cancer chemo, also used as DMARD for treating RA MTX indications ○ Variety of uses including treating… Trophoblastic tumors (e.g., choriocarcinoma) Breast cancer Osteosarcoma ALL (given intrathecally to prevent meningeal mets) Adverse effects  ○ BM and GI mucosa are most sensitive to MTX toxicity ○ Severe oral ulceration (Stomatitis) can occur Reaction with allopurinol ○ FYI, allopurinol is often given to people undergoing chemo because it inhibits synthesis of uric acid and prevents hyperuricemia and gout Chemo increases purine catabolism and increase uric acid formation (tumor lysis syndrome) ○ If a patient takes allopurinol, doses of mercaptopurine have to be cut 50% because it increases plasma levels Uses ○ Gemcitabine is indicated as a first line treatment for pancreatic carcinoma Also used to treat biliary tract, gallbladder, breast and ovarian cancer ○ Gemcitabine and cisplatin as first line therapy for inoperable non-small cell lung cancer Ribonucleotide reductase inhibitor ○ Hydroxyurea Inhibits ribonucleotide reductase which stops DNA synthesis and causes cells to accumulate in S phase of cell cycle Given orally to treat CML, ovarian cancer, melanoma Also used to manage sickle cell anemia because it elevated concentration of fetal hemoglobin and decreases frequency of crises Dose-limiting toxicity of rapid-onset myelosuppression Adverse effects ○ Both can cause alopecia, N/V, myelosuppression and hemorrhagic cystitis ○ Ingestion of large amount fluids and mesna can reduce incidence of cystitis Mesna binds to acrolein and converts it to an inactive substance Chlorambucil ○ Given orally ○ Selective cytotoxicity for lymphocytic cell lines ○ Primarily used to manage CLL ○ Well tolerated but can cause myelosuppression and sterility ○ Long-term treatment associated with secondary leukemia Indications ○ Cisplatin has efficacy against many neoplasms Given IV as first line drug for testicular, ovarian, cervical and bladder cancer Also useful for treating melanoma and other solid tumors ○ Carboplatin only approved for ovarian cancer ○ Oxaliplatin used for advanced colon cancer Adverse effects ○ Mild myelosuppression but can cause severe N/V and nephrotoxicty ○ Pre-treatment with antiemetic prevents or significantly reduces severity of N/V ○ Mannitol and sodium thiosulfate decrease severity of nephrotoxicity Busulfan  ○ Works like nitrogen mustards but has greater activity against myeloid cells than lymphoid cells ○ Used to manage CML but importance has decreased because of newer drugs ○ Causes mild N/V, myelosuppression ○ Can cause pulmonary fibrosis (“busulfan lung”) Usually occurs 3 years after treatment No treatment average survival after diagnosis is about 5 months Dacarbazine ○ Exact mechanisms unknown; inhibits DNA, RNA, and protein synthesis ○ Given as part of ABVD regimen to treat Hodgkin’s disease A – adriamycin (doxorubicin) B– bleomycin V– vinblastine D– dacarbazine Mitomycin ○ Anti-neoplastic abx; alkylates DNA and causes strand breakage, inhibits synthesis ○ Used for stomach cancer, pancreatic cancer, and transitional cell carcinoma of bladder Given intravesically for bladder cancer ○ Causes pulmonary damage, hemolytic anemia, and renal dysfunction ○ Extravasation can cause severe necrosis Indications ○ Daunorubicin and Idarubicin are indicated for induction and consolidation therapy for AML ○ Doxorubicin (adriamycin) has a broader spectrum of activity … Breast cancer Hodgkin's disease Bladder cancer Ovarian cancer Other heme ca+ solid tumor Etoposide ○ Synergistic with platinum compounds ○ Broad coverage against hematologic cancer and solid tumors ○ Used for testicular cancer, lung cancer, NHL Vinca alkaloids ○ Vincristine (oncovin) ○ Vinblastine Natural alkaloids from periwinkle plant Different antitumor activity even though names are very similar Given IV only Adverse effects ○ Dose-limiting neurotoxicity ○ Suppression of DTRs is earliest sign ○ Paresthesias of hands and toes ○ Can cause cranial nerve damage and autonomic neuropathies  Rituximab (Rituxan) ○ Chimeric human–murine Ab used to treat tumors ○ First mAb approved for cancer chemotherapy ○ Used to treat relapsed or refractory B-cell NHL ○ Binds to the CD20 antigen on surface of >90% of NHL cells and normal B lymphocytes ○ Recruits immune effectors which leads to cell lysis Cytokines and interferons ○ IFNs are endogenous proteins that increase activity of various cytotoxic cells in immune system ○ IFN alfa-2b directly suppresses cancer cell growth by inhibiting expression of oncogenes and reducing proliferation Used to treat KS in AIDs patients, bladder cancer, renal cancer, melanoma, and MM Causes clinical response in 70% of people with hairy cell leukemia or CML Adverse effects include leukopenia, thrombocytopenia, flu-like symptoms, N/V/D, tiredness, altered taste Breast cancer receptors ○ ER (+) cancer cells depend on estrogen for growth, so estrogen receptor antagonists (tamoxifen) can be used ○ HER2 (+) breast cancer is usually more aggressive, but respond better to drugs like mAbs like Trastuzumab (Herceptin®) + conventional chemo ○ Cancer cells that do not have any of these receptor types are considered “triple-negative”, although they frequently express other hormone receptors (e.g., androgen receptor, PRL receptor)