Cancer Chemotherapy: Drug Classification and Mechanism of Action

Polyfunctional alkylating agents o Mechanism of Action o Drug Resistance o Pharmacological Effects o Nitrosoureas Other Alkylating Drugs o Procarbazine (Matulane) o Dacarbazine (DTIC) o Altretamine (Hexalen) o Cisplatin cisplatin (Platinol) Alkylating Agent Toxicity Antimetabolites

Methotrexate Purine antagonists o Mercaptopurine (6-MP) o Thioguanine (6-TG) o Fludarabine Phosphate o Cladribine (Leustatin) o Pentostatin (Nipent) Pyrimidine antagonists o Fluorouracil (5-FU) o Cytarabine (ARA-C) o Azacitidine Plant alkaloids o Vinblastine (Velban) o Vincristine (Oncovin) o Etoposide (VP-16,VePesid) o Teniposide (Vumon) o Topotecan (Hycamtin) o Irinotecan (Camptosar) o Paclitaxel (Taxol) o Docetaxel (Taxotere)

Antibiotics o Anthracyclines Doxorubicin (Adriamycin, Rubex, Doxil) Daunorubicin (DaunoXome) o Dactinomycin (Cosmegen) o Idarubincin (Idamycin) o Plicamycin (Mithramycin) o Mitomycin (Mutamycin) o Bleomycin (Blenoxane) Hormonal agents o Introduction o Tamoxifen (Nolvadex) o Flutamide (Eulexin) o Gonadotropin-Releasing Hormone Agonists (Leuprolide and Goserelin (Zoladex)) o Aromatase Inhibitors Aminoglutethimide Anastrozole (Arimidex) Miscellaneous anticancer drugs o Amsacrine o Hydroxyurea (Hydrea) o Asparaginase (El-spar) o Mitoxantrone (Novantrone) o Mitotane o Retinoic Acid Derivatives o Bone Marrow Growth Factors o Amifostine

Polyfunctional alkylating agents

Common Structural Features: o bis(chloroethyl)amine o ethylenimine o nitrosoureas Not cell-cycle specific: Cells most susceptible in late G1 and S phase-- Blocks in G2 Most useful agents:

Secondary agents

Cyclophosphamide (Cytoxan) o fosfamide Mechlorethamine Melphalan (Alkeran) Chlorambucil (Leukeran)

Thiopeta (Thioplex) o Ovarian cancer Busulfan (Myleran) o Chronic myeloid leukemia

Major nitrosoureas: Carmustine (BCNU) Lomustine (CCNU) Semustine (methyl CCNU)

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Polyfunctional Alkylating Drugs: Mechanism of Action:

Alkyl group transfer o Major interaction: Alkylation of DNA Primary DNA alkylation site: N7 position of guanine (other sites as well) interaction may involve single strands or both strands (cross linking, due to bifunctional [2 reactive centers] characteristics) o Other interactions: these drugs react with carboxyl, sulfhydryl, amino, hydroxyl, and phosphate groups of other cellular constituents o These drugs usually form a reactive intermediate -- ethyleneimonium ion Polyfunctional Alkylating Drug Resistance

Increased ability to repair DNA defects Decreased cellular permeability to the drug Increased glutathione synthesis o inactivates alkylating agents through conjugation reactions (catalyzed by glutathione S-transferase)

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Pharmacological Effects: Polyfunctional Alkylating Drugs

Injection site damage (vesicant effects) and systemic toxicity. Toxicity: o dose related o primarily affecting rapidly dividing cells bone marrow GI tract nausea and vomiting within less than an hour-- with mechlorethamine, carmustine (BCNU) or cyclophosphamide Emetic effects: CNS reduced by pre-treatment with phenothiazines or cannabinoids. gonads o Cyclophosphamide cytotoxicity depends on activation by microsomal enzyme system. Hepatic microsomal P450 mixed-function oxidase catalyzes conversion of cyclophosphamide to the active forms: 4-hydroxycyclophosphamide aldophosphamide o Major Toxicity: bone marrow suppression dose-related suppression of myelopoiesis: primary effects on megakaryocytes platelets granulocytes Bone marrow suppression is worse when alkylating agents are combined with other myelosuppressive drugs and/or radiation (dose reduction required) If bone marrow suppression is severe, treatment may have to be suspended and then re--initiated upon hematopoietic recovery. Long-term consequences of alkylating agent treatment include: ovarian failure (common) testicular failure (common) acute leukemia (rare) Oral Route of Administration:cyclophosphamide (Cytoxan), melphalan

(Alkeran), chlorambucil (Leukeran), busulfan (Myleran), lomustine (CCNU,CeeNU)

Cyclophosphamide (Cytoxan): most useful alkylating agent at present. Busulfan (Myleran): specificity for granulocytes -- chronic myelogenous leukemia

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Nitrosoureas: o not cross reactive ( with respect to tumor resistance) with other alkylating drugs. o Nonenzymatic by transformation required to activate compounds. o Highly lipid- soluble-- crosses the blood-brain barrier (BBB) useful in treating brain tumors o Act by cross-linking: DNA alkylation o More effective against cells in plateau phase than cells in exponential growth phase o Major route of elimination:urinary excretion o Steptozocin: sugar-containing nitrosourea minimal bone marrow suppression effective in insulin-secreting islet cell pancreatic carcinoma and sometimes in non-Hodgkin's lymphoma

Other Alkylating Drugs

Procarbazine (Matulane) o Methylhydrazine derivative o Active in Hodgkin's disease (combination therapy) o Teratogenic, mutagenic, leukemogenic. o Side effects: nausea, vomiting, myelosuppression hemolytic anemia pulmonary effects Dacarbazine (DTIC) o Clinical use: Melanoma Hodgkin's disease soft tissue sarcoma o Synthetic drug; requires activation by liver microsomal system. o Parenteral administration

Side effects: nausea, vomiting, myelosuppression Altretamine (Hexalen) o Clinical use: alkylating agent-resistant: ovarian carcinoma o Activated by biotransformation (demethylation) o Side effects: nausea, vomiting, central and peripheral nervous system neuropathies. relatively mild myelosuppressive effects. Cisplatin (Platinol) o Clinical use: Genitourinary cancers testicular ovarian bladder In combination with bleomycin and vinblastine: curative treatment for nonseminomatous testicular cancer Carboplatin (less GI and renal toxicity; with myelosuppressive toxicity): alternative to cisplatin o Inhibits DNA synthesis; cross-linking; guanine N7 site o Platinum compounds: synergistic with other anticancer agents o Site effects: major acute effect: nausea, vomiting relatively little bone marrow effects significant renal dysfunction (minimized by adequate hydration/diuretics) acoustic nerve dysfunction

Alkylating Agent Toxicity: Summary

IV mechlorethamine, cyclophosphamide, carmustine: Nausea and Vomiting (common) Oral cyclophosphamide: Nausea and Vomiting (less frequently) Most Important Toxic Effect:Bone marrow suppression, leukopenia, thrombocytopenia o secondary to myelosuppression - severe infection septicemia

hemorrhage

Cyclophosphamide (Cytoxan):alopecia, hemorrhagic cystitis (may be avoided by adequate hydration)

Antimetabolites

Structural analogues: Neoplastic cells' metabolic differences -- increased susceptibility to actions of antimetabolites. Most antimetabolites interfere with nucleic acid synthesis or nucleotide synthesis. Methotrexate (MTX) o Mechanism of Action: Folic acid antagonist: acts at catalytic side of dihydrofolate reductase o Polyglutamate: important in methotrexate action o Tumor resistance to methotrexate: decreased drug transport into the cell altered dihydrofolate reductase enzyme -- lower affinity for methotrexate decreased polyglutamate formation quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message) o Adverse effects: Bone marrow suppression Dermatologic GI mucosa Adverse effects reversed by leucovorin (citrovorum factor) Leucovorin "rescue" may be used in cases of over dosage or in high-dose methotrexate protocols o Other uses: Treatment of rheumatoid arthritis In combination with a prostaglandin: induces abortion

Purine Antagonists o 6-Thiopurines (Mercaptopurine [6-MP]; Thioguanine [6-TG]) o Mercaptopurine (Purinethol) Mechanism of Action:Activation by hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form 6-thioinosinic acid which inhibits enzymes involved in purine metabolism. (thioguanylic acid and 6-methylmercaptopurine ribotide (MMPR) also active)

Clinical Use: childhood acute leukemia the analog, azathioprine (Imuran)-- immunosuppressive agent. Thioguanine purine nucleotide pathway enzyme-inhibitor decreased intracellular concentration of guanine nucleotides inhibition of glycoprotein synthesis Mechanism of Action: inhibits DNA/RNA synthesis Clinical Use: Synergistic with cytarabine in treating adult acute leukemia. Drug resistance Decreased HGPRT activity In acute leukemia -- increased alkaline phosphatase, which dephosphorylates thiopurines nucleotides Adverse Effects: Both mercaptopurine and thioguanine, given orally, are excreted in the urine. 6-MP is converted to an inactive metabolite, 6-thioruric acid, by xanthine oxidase .6-TG: requires deamination before metabolism by xanthine oxidase. In cancer (hematologic) chemotherapy, allopurinol is used to inhibit xanthine oxidase, to prevent hyperuricemia associated with tumor cell lysis {xanthine oxidase inhibition blocks purine degradation -- purines (more soluble) are excreted instead of uric acid (less soluble)} use of allopurinol thus blocks acute gout and nephrotoxicity. However, the combination of allopurinol and 6mercaptopurine, because of xanthine oxidase inhibition, can lead to mercaptopurine toxicity; This interaction does not occur with 6-TG. Fludarabine phosphate parenteral administration; renal excretion dephosphorylated to active form: Mechanism of Action:DNA synthesis inhibition Clinical Use: lymphoproliferative disease Adverse Effect:dose-limiting -- myelosuppression. Cladribine: (Leustatin) phosphorylated by deoxycytidine kinase incorporated into DNA Mechanism of Action: increased strand breaks (inhibition of repair mechanisms) Clinical Use: Hairy cell leukemia

Adverse Effects: Transient severe myelosuppression; possibly associated with infection. Pentostatin: irreversible inhibitor adenosine deaminase results in toxic accumulation of deoxyadenosine nucleotides (especially in lymphocytes) Adverse Effects: immunosuppression (T cell mediated immunity) myelosuppression kidney function impairment CNS toxicity liver toxicity

Pyrimidine Antagonists: o Flurouracil (5-FU), normally given by IV administration (oral absorption erratic) Biotransformed to ribosyl- and deoxyribosyl- derivatives. Mechanism of Action: One derivative, 5-fluoro-2'-deoxyuridine 5'phosphate (FdUMP), inhibits thymidylate synthase and its cofactor,a tetrahydrofolate derivative, resulting in inhibition of thymidine nucleotide synthesis. Another derivative, 5-fluorouridine triphosphate is incorporated into RNA, interfering with RNA function. Cytotoxicity:effects on both RNA and DNA Clinical Use: Systemically -- adenocarcinomas; Topically: skin cancer Floxuridine (FUDR): similar to 5-FU, used for hepatic artery infusion. Major Toxicity: myelosuppression, mucositis. o Cytarabine (ara-C) IV administration Mechanism of Action:S phase-specific antimetabolite Biotransformed to active forms: ara-CTP, competitive inhibitor of DNA polymerase. Blocks DNA synthesis; no effect on RNA or protein synthesis cytarabine incorporated into RNA and DNA -- interfering with chain elongation Clearance: deamination (inactive form) S phase specificity: highly schedule-dependent Clinical Use: almost exclusively for acute myelogenous leukemia

Adverse Effects: nausea alopecia stomatitis severe myelosuppression Azacitidine (IV administration): Mechanism of Action: active derivatives inhibit orotidylate decarboxylase -- reducing pyrimidine nucleotide synthesis; azacitidine -- incorporated into DNA and RNA; inhibits DNA, RNA, and protein synthesis. Investigational drug -- second-line agent in treatment of acute leukemia Adverse Effect: myelosuppression.

Plant Alkaloids

Vinblastine -- (Velban) o Mechanism of action: microtubule depolymerization Mitotic arrest at metaphase; interferes with chromosome segregation o Clinical Use:: Systemic treatment of Hodgkin's disease Lymphomas o Adverse Effects: nausea vomiting alopecia bone marrow suppression Vincristine -- (Oncovin) o Mechanism of action: microtubule depolymerization Mitotic arrest at metaphase; interferes with chromosome segregation o Clinical Use:: In combination with prednisone: induction of remission in children with acute leukemia useful in treating some other rapidly proliferating neoplasms o Adverse Effects: significant frequency of neurotoxic reactions occasional: bone marrow depression

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Podophyllotoxins (etoposide {VP- 16}and teniposide {VM-26}) o Etoposide and teniposide: structurally similar o Mechanism of action: Block cell cycle: in late S-G2 phase inhibition of topoisomerase II -- DNA damage o IV administration o Urinary excretion; some in bile o Clinical Use: Etoposide (VP-16,VePe-sid): monocytic leukemia testicular cancer oat cell lung carcinoma Teniposide (Vumon): lymphomas o Adverse Effects: nausea vomiting alopecia significant hematopoietic toxicity and lymphoid toxicity

Camptothecins (topotecan and irinotecan ) o Mechanism of action: interfere with activity of topoisomerase I (cuts and religates single stranded DNA. DNA is damaged o Clinical Uses: Topotecan: metastatic ovarian cancer -- including cisplatinresistant forms (as effective as paclitaxel) Adverse Effects: Topotecan - Primary neutropenia thrombocytopenia anemia Other nausea nominee alopecia Irinotecan:prodrug-metabolized active topoisomerase I inhibitor Used in management of colon and rectal cancer, including tumors not responding to 5-FU Adverse Effects: Irinotecan - Most common: diarrhea also common: nausea, vomiting Dose limiting adverse effect: myelosuppression

Taxanes (Paclitaxel (Taxol) and Docetaxel (Taxotere))

o o o

Paclitaxel (Taxol): derivative of the Western Yew Mitotic spindle inhibitor: enhances tubulin polymerization Clinical Uses: Ovarian Advanced breast cancer Dose-limiting Adverse Effects: neutropenia thrombocytopenia peripheral neuropathy Docetaxel (Taxotere):Used in advanced breast cancer Adverse Effects:bone marrow suppression

Anticancer Drugs: Antibiotics

Clinically useful anticancer antibiotics: derived from Streptomyces These antibiotics act by: o DNA intercalation, blocking synthesis of DNA and RNA Anthracyclines: Doxorubicin (Adriamycin, Rubex, Doxil) and Daunorubicin (DaunoXome) o IV administration; hepatic metabolism; biliary excretion; some urinary excretion; enterohepatic recirculation. o Among the most useful anticancer antibiotics o Mechanism of action: DNA intercalation -- blocking synthesis of DNA and RNA; DNA strands scission -- by affecting topoisomerase II Altering membrane fluidity and ion transport Semiquinone free radical an oxygen radical generation (may be responsible for myocardial damage)

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Clinical Uses: o Doxorubicin (Adriamycin, Rubex, Doxil)-- very important anticancer agent -Carcinomas-Doxorubicin ovarian carcinoma testicular carcinoma

breast carcinoma endometrial carcinoma

thyroid carcinoma lung carcinoma

Ewing's sarcoma

Sarcomas-Doxorubicin osteosarcoma

rhabdomyosarcomas

acute leukemia

Hematologic Cancers-Doxorubicin multiple Hodgkin's myeloma disease

non-Hodgkin's lymphoma

Adjuvant therapy in: osteogenic sarcoma and breast cancer Generally used in combination protocols with: o cyclophosphamide (Cytoxan) o cisplatin (Platinol) o nitrosoureas Major Use: Acute Leukemia Daunorubicin: limited utility-- limited efficacy in treating solid tumors. Idarubicin: approved for acute myeloid leukemia o Idarubicin in combination with cytarabine: more active than daunorubicin in inducing complete remission in acute myelogenous leukemia. Adverse Effects: o Bone marrow depression (short duration) o Cumulative, dose-related, possibly irreversible cardiotoxicity. o Total, severe alopecia

Dactinomycin (Cosmegen) o IV administration; 50 percent remains unmetabolized. o Mechanism of action: intercalation between guanine-cytosine base pairs inhibits DNA-dependent RNA synthesis blocks protein synthesis o Clinical Uses: dactinomycin in combination with vincristine (Oncovin)and surgery (may include radiotherapy) in treatment of Wilms' tumor dactinomycin with methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma. o Adverse Effects:

Major dose limiting toxicity: bone marrow suppression (all blood elements affected -- particularly platelets and leukocytes) occasional severe thrombocytopenia nausea vomiting diarrhea oral ulcers Dactinomycin: immunosuppressive (patient should not receive live virus vaccines) alopecia/skin abnormalities interaction with radiation ("radiation recall")

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Plicamycin (Mithramycin)

Mechanism of action:binds to DNA -- interrupts DNA-directed RNA synthesis o Also decreases plasma calcium (independent tumor cell action;acts on osteoclasts) Clinical Uses: o some efficacy in testicular cancer that is unresponsive to standard treatment: o especially useful in managing severe hypercalcemia associated with cancer Adverse Effects: o nausea o vomiting o thrombocytopenia o leukopenia o hypocalcemia o liver toxicity o bleeding disorders

Mitomycin: (Mutamycin) o Mechanism of action: metabolic activation to produce a DNA alkylating agent. Solid tumor hypoxic stem cells may be more sensitive to the action of mitomycin.

Best available drug, in combination with x-rays, to kill hypoxic tumor cells. Clinical Use: in combination chemotherapy {with vincristine and bleomycin}: squamous sell carcinoma of the cervix adenocarcinoma of the stomach, pancreas, and lung {along with flurouracil and doxorubicin} second-line drug: metastatic colon cancer topical intravesical treatment of small bladder papillomas. Adverse Effects: severe myelosuppression, especially after repeated doses, suggest action on hematopoietic stem cells. Vomiting anorexia occasional nephrotoxicity occasional interstitial pneumonitis

Bleomycin (Blenoxane)

Mechanism of Action:binds to DNA -- produces single- and doublestrand breaks (free radical formation) o Cell cycle specific: arrests division in G2 o Synergistic effects with vinblastine and cisplatin (curative protocol for testicular cancer) Clinical Uses: o Testicular cancer o Squamous cell carcinoma: head, neck, cervix, skin, penis, and rectum o combination treatment: lymphoma o intracavity treatment: malignant effusions in ovarian breast cancer Adverse Effects: o Anaphylactoid reaction (potentially fatal) o Fever o anorexia, blistering, hyperkeratosis (palms) o pulmonary fibrosis (uncommon) o No significant myelosuppression

Anticancer Agents: Hormones

Introduction

Breast and prostatic cancer: palliation with sex hormone therapy Adrenal corticosteroid treatment-- useful in: o acute leukemia o myeloma o lymphomas o other hematologic cancers Pharmacological effects: o Steroid hormones bind to steroid receptors: o Efficacy of steroid treatment depends on specific receptor presence on malignant cell surface. Clinical Use:Treatment of: o female and male breast cancer o prostatic cancer o endometrial cancer of uterus Adverse Effects: o Fluid retention (secondary to Na-retaining properties) o Androgens-masculinization (long-term use) o Estrogens-feminization (long-term use) o Adrenocortical steroids: hypertension diabetes enhanced susceptibility to infection cushingoid appearance

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Estrogen and Androgen Inhibitors: (Tamoxifen and Flutamide)

Tamoxifen: Breast cancer treatment o Oral administration. o Activity against progesterone-resistant endometrial neoplasm o Chemopreventive:women -- high-risk for breast cancer o Mechanism of Action: Competitive partial agonist-inhibitor of estrogen Binds to estrogen-sensitive tissues (receptors present) Best antiestrogen effect requires minimal endogenous estrogen presence {estradiol has a much higher affinity for the estrogen receptor than tamoxifen's affinity for the estrogen receptor} Suppresses serum levels of insulin-like growth factor-1; and up-

regulates local TGF-beta production. These properties may explain tamoxifen antitumor activity in melanoma and ovarian cancer. o Adverse Effects: Generally mild Most frequent: hot flashes Occasionally: fluid retention, nausea o Clinical Use: Advanced breast cancer Most likely to be effective if: lack endogenous estrogens {oophorectomy; postmenopausal} Presence of cytoplasmic estrogen receptor;presence of cytoplasmic progesterone receptorColeman Prolongs survival {surgical adjuvant therapy} in postmenopausal women with estrogen receptor-positive breast cancer. Flutamide (Eulexin): prostatic cancer o Antagonizes remaining androgenic effects after orchiectomy or leuprolide treatment

Gonadotropin-Releasing Hormone Agonists (Leuprolide and Goserelin (Zoladex))

Leuprolide and goserelin: synthetic peptide analogues of gonadotropinreleasing hormone (GnRH, LHRH) o Mechanism of Action: Analogues more potent -- behave as GnRH agonists. pituitary effects: when given continuously -- initial stimulation then inhibition of follicle-stimulating hormone and leutinizing hormone. Causes reduced testicular androgen synthesis, the reason why these agents are effective in treating metastatic prostate carcinoma Clinical Use: treating metastatic prostate carcinoma Comparing leuprolide with diethylstilbestrol (DES): o Similar suppression of androgens synthesis and serum prostatic acid phosphatase (an index of metastatic tumor load) o Adverse Effects: Leuprolide less frequently causes: nausea vomiting edema thromboembolism

painful gynecomastia Leuprolide and goserelin: medication more costly, the more costeffective given reduced frequency of complications.

Aromatase Inhibitors (Aminoglutethimide and Anastrozole (Arimidex))

Aminoglutethimide: o Mechanisms of action: Reduction in estrogen concentration Aminoglutethimide: inhibitor of adrenal steroid synthesis ( blocks conversion of cholesterol to pregnenolone {first-step}) Aminoglutethimide inhibits extra-adrenal estradiol and estrone synthesis. Aminoglutethimide inhibits an aromatase enzyme {catalyzes conversion of androstenedione to estrone} This conversion may occur in fat. o Clinical Use: Metastatic breast cancer (tumors contain estrogen or progesterone receptors) Aminoglutethimide is administered with adrenalreplacement doses of hydrocortisone to ensure avoidance of adrenal insufficiency. Hydrocortisone is used in preference to dexamethasone, because dexamethasone increases the degradation of aminoglutethimide. Aminoglutethimide in combination with hydrocortisone: Second-Line Therapy for women treated with tamoxifen (aminoglutethimide causes more adverse side effects than tamoxifen) Anastrozole (Arimidex): new, selective, nonsteroidal aromatase inhibitor. o appears to have no effect on glucocorticoid or mineralocorticoid synthesis o Clinical Use: Treatment of advanced estrogen-or progesterone-receptor positive non--tamoxifen responsive breast cancer

Miscellaneous Anticancer Drugs

Amsacrine: o Hepatic metabolism o Mechanism of Action: DNA intercalation: produces single-and double-strand breaks interaction with topoisomerase II-DNA complexes o Clinical Uses: Anthracyclines- and cytarabine-resistant acute

myelogenous leukemia Advanced ovarian cancer Lymphomas Adverse Effects: Does-limiting hepatic toxicity Cardiac arrest has been noted with amsacrine infusion

Asparaginase (El-spar): o Mechanism of action: depletion of serum asparagine {forming aspartic acid and ammonia} Decreased blood levels of asparagine and glutamine inhibit protein synthesis in those neoplastic cells that express decreased levels of asparagine synthase. Most normal cells express sufficient levels of asparagine synthase to avoid toxicity. Hydroxyurea: o Mechanism of action: Inhibits ribonucleotide reductase; depletes deoxyribonucleoside triphosphate pools Acts at S phase. o Clinical Uses: Melanoma [secondary role] Chronic myelogenous leukemia [secondary role] o Adverse Effects: Bone marrow suppression nausea vomiting diarrhea Mitoxantrone (Novantrone): o Mechanism of action: Induces DNA strand breaks Inhibits RNA and DNA synthesis o Clinical Uses: Refractory acute leukemia Pediatric and adult acute myelogenous leukemia non-Hodgkin's lymphoma's breast cancer o Adverse Effects: Dose-limiting: leukopenia

mild nausea vomiting stomatitis alopecia some cardiotoxicity {arrhythmias} Mitotane (Lysodren): o Clinical Use:Single indication-- adrenal carcinoma Reduces excessive steroid secretion o Adverse Effects: diarrhea mental depression skin eruption anorexia nausea somnolence dermatitis Retinoic acid Derivatives: o Clinical Uses: Remissions -- acute promyelocytic leukemia 13-cis-Retinoic acid: chemopreventive -- second primary tumors in patients with hand and neck squamous cell carcinoma. o Adverse Effects: skeletal effects hepatic effects teratogenic effects mucocutaneous effects Bone Marrow Growth Factors (sargramostim and filgrastim): o Reduces neutropenic sepsis and other complications of chemotherapy o Filgrastim shortens neutropenic state following induction chemotherapy for acute nonlymphocytic leukemia. Amifostine o Cytoprotective from effects of chemotherapy