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

Chapter 21:Chapter 21:

Antineoplastic DrugsAntineoplastic Drugs

Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

22Copyright © 2011, 2007 Mosby, Inc., an affiliate of Elsevier. All rights reserved.

Chapter 21 OutlineChapter 21 Outline

Antineoplastic DrugsAntineoplastic Drugs Use of antineoplastic agentsUse of antineoplastic agents Mechanisms of actionMechanisms of action ClassificationClassification Adverse drug effectsAdverse drug effects CombinationsCombinations Dental implicationsDental implications



Haveles (p. 269)Haveles (p. 269) Designed to treat malignanciesDesigned to treat malignancies

May also be used for the treatment of diseases May also be used for the treatment of diseases with an inflammatory componentwith an inflammatory component

The dental health care worker should be The dental health care worker should be aware of the timing of treatments and the aware of the timing of treatments and the effect on bone marroweffect on bone marrow Side effects include oral manifestationsSide effects include oral manifestations

cont’d…cont’d…



Mechanisms involved in the etiology of Mechanisms involved in the etiology of cancer include genetics, viruses, deleted or cancer include genetics, viruses, deleted or damaged tumor suppressor genes, specific damaged tumor suppressor genes, specific oncogenes, and changes in both ribonucleic oncogenes, and changes in both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)acid (RNA) and deoxyribonucleic acid (DNA)


Use of Antineoplastic AgentsUse of Antineoplastic Agents

Haveles (pp. 269-270) (Box 21-1)Haveles (pp. 269-270) (Box 21-1) Antineoplastic agents are used clinically to Antineoplastic agents are used clinically to

interfere with neoplastic cellsinterfere with neoplastic cells Suppress growth and attempt to destroy and Suppress growth and attempt to destroy and

prevent the spread of malignant cellsprevent the spread of malignant cells May be used alone or in combination or with May be used alone or in combination or with

radiation or surgeryradiation or surgery Current philosophy involves treating the initial Current philosophy involves treating the initial

stages of the disease very aggressivelystages of the disease very aggressively


Mechanisms of ActionMechanisms of Action

Haveles (pp. 270-271) (Fig. 21-1)Haveles (pp. 270-271) (Fig. 21-1) Efficacy is based primarily on their ability to Efficacy is based primarily on their ability to

interfere with the metabolism or the interfere with the metabolism or the reproductive cycle of tumor cellsreproductive cycle of tumor cells

Four stages in the cycleFour stages in the cycle GG11: the postmitotic or pre-DNA synthesis phase: the postmitotic or pre-DNA synthesis phase

S: period of DNA synthesisS: period of DNA synthesis GG22: premitotic or post-DNA synthesis phase: premitotic or post-DNA synthesis phase

M: period of mitosisM: period of mitosiscont’d…cont’d…


Mechanisms of ActionMechanisms of Action

Most antineoplastic agents are labeled as Most antineoplastic agents are labeled as Cell-cycle specific: effective only at certain phases Cell-cycle specific: effective only at certain phases

of cell growthof cell growth Cell-cycle nonspecific: effective at all stages of the Cell-cycle nonspecific: effective at all stages of the

cyclecycle Resistance is eitherResistance is either

De novo: the neoplasm was always resistantDe novo: the neoplasm was always resistant Acquired resistance: resistance through natural Acquired resistance: resistance through natural

selection of mutationsselection of mutations


ClassificationClassification

Haveles (pp. 271-272) (Fig. 21-2; Box 21-2)Haveles (pp. 271-272) (Fig. 21-2; Box 21-2) Antineoplastic agents are divided into groups, Antineoplastic agents are divided into groups,

depending on their mechanism and site of actiondepending on their mechanism and site of action Alkylating agents contain alkyl radicals that react with Alkylating agents contain alkyl radicals that react with

DNA in all cycles of the cell to prevent reproductionDNA in all cycles of the cell to prevent reproduction Antimetabolites attack cells in the S period of Antimetabolites attack cells in the S period of

reproduction by interfering with purine or pyrimidine reproduction by interfering with purine or pyrimidine synthesissynthesis• They are more effective on rapidly proliferating neoplasmsThey are more effective on rapidly proliferating neoplasms



ClassificationClassification Miscellaneous antineoplasticsMiscellaneous antineoplastics

Plant alkaloids: mitotic inhibitors and arrest cells in Plant alkaloids: mitotic inhibitors and arrest cells in metaphasemetaphase

Antibiotics: cell-cycle nonspecific and are effective for solid Antibiotics: cell-cycle nonspecific and are effective for solid tumorstumors

Hormones: interrupt the cell cycle at the G stage Hormones: interrupt the cell cycle at the G stage Steroids: used to suppress lymphocytes in leukemias and Steroids: used to suppress lymphocytes in leukemias and

lymphomas and in combination therapieslymphomas and in combination therapies Estrogens: used palliatively in operative breast cancerEstrogens: used palliatively in operative breast cancer Tamoxifen: used to manage breast cancerTamoxifen: used to manage breast cancer Cisplatin: cell-cycle nonspecificCisplatin: cell-cycle nonspecific Hydroxyurea: inhibits ribonucleotide reductase, which Hydroxyurea: inhibits ribonucleotide reductase, which

interferes with RNA synthesisinterferes with RNA synthesis Procarbazine: produces chromosomal breakageProcarbazine: produces chromosomal breakage


Adverse Drug EffectsAdverse Drug Effects

Haveles (pp. 272-274)Haveles (pp. 272-274) Bone marrow suppression Bone marrow suppression OsteonecrosisOsteonecrosis Gastrointestinal (GI) effects Gastrointestinal (GI) effects Dermatologic effects Dermatologic effects HepatotoxicityHepatotoxicity Neurologic effectsNeurologic effects Nephrotoxicity Nephrotoxicity Immunosuppression Immunosuppression Germ cellsGerm cells Oral effectsOral effects




Haveles (pp. 272-273) (Table 21-2)Haveles (pp. 272-273) (Table 21-2) Rapidly growing cells are more susceptible to Rapidly growing cells are more susceptible to

inhibition or destruction by antineoplastic agentsinhibition or destruction by antineoplastic agents Some normal cells have a faster reproductive cycle Some normal cells have a faster reproductive cycle

than slowly growing tumor cellsthan slowly growing tumor cells Because cells of the GI tract, bone marrow, and hair Because cells of the GI tract, bone marrow, and hair

follicles are among the faster growing normal cells, follicles are among the faster growing normal cells, early side effects are associated with these tissuesearly side effects are associated with these tissues




Haveles (p. 273)Haveles (p. 273) Bone marrow suppression: inhibition results in Bone marrow suppression: inhibition results in

leukopenia or agranulocytosis, leukopenia or agranulocytosis, thrombocytopenia, and anemiathrombocytopenia, and anemia Symptoms may include susceptibility to infection, Symptoms may include susceptibility to infection,

bleeding, and fatiguebleeding, and fatigue Osteonecrosis: a recently recognized adverse Osteonecrosis: a recently recognized adverse

effect of bisphosphonateseffect of bisphosphonates 94% of all cases of osteonecrosis have been reported 94% of all cases of osteonecrosis have been reported

in cancer patients receiving intravenous in cancer patients receiving intravenous bisphosphonates for multiple myeloma or metastatic bisphosphonates for multiple myeloma or metastatic carcinomacarcinoma




Haveles (p. 273)Haveles (p. 273) GI effects: sloughing of GI mucosa can produce GI effects: sloughing of GI mucosa can produce

many symptomsmany symptoms May be expressed as nausea, stomatitis, oral May be expressed as nausea, stomatitis, oral

ulcerations, vomiting, and hemorrhagic diarrheaulcerations, vomiting, and hemorrhagic diarrhea Dermatologic effects: cutaneous reactions vary Dermatologic effects: cutaneous reactions vary

from mild erythema and maculopapular from mild erythema and maculopapular eruptions to exfoliative dermatitis and Stevens-eruptions to exfoliative dermatitis and Stevens-Johnson syndromeJohnson syndrome Alopecia is frequentAlopecia is frequent




Hepatotoxicity: liver problems occur primarily Hepatotoxicity: liver problems occur primarily with antimetaboliteswith antimetabolites

Neurologic effects: peripheral neuropathy, Neurologic effects: peripheral neuropathy, ileus, inappropriate antidiuretic hormone ileus, inappropriate antidiuretic hormone secretion, and convulsions have been secretion, and convulsions have been associated primarily with vincristine or associated primarily with vincristine or vinblastine vinblastine




Nephrotoxicity: renal tubular impairment occurring Nephrotoxicity: renal tubular impairment occurring secondary to hyperuricemia is caused by rapid cell secondary to hyperuricemia is caused by rapid cell destruction and release of nucleotidesdestruction and release of nucleotides

Immunosuppression: enhanced susceptibility to Immunosuppression: enhanced susceptibility to infection or a second malignancy may occur after infection or a second malignancy may occur after treatmenttreatment

Germ cells: inhibition is frequent, at least Germ cells: inhibition is frequent, at least temporarilytemporarily Mutations within germ cells may occurMutations within germ cells may occur




Haveles (p. 274) (Box 21-3)Haveles (p. 274) (Box 21-3) Oral effects: primarily discomfort, sensitivity Oral effects: primarily discomfort, sensitivity

of the teeth and gums, mucosal pain and of the teeth and gums, mucosal pain and ulceration, gingival hemorrhage, dryness, and ulceration, gingival hemorrhage, dryness, and impaired taste sensationimpaired taste sensation Infection of oral mucosa from leukopenia and Infection of oral mucosa from leukopenia and

bleeding from thrombocytopenia can occurbleeding from thrombocytopenia can occur Patients may experience inflammation of the Patients may experience inflammation of the

mouth, xerostomia, or glossitismouth, xerostomia, or glossitis


CombinationsCombinations

Haveles (p. 274)Haveles (p. 274) Agents with different mechanisms of action Agents with different mechanisms of action

are often used together to inhibit the are often used together to inhibit the reproduction of neoplastic cells in all phasesreproduction of neoplastic cells in all phases Mixtures may act synergistically, leading to Mixtures may act synergistically, leading to

enhanced cytotoxicity with fewer side effectsenhanced cytotoxicity with fewer side effects



CombinationsCombinations

Haveles (p. 274)Haveles (p. 274) Used in lower doses to treat diseases Used in lower doses to treat diseases

associated with inflammation or autoimmune associated with inflammation or autoimmune conditions and transplantsconditions and transplants Diseases include rheumatoid arthritis, systemic Diseases include rheumatoid arthritis, systemic

lupus erythematosus, pemphigus vulgaris, and lupus erythematosus, pemphigus vulgaris, and psoriasispsoriasis

Doses of these agents used to treat diseases with Doses of these agents used to treat diseases with an autoimmune component are often lower than an autoimmune component are often lower than the doses used to treat cancerthe doses used to treat cancer


Dental ImplicationsDental Implications

Haveles (p. 274) (Boxes 21-3, 21-4) Haveles (p. 274) (Boxes 21-3, 21-4) The best times for oral hygiene procedures The best times for oral hygiene procedures

are when they would coincide with the are when they would coincide with the presence of the highest level of formed blood presence of the highest level of formed blood elementselements This time frame would be either just before This time frame would be either just before

treatment or on the first few days of treatmenttreatment or on the first few days of treatment


Antineoplastic Agents by Group Antineoplastic Agents by Group

Haveles (p. 272) (Box 21-2) Haveles (p. 272) (Box 21-2) Alkylating agentsAlkylating agents

Nitrogen mustardNitrogen mustard• mechlorethamine (Mustargen)mechlorethamine (Mustargen)• cyclophosphamide, chlorambucil (Leukeran)cyclophosphamide, chlorambucil (Leukeran)• melphalan (Alkeran)melphalan (Alkeran)• uracil mustarduracil mustard• ifosfamide (Ifex)ifosfamide (Ifex)

NitrosoureasNitrosoureas• 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)




Haveles (p. 272) (Box 21-2) Haveles (p. 272) (Box 21-2) Alkylating AgentsAlkylating Agents

MiscellaneousMiscellaneous• busulfan (Myleran)busulfan (Myleran)

• pipobroman (Vercyte)pipobroman (Vercyte)

• thiotepathiotepa

• cisplatin (Platinol)cisplatin (Platinol)

• carboplatin (Paraplatin)carboplatin (Paraplatin)



Antineoplastic Agents by Group Antineoplastic Agents by Group Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2)

AntimetabolitesAntimetabolites Folic acid analogFolic acid analog

• methotrexate (Amethopterin)methotrexate (Amethopterin) Pyrimidine analogPyrimidine analog

• fluorouracil (5-FU)fluorouracil (5-FU)• floxuridine (FUDR)floxuridine (FUDR)• cytosine arabinoside (ARA-C) (Cytosar-U)cytosine arabinoside (ARA-C) (Cytosar-U)• azacitidineazacitidine

Purine analogPurine 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)




Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2) Miscellaneous antineoplasticsMiscellaneous antineoplastics

Plant alkaloidsPlant alkaloids• vinblastine (Velban)vinblastine (Velban)

• vincristine (Oncovin)vincristine (Oncovin)

AntibioticsAntibiotics• 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…cont’d…


Antineoplastic Agents by Group Antineoplastic Agents by Group Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2)

Miscellaneous antineoplasticsMiscellaneous antineoplastics HormonesHormones

• Adrenocorticosteroids (prednisone)Adrenocorticosteroids (prednisone)• Androgen Androgen

testolactone (Teslac)testolactone (Teslac) fluoxymesterone (Halotestin)fluoxymesterone (Halotestin)

• Antiandrogen Antiandrogen flutamide (Eulexin)flutamide (Eulexin) nilutamide (Nilandron)nilutamide (Nilandron) bicalutamide (Casodex)bicalutamide (Casodex)

• Estrogen Estrogen diethylstilbestroldiethylstilbestrol ethinyl estradiol (Estinyl)ethinyl estradiol (Estinyl)





HormonesHormones• Antiestrogen Antiestrogen

tamoxifen (Nolvadex)tamoxifen (Nolvadex) raloxifene (Evista)raloxifene (Evista) fulvestrant (Faslodex)fulvestrant (Faslodex) toremifene (Fareston)toremifene (Fareston)

• Aromatase inhibitorsAromatase inhibitors anastrozole (Arimidex)anastrozole (Arimidex) exemestane (Aromasin)exemestane (Aromasin) letrozole (Femara)letrozole (Femara)





HormonesHormones• Progestin Progestin

medroxyprogesterone medroxyprogesterone megestrol (Megace)megestrol (Megace)

• goserelin (Zoladex)goserelin (Zoladex)

• leuprolide (Lupron)leuprolide (Lupron)



Antineoplastic Agents by GroupAntineoplastic Agents by Group

Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2) Immune modulatorsImmune modulators

levamisole (Ergamisol)levamisole (Ergamisol) interferon interferon αα--n3 (Alferon N)n3 (Alferon N) interferon interferon αα--2b (Intron A)2b (Intron A) interferon interferon αα--2a (Roferon-A)2a (Roferon-A)

Podophyllotoxin derivativesPodophyllotoxin derivatives etoposide (VePesid)etoposide (VePesid) teniposide (Vumon)teniposide (Vumon)




Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2) AminobisphosphonatesAminobisphosphonates

alendronate (Fosamax)alendronate (Fosamax) ibandronate (Boniva)ibandronate (Boniva) pamidronate (Aredia)pamidronate (Aredia) risedronate (Actonel)risedronate (Actonel) zoledronic acid (Zometa)zoledronic acid (Zometa)

cont’dcont’d



Haveles (p. 272) (Box 21-2)Haveles (p. 272) (Box 21-2) OtherOther

L-asparaginase (Elspar)L-asparaginase (Elspar) hydroxyurea (Hydrea)hydroxyurea (Hydrea) procarbazine (Matulane)procarbazine (Matulane) paclitaxel (Taxol)paclitaxel (Taxol) altretamine (Hexalen)altretamine (Hexalen) trastuzumab (Herceptin)trastuzumab (Herceptin) imatinib mesylate (Gleevec)imatinib mesylate (Gleevec)

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