1. Chapter 21: Antineoplastic Drugs Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

2. 2 Chapter 21 Outline  Antineoplastic Drugs  Use of antineoplastic agents  Mechanisms of action  Classification  Adverse drug effects  Combinations  Dental implications

3. 3Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Drugs  Haveles (p. 269)  Designed to treat malignancies  May also be used for the treatment of diseases with an inflammatory component  The dental health care worker should be aware of the timing of treatments and the effect on bone marrow  Side effects include oral manifestations cont’d…

4. 4Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Drugs  Mechanisms involved in the etiology of cancer include genetics, viruses, deleted or damaged tumor suppressor genes, specific oncogenes, and changes in both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)

5. 5Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Use of Antineoplastic Agents  Haveles (pp. 269-270) (Box 21-1)  Antineoplastic agents are used clinically to interfere with neoplastic cells  Suppress growth and attempt to destroy and prevent the spread of malignant cells  May be used alone or in combination or with radiation or surgery  Current philosophy involves treating the initial stages of the disease very aggressively

6. 6Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mechanisms of Action  Haveles (pp. 270-271) (Fig. 21-1)  Efficacy is based primarily on their ability to interfere with the metabolism or the reproductive cycle of tumor cells  Four stages in the cycle  G 1 : the postmitotic or pre-DNA synthesis phase  S: period of DNA synthesis  G 2 : premitotic or post-DNA synthesis phase  M: period of mitosis cont’d…

7. 7Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Mechanisms of Action  Most antineoplastic agents are labeled as  Cell-cycle specific: effective only at certain phases of cell growth  Cell-cycle nonspecific: effective at all stages of the cycle  Resistance is either  De novo: the neoplasm was always resistant  Acquired resistance: resistance through natural selection of mutations

8. 8Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Classification  Haveles (pp. 271-272) (Fig. 21-2; Box 21-2)  Antineoplastic agents are divided into groups, depending on their mechanism and site of action  Alkylating agents contain alkyl radicals that react with DNA in all cycles of the cell to prevent reproduction  Antimetabolites attack cells in the S period of reproduction by interfering with purine or pyrimidine synthesis They are more effective on rapidly proliferating neoplasms They are more effective on rapidly proliferating neoplasmscont’d…

9. 9Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Classification  Miscellaneous antineoplastics  Plant alkaloids: mitotic inhibitors and arrest cells in metaphase  Antibiotics: cell-cycle nonspecific and are effective for solid tumors  Hormones: interrupt the cell cycle at the G stage  Steroids: used to suppress lymphocytes in leukemias and lymphomas and in combination therapies  Estrogens: used palliatively in operative breast cancer  Tamoxifen: used to manage breast cancer  Cisplatin: cell-cycle nonspecific  Hydroxyurea: inhibits ribonucleotide reductase, which interferes with RNA synthesis  Procarbazine: produces chromosomal breakage

10. 10Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Haveles (pp. 272-274)  Bone marrow suppression  Osteonecrosis  Gastrointestinal (GI) effects  Dermatologic effects  Hepatotoxicity  Neurologic effects  Nephrotoxicity  Immunosuppression  Germ cells  Oral effects cont’d…

11. 11Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Haveles (pp. 272-273) (Table 21-2)  Rapidly growing cells are more susceptible to inhibition or destruction by antineoplastic agents  Some normal cells have a faster reproductive cycle than slowly growing tumor cells  Because cells of the GI tract, bone marrow, and hair follicles are among the faster growing normal cells, early side effects are associated with these tissues cont’d…

12. 12Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Haveles (p. 273)  Bone marrow suppression: inhibition results in leukopenia or agranulocytosis, thrombocytopenia, and anemia  Symptoms may include susceptibility to infection, bleeding, and fatigue  Osteonecrosis: a recently recognized adverse effect of bisphosphonates  94% of all cases of osteonecrosis have been reported in cancer patients receiving intravenous bisphosphonates for multiple myeloma or metastatic carcinoma cont’d…

13. 13Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Haveles (p. 273)  GI effects: sloughing of GI mucosa can produce many symptoms  May be expressed as nausea, stomatitis, oral ulcerations, vomiting, and hemorrhagic diarrhea  Dermatologic effects: cutaneous reactions vary from mild erythema and maculopapular eruptions to exfoliative dermatitis and Stevens- Johnson syndrome  Alopecia is frequent cont’d…

14. 14Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Hepatotoxicity: liver problems occur primarily with antimetabolites  Neurologic effects: peripheral neuropathy, ileus, inappropriate antidiuretic hormone secretion, and convulsions have been associated primarily with vincristine or vinblastine cont’d…

15. 15Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Nephrotoxicity: renal tubular impairment occurring secondary to hyperuricemia is caused by rapid cell destruction and release of nucleotides  Immunosuppression: enhanced susceptibility to infection or a second malignancy may occur after treatment  Germ cells: inhibition is frequent, at least temporarily  Mutations within germ cells may occur cont’d…

16. 16Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Adverse Drug Effects  Haveles (p. 274) (Box 21-3)  Oral effects: primarily discomfort, sensitivity of the teeth and gums, mucosal pain and ulceration, gingival hemorrhage, dryness, and impaired taste sensation  Infection of oral mucosa from leukopenia and bleeding from thrombocytopenia can occur  Patients may experience inflammation of the mouth, xerostomia, or glossitis

17. 17Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Combinations  Haveles (p. 274)  Agents with different mechanisms of action are often used together to inhibit the reproduction of neoplastic cells in all phases  Mixtures may act synergistically, leading to enhanced cytotoxicity with fewer side effects cont’d…

18. 18Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Combinations  Haveles (p. 274)  Used in lower doses to treat diseases associated with inflammation or autoimmune conditions and transplants  Diseases include rheumatoid arthritis, systemic lupus erythematosus, pemphigus vulgaris, and psoriasis  Doses of these agents used to treat diseases with an autoimmune component are often lower than the doses used to treat cancer

19. 19Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Dental Implications  Haveles (p. 274) (Boxes 21-3, 21-4)  The best times for oral hygiene procedures are when they would coincide with the presence of the highest level of formed blood elements  This time frame would be either just before treatment or on the first few days of treatment

20. 20Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Alkylating agents  Nitrogen mustard mechlorethamine (Mustargen) mechlorethamine (Mustargen) cyclophosphamide, chlorambucil (Leukeran) cyclophosphamide, chlorambucil (Leukeran) melphalan (Alkeran) melphalan (Alkeran) uracil mustard uracil mustard ifosfamide (Ifex) ifosfamide (Ifex)  Nitrosoureas carmustine (BCNU) (BiCNU) carmustine (BCNU) (BiCNU) lomustine (CCNU) (CeeNU) lomustine (CCNU) (CeeNU) semustine (Methyl-CeeNU) semustine (Methyl-CeeNU) streptozocin (Zanosar) streptozocin (Zanosar) estramustine (Emcyt) estramustine (Emcyt)cont’d…

21. 21Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Alkylating Agents  Miscellaneous busulfan (Myleran) busulfan (Myleran) pipobroman (Vercyte) pipobroman (Vercyte) thiotepa thiotepa cisplatin (Platinol) cisplatin (Platinol) carboplatin (Paraplatin) carboplatin (Paraplatin)cont’d…

22. 22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Antimetabolites  Folic acid analog methotrexate (Amethopterin) methotrexate (Amethopterin)  Pyrimidine analog fluorouracil (5-FU) fluorouracil (5-FU) floxuridine (FUDR) floxuridine (FUDR) cytosine arabinoside (ARA-C) (Cytosar-U) cytosine arabinoside (ARA-C) (Cytosar-U) azacitidine azacitidine  Purine analog mercaptopurine (6-MP) (Purinethol) mercaptopurine (6-MP) (Purinethol) thioguanine (6-TG) thioguanine (6-TG) cladribine (Leustatin) cladribine (Leustatin) fludarabine (Fludara) fludarabine (Fludara) pentostatin (Nipent) pentostatin (Nipent)cont’d…

23. 23Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Miscellaneous antineoplastics  Plant alkaloids vinblastine (Velban) vinblastine (Velban) vincristine (Oncovin) vincristine (Oncovin)  Antibiotics dactinomycin (Actinomycin-D, Cosmegen) dactinomycin (Actinomycin-D, Cosmegen) doxorubicin (Adriamycin) doxorubicin (Adriamycin) bleomycin (Blenoxane) bleomycin (Blenoxane) mitomycin-C (Mutamycin) mitomycin-C (Mutamycin) plicamycin (Mithramycin, Mithracin) plicamycin (Mithramycin, Mithracin) daunorubicin (Cerubidine) daunorubicin (Cerubidine)cont’d…

24. 24Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Miscellaneous antineoplastics  Hormones Adrenocorticosteroids (prednisone) Adrenocorticosteroids (prednisone) Androgen Androgen  testolactone (Teslac)  fluoxymesterone (Halotestin) Antiandrogen Antiandrogen  flutamide (Eulexin)  nilutamide (Nilandron)  bicalutamide (Casodex) Estrogen Estrogen  diethylstilbestrol  ethinyl estradiol (Estinyl) cont’d…

25. 25Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Miscellaneous antineoplastics  Hormones Antiestrogen Antiestrogen  tamoxifen (Nolvadex)  raloxifene (Evista)  fulvestrant (Faslodex)  toremifene (Fareston) Aromatase inhibitors Aromatase inhibitors  anastrozole (Arimidex)  exemestane (Aromasin)  letrozole (Femara) cont’d…

26. 26Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Miscellaneous antineoplastics  Hormones Progestin Progestin  medroxyprogesterone  megestrol (Megace) goserelin (Zoladex) goserelin (Zoladex) leuprolide (Lupron) leuprolide (Lupron)cont’d…

27. 27Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Immune modulators  levamisole (Ergamisol)  interferon α-n3 (Alferon N)  interferon α-2b (Intron A)  interferon α-2a (Roferon-A)  Podophyllotoxin derivatives  etoposide (VePesid)  teniposide (Vumon) cont’d…

28. 28Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Aminobisphosphonates  alendronate (Fosamax)  ibandronate (Boniva)  pamidronate (Aredia)  risedronate (Actonel)  zoledronic acid (Zometa) cont’d

29. 29Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved. Antineoplastic Agents by Group  Haveles (p. 272) (Box 21-2)  Other  L-asparaginase (Elspar)  hydroxyurea (Hydrea)  procarbazine (Matulane)  paclitaxel (Taxol)  altretamine (Hexalen)  trastuzumab (Herceptin)  imatinib mesylate (Gleevec)