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Drugs to Treat Head and Neck Cancers: Mechanisms of Action

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Head & Neck Cancer: Current Perspectives, Advances, and Challenges

Abstract

This chapter presents the anticancer agents used for the treatment of head and neck squamous cell carcinomas (HNSCC), emphasizing the mechanisms of action of the various drug classes. Current therapies for HNSCC can be broadly divided into four categories: (1) DNA damaging agents, (2) Antimetabolites that interfere with DNA synthesis, (3) Antimitotic agents that interfere with cell division, (4) Agents that target pathways whose dysregulation are critical for tumorigenesis, including apoptosis and angiogenesis. Agents from the first three groups interfere with cell division and are therefore fundamentally non-selective. Most of their significant adverse effects result from the damage they inflict on normal cells that divide or remodel rapidly. Targeted therapies in contrast have greater potential to selectively inhibit transformed cells while sparing normal tissues. All HNSCC therapies are affected by resistance mechanisms that decrease drug efficacy. Typical mechanisms of tumor resistance include reduced drug uptake, increased drug efflux, rapid metabolism, and overexpression/mutation of target enzymes and receptors. Resistance can be pre-empted using combination chemotherapy regimens in which several anticancer agents are given simultaneously. These agents are also used in multimodal therapies, i.e. as a complement to surgery and/or radiation. Indeed, most HNSCC is treated with multimodal therapy and combination chemotherapy. Intravenous injection is the typical route of administration, however a few can be given orally. We also discuss several compounds in various stages of investigation.

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Abbreviations

5-FU:

5-Fluorouracil

5HT:

5 hydroxytryptamine

Ala:

Alanine

Arg:

Arginine

Asn:

Asparagine

Asp:

Aspartate

ATP:

adenosine triphosphate

Bcl-2:

B cell lymphoma-2

BCR-ABL:

Break point cluster region-abelson

BLM:

Bleomycin

BP-I:

Back pocket I

BP-II:

Back pocket II

BP-III:

Back pocket III

BP-IV:

Back pocket IV

CDK:

Cyclin-dependent kinase

c-Kit:

stem cell factor

CML:

Chronic myeloid leukemia

CNS:

Central nervous system

CTR1:

Copper Transport Receptor −1

Cu++ :

Copper (II)

Cys:

Cysteine

DCA:

Dichloroacetate

DFG:

Aspartate-Phenylalanine-Glycine

DHF:

Dihydrofolate

DHFR:

Dihydrofolate Reductase

DNA:

Deoxyribonucleic acid

DTX:

Docetaxel

EGCG:

Epigallocatechin

EGF:

Epidermal growth factor

EGFR:

Epidermal Growth Factor Receptor

ERB:

Eukaryotic ribosome biogenesis protein

FADD:

Fas-associated protein with death domain

FAK:

Focal adhesion kinase

FBP:

Folate Binding Protein

FGFR:

Fibroblast growth factor receptor

Flk-1:

Fetal liver tyrosine kinase 1

Flt-1:

Fms-like tyrosine kinase

FPGS:

Folypoly-γ-glutamate synthetase

FR:

Folate Receptor

GARFT:

Glycine Amide Ribonucleotide Transformylase

GIST:

Gastrointestinal stromal tumors

Gln:

Glutamine

Glu:

Glutamate

Gly:

Glycine

HeLa:

Henrietta Lacks (cervical cell variety named for deceased patient)

HER:

Human Epidermal Receptor

HGF:

Hepatocyte growth factor

HNSCC:

Head and Neck Squamous Cell Carcinoma

IGF:

Insulin-like growth factor

IGF-I-R:

Insulin-like growth factor I receptor

Ile:

Isoleucine

IM:

Intramuscularly

IR:

Insulin receptor

IRK:

Insulin receptor kinase

IV:

Intravenously

kDa:

KiloDalton

KDR:

Kinase insert domain-containing receptor

Leu:

Leucine

Lys:

Lysine

MDR:

Multi-drug resistance

MET:

Receptor for hepatocyte growth factor

MMR:

Mismatch repair (DNA repair mechanism)

MT:

Microtubules

MTA:

Multi targeted antifolate

mTOR:

Mammalian Target of Rapamycin (a serine/threonine protein kinase)

MTX:

Methotrexate

N5,N10-CH2THF:

N5,N10-methylenetetrahydrofolate

NSCLC:

Non-small cell lung cancer

PDH:

Pyruvate Dehydrogenase

Pgp:

P-glycoprotein

PI3K:

Phosphoinositol 3-Kinase

PKC:

Protein kinase C

PORT:

Post Operative Radiation Therapy

Pt:

Platinum

PTX:

Paclitaxel

RFC:

Reduced Folate Carrier

RTK:

Receptor Tyrosine Kinase

THF:

Tetrahydrofolate

TNF-α:

Tumor necrosis factor–alpha

TPF therapy:

Three-drug regimen: docetaxel (Taxotere)/cisplatin (Platinol)/5-fluorouracil (5-FU)

TS:

Thymidylate Synthase

VEGFR:

Vascular Endothelial Cell Growth Factor Receptor

VFL:

Vinflunine

VBN:

Vinorelbine

References

  1. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  2. Price KAR, Cohen EE (2012) Current treatment options for metastatic head and neck cancer. Curr Treat Options Oncol 13:35–46

    Article  PubMed  Google Scholar 

  3. Al-Sarraf M (2002) Treatment of locally advanced head and neck cancer: historical and critical review. Cancer Control 9:387–399

    PubMed  Google Scholar 

  4. Rodriguez CP, Adelstein DJ (2011) Principles of systemic chemotherapy for squamous cell head and neck cancer. In: Bernier J (ed) Head and neck cancer, 1st edn. Springer, New York, pp 281–291

    Chapter  Google Scholar 

  5. Devita VT, Chu E (2008) A history of cancer chemotherapy. Cancer Res 68:8643–8653

    Article  PubMed  CAS  Google Scholar 

  6. Chabner BA (2011) General principles of cancer chemotherapy. In: Brunton L, Chabner B, Knollman B (eds) Goodman & Gilman’s the pharmacological basis of therapeutics. McGraw-Hill, New York, pp 1667–1676

    Google Scholar 

  7. Sahu N, Grandis JR (2011) New advances in molecular approaches to head and neck squamous cell carcinoma. Anti-Cancer Drugs 22:656–664

    Article  PubMed  CAS  Google Scholar 

  8. Gondi V, Traynor AM, Harari PM (2011) Molecular targeted therapies in head and neck cancer. In: Bernier J (ed) Head and neck cancer, 1st edn. Springer, New York, pp 293–305

    Chapter  Google Scholar 

  9. Capdeville R, Buchdunger E, Zimmermann J et al (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov 1:493–502

    Article  PubMed  CAS  Google Scholar 

  10. Atkins M, Jones CA, Kirkpatrick P (2006) Sunitinib malate. Nat Rev Drug Discov 5:279–280

    Article  PubMed  CAS  Google Scholar 

  11. Muhsin M, Graham J, Kirkpatrick P (2003) Fresh from the pipeline: Gefitinib. Nat Rev Drug Discov 2:515–516

    Article  PubMed  CAS  Google Scholar 

  12. Muhsin M, Graham J, Kirkpatrick P (2004) Bevacizumab. Nat Rev Drug Discov 3:995–996

    Article  PubMed  CAS  Google Scholar 

  13. Kirkpatrick P, Graham J, Muhsin M (2004) Fresh from the pipeline: Cetuximab. Nat Rev Drug Discov 3:549–550

    Article  PubMed  CAS  Google Scholar 

  14. Szakács G, Paterson JK, Ludwig JA et al (2006) Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5:219–234

    Article  PubMed  CAS  Google Scholar 

  15. Anthoney DA, Kaye SB (1997) Drug resistance: the clinical perspective. In: Brown R, Boger-Brown U (eds) Molecular medicine: cytotoxic drug resistance mechanisms. Humana Press, Totowa, pp 1–16

    Google Scholar 

  16. Roche VF (2008) Cancer and chemotherapy. In: Lemke TL, Williams DA, Roche VF, Zito SW (eds) Foye’s principles of medicinal chemistry. Lippincott Williams & Wilkins, Baltimore, pp 1147–1192

    Google Scholar 

  17. Conley BA (2006) Treatment of advanced head and neck cancer: what lessons have we learned? J Clin Oncol 24:1023–1025

    Article  PubMed  Google Scholar 

  18. Hall MD, Mellor HR, Callaghan R et al (2007) Basis for design and development of platinum(IV) anticancer complexes. J Med Chem 50:3403–3411

    Article  PubMed  CAS  Google Scholar 

  19. Werner ME, Copp JA, Karve S et al (2011) Folate-targeted polymeric nanoparticle formulation of docetaxel is an effective molecularly targeted radiosensitizer with efficacy dependent on the timing of radiotherapy. ACS Nano 5:8990–8998

    Article  PubMed  CAS  Google Scholar 

  20. Leemans CR, Braakhuis BJM, Brakenhoff RH (2011) The molecular biology of head and neck cancer. Nat Rev Cancer 11:9–22

    Article  PubMed  CAS  Google Scholar 

  21. Fung C, Grandis JR (2010) Emerging drugs to treat squamous cell carcinomas of the head and neck. Expert Opin Emerg Drugs 15:355–373

    Article  PubMed  CAS  Google Scholar 

  22. Seiwert TY, Salama JK, Vokes EE (2007) The chemoradiation paradigm in head and neck cancer. Nat Clin Pract Oncol 4:156–171

    Article  PubMed  CAS  Google Scholar 

  23. Hannon MJ (2007) Metal-based anticancer drugs: from a past anchored in platinum chemistry to a post-genomic future of diverse chemistry and biology. Pure Appl Chem 79:2243–2261

    Article  CAS  Google Scholar 

  24. Rosenberg B (1999) The start. In: Lippert B (ed) Cisplatin. Wiley-VCH, Weinheim, pp 3–30

    Google Scholar 

  25. Boulikas T, Pantos A, Bellis E et al (2007) Designing platinum compounds in cancer: structures and mechanisms. Cancer Ther 5:537–583

    Google Scholar 

  26. Huang H, Zhu L, Reid BR, Drobny GP, Hopkins PB (1995) Solution structure of a cisplatin-induced DNA interstrand cross-link. Science 270:1842–1845

    Article  PubMed  Google Scholar 

  27. O’Dwyer PJ, Stevenson JP, Johnson SW (1999) Cisplatin – how good is it? In: Lippert B (ed) Cisplatin. Wiley-VCH, Weinheim, pp 31–72

    Google Scholar 

  28. Percie du Sert N, Rudd JA, Apfel CC et al (2010) Cisplatin-induced emesis: systematic review and meta-analysis of the ferret model and the effects of 5-HT3 receptor antagonists. Cancer Chemother Pharmacol 67:667–686

    Article  PubMed  CAS  Google Scholar 

  29. Hesketh PJ (2008) Chemotherapy-induced nausea and vomiting. N Engl J Med 358:2482–2494

    Article  PubMed  CAS  Google Scholar 

  30. Grunberg SM, Dugan M, Muss H et al (2008) Effectiveness of a single-day three-drug regimen of dexamethasone, palonosetron, and aprepitant for the prevention of acute and delayed nausea and vomiting caused by moderately emetogenic chemotherapy. Support Care Cancer 17:589–594

    Article  PubMed  Google Scholar 

  31. Mollman JE (1990) Cisplatin neurotoxicity. N Engl J Med 322:126–127

    Article  PubMed  CAS  Google Scholar 

  32. Cooley ME, Davis L, Abrahm J (1994) Cisplatin: a clinical review. Part II–Nursing assessment and management of side effects of cisplatin. Cancer Nurs 17:283–293

    PubMed  CAS  Google Scholar 

  33. Park SB, Krishnan AV, Lin CS-Y et al (2008) Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 15:3081–3094

    Article  PubMed  CAS  Google Scholar 

  34. Rybak LP, Ramkumar V (2007) Ototoxicity. Kidney Int 72:931–935

    Article  PubMed  CAS  Google Scholar 

  35. Köberle B, Tomicic MT, Usanova S et al (2010) Cisplatin resistance: preclinical findings and clinical implications. BBA Rev Cancer 1806:172–182

    Google Scholar 

  36. Kartalou M, Essigmann JM (2001) Mechanisms of resistance to cisplatin. Mutat Res 478:23–43

    Article  PubMed  CAS  Google Scholar 

  37. Nehmé A, Baskaran R, Nebel S et al (1999) Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells. Br J Cancer 79:1104–1110

    Article  PubMed  Google Scholar 

  38. Vermorken JB, Mesia R, Rivera F et al (2008) Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359:1116–1127

    Article  PubMed  CAS  Google Scholar 

  39. Ho JW (2006) Potential and cytotoxicity of cis-platinum complex with anti-tumor activity in combination therapy. Recent Pat Anticancer Drug Discov 1:129–134

    Article  PubMed  CAS  Google Scholar 

  40. Schultz JD, Bran G, Anders C et al (2010) Induction chemotherapy with TPF (Docetaxel, Carboplatin and Fluorouracil) in the treatment of locally advanced squamous cell carcinoma of the head and neck. Oncol Rep 24:1213–1216

    Article  PubMed  CAS  Google Scholar 

  41. Lokich J, Anderson N (1998) Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol 9:13–21

    Article  PubMed  CAS  Google Scholar 

  42. Yamada H, Maki H, Takeda Y et al (2006) Evaluation of combined nedaplatin and docetaxel therapy for human head and neck cancer in vivo. Anticancer Res 26:989–994

    PubMed  CAS  Google Scholar 

  43. Espinosa M, Martinez M, Aguilar JL et al (2004) Oxaliplatin activity in head and neck cancer cell lines. Cancer Chemother Pharmacol 55:301–305

    Article  PubMed  CAS  Google Scholar 

  44. Chaney SG, Campbell SL, Bassett E et al (2005) Recognition and processing of cisplatin- and oxaliplatin-DNA adducts. Crit Rev Oncol Hematol 53:3–11

    Article  PubMed  Google Scholar 

  45. Hecht SM (2000) Bleomycin: new perspectives on the mechanism of action 1. J Nat Prod 63:158–168

    Article  PubMed  CAS  Google Scholar 

  46. Chow MS, Liu LV, Solomon EI (2008) Further insights into the mechanism of the reaction of activated bleomycin with DNA. Proc Natl Acad Sci U S A 105:13241–13245

    Article  PubMed  CAS  Google Scholar 

  47. Chen J, Ghorai MK, Kenney G et al (2008) Mechanistic studies on bleomycin-mediated DNA damage: multiple binding modes can result in double-stranded DNA cleavage. Nucleic Acids Res 36:3781–3790

    Article  PubMed  CAS  Google Scholar 

  48. Thomas CJ, McCormick MM, Vialas C et al (2002) Alteration of the selectivity of DNA cleavage by a deglycobleomycin analogue containing a trithiazole moiety. J Am Chem Soc 124:3875–3884

    Article  PubMed  CAS  Google Scholar 

  49. Hecht SM (2005) Bleomycin group antitumor agents. In: Cragg GM, Kingston DG, Newman DJ (eds) Anticancer agents from natural products. Taylor & Francis, Boca Raton, pp 357–382

    Google Scholar 

  50. Ma Q, Xu Z, Schroeder BR et al (2007) Biochemical evaluation of a 108-member deglycobleomycin library: viability of a selection strategy for identifying bleomycin analogues with altered properties. J Am Chem Soc 129:12439–12452

    Article  PubMed  CAS  Google Scholar 

  51. Boger DL, Aquila BM, Tse WC et al (2000) Synthesis and evaluation of a novel bleomycin A2 analogue: continuing assessment of the linker domain. Tetrahedron Lett 41:9493–9498

    Article  CAS  Google Scholar 

  52. Chen J, Stubbe J (2005) Bleomycins: towards better therapeutics. Nat Rev Cancer 5:102–112

    Article  PubMed  CAS  Google Scholar 

  53. Aouida M, Ramotar D (2006) Bleomycin transport holds the key for improved anticancer therapy. Cancer Ther 4:171–182

    Google Scholar 

  54. Kumar P, Yadav A, Patel SN et al (2010) Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis. Mol Cancer 9:206

    Article  PubMed  CAS  Google Scholar 

  55. Fyfe AJ, McKay P (2010) Toxicities associated with bleomycin. J R Coll Physicians Edinb 40:213–215

    Article  PubMed  CAS  Google Scholar 

  56. Schwartz DR, Homanics GE, Hoyt DG et al (1999) The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance. Proc Natl Acad Sci U S A 96:4680–4685

    Article  PubMed  CAS  Google Scholar 

  57. Aouida M, Poulin R, Ramotar D (2010) The human carnitine transporter SLC22A16 mediates high affinity uptake of the anticancer polyamine analogue bleomycin-A5. J Biol Chem 285:6275–6284

    Article  PubMed  CAS  Google Scholar 

  58. Ramotar D, Wang H (2003) Protective mechanisms against the antitumor agent bleomycin: lessons from Saccharomyces cerevisiae. Curr Genet 43:213–224

    Article  PubMed  CAS  Google Scholar 

  59. DeGraw JI, Christie PH, Brown EG et al (1984) Synthesis and antifolate properties of 10-alkyl-8,10-dideazaminopterins. J Med Chem 27:376–380

    Article  PubMed  CAS  Google Scholar 

  60. Berman EM, Werbel LM (1991) The renewed potential for folate antagonists in contemporary cancer chemotherapy. J Med Chem 34:479–485

    Article  PubMed  CAS  Google Scholar 

  61. Blakley R, Benkovic S (1984) Folates and pterins: chemistry and biochemistry of folates. Wiley, New York

    Google Scholar 

  62. Heidelberger C, Chaudhuri N, Danneberg P et al (1957) Fluorinated pyrimidines, a new class of tumor-inhibitory compounds. Nature 179:663–666

    Article  PubMed  CAS  Google Scholar 

  63. Chu E (2007) Clinical colorectal cancer: “ode to 5-fluorouracil”. Clin Colorectal Cancer 6:609

    Article  Google Scholar 

  64. Grem JL, Chabner BA, Ryan DP et al (2011) 5-fluoropyrimidines. In: Chabner BA, Longo DL (eds) Cancer chemotherapy and biotherapy: principles and practice. Lippincott Williams & Wilkins, Philadelphia, pp 139–170

    Google Scholar 

  65. Nord LD, Stolfi RL, Martin DS (1992) Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA. Biochem Pharmacol 43:2543–2549

    Article  PubMed  CAS  Google Scholar 

  66. Rich TA, Shepard RC, Mosley ST (2004) Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol 22:2214–2232

    Article  PubMed  CAS  Google Scholar 

  67. Wisniewska-Jarosinska M, Sliwinski T, Kasznicki J et al (2010) Cytotoxicity and genotoxicity of capecitabine in head and neck cancer and normal cells. Mol Biol Rep 38:3679–3688

    Article  PubMed  CAS  Google Scholar 

  68. Pivot X, Chamorey E, Guardiola E et al (2003) Phase I and pharmacokinetic study of the association of capecitabine-cisplatin in head and neck cancer patients. Ann Oncol 14:1578–1586

    Article  PubMed  CAS  Google Scholar 

  69. Alexandre J, Kahatt C, Bertheault-Cvitkovic F et al (2007) A phase I and pharmacokinetic study of irofulven and capecitabine administered every 2 weeks in patients with advanced solid tumors. Invest New Drugs 25:453–462

    Article  PubMed  CAS  Google Scholar 

  70. Townsley C, Oza A, Tang P et al (2008) Expanded phase I study of vorinostat (VOR) in combination with capecitabine (CAP) in patients (pts) with advanced solid tumors. In: ASCO Annual Meeting, McCormick Place, Chicago

    Google Scholar 

  71. Bajetta E, Di Bartolomeo M, Buzzoni R et al (2007) Uracil/ftorafur/leucovorin combined with irinotecan (TEGAFIRI) or oxaliplatin (TEGAFOX) as first-line treatment for metastatic colorectal cancer patients: results of randomised phase II study. Br J Cancer 96:439–444

    Article  PubMed  CAS  Google Scholar 

  72. Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215–237

    Article  PubMed  CAS  Google Scholar 

  73. Gräslund A, Sahlin M, Sjöberg BM (1985) The tyrosyl free radical in ribonucleotide reductase. Environ Health Perspect 64:139–149

    PubMed  Google Scholar 

  74. Cummins PL, Gready JE (2001) Energetically most likely substrate and active-site protonation sites and pathways in the catalytic mechanism of dihydrofolate reductase. J Am Chem Soc 123:3418–3428

    Article  PubMed  CAS  Google Scholar 

  75. Bertino JR (1993) Karnofsky memorial lecture. Ode to methotrexate. J Clin Oncol 11:5–14

    PubMed  CAS  Google Scholar 

  76. Falco EA, Goodwin LG, Hitchings GH et al (1951) 2:4-diaminopyrimidines – a new series of antimalarials. Br J Pharmacol Chemother 6:185–200

    Article  PubMed  CAS  Google Scholar 

  77. Roth B, Falco E, Hitchings G et al (1962) 5-Benzyl-2,4-diaminopyrimidines as antibacterial agents. I. Synthesis and antibacterial activity in vitro. J Med Pharm Chem 91:1103–1123

    Article  PubMed  CAS  Google Scholar 

  78. Bolin JT, Filman DJ, Matthews DA et al (1982) Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate. J Biol Chem 257:13650–13662

    PubMed  CAS  Google Scholar 

  79. Li WW, Waltham M, Tong W et al (1993) Increased activity of gamma-glutamyl hydrolase in human sarcoma cell lines: a novel mechanism of intrinsic resistance to methotrexate (MTX). Adv Exp Med Biol 338:635–638

    Article  PubMed  CAS  Google Scholar 

  80. Rodenhuis S, McGuire JJ, Narayanan R et al (1986) Development of an assay system for the detection and classification of methotrexate resistance in fresh human leukemic cells. Cancer Res 46:6513–6519

    PubMed  CAS  Google Scholar 

  81. Waltham MC, Li WW, Gritsman H et al (1997) gamma-Glutamyl hydrolase from human sarcoma HT-1080 cells: characterization and inhibition by glutamine antagonists. Mol Pharmacol 51:825–832

    PubMed  CAS  Google Scholar 

  82. Widemann BC, Balis FM, Kim A et al (2010) Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol 28:3979–3986

    Article  PubMed  CAS  Google Scholar 

  83. Nelson R (2012) FDA approves glucarpidase to reduce toxic methotrexate levels. http://www.medscape.com; http://www.medscape.com/viewarticle/757023. Accessed 14 Apr 2012

  84. Jones TR, Calvert AH, Jackman AL et al (1981) A potent antitumour quinazoline inhibitor of thymidylate synthetase: synthesis, biological properties and therapeutic results in mice. Eur J Cancer 17:11–19

    PubMed  CAS  Google Scholar 

  85. Matherly LH, Taub JW, Ravindranath Y et al (1995) Elevated dihydrofolate reductase and impaired methotrexate transport as elements in methotrexate resistance in childhood acute lymphoblastic leukemia. Blood 85:500–509

    PubMed  CAS  Google Scholar 

  86. Jackman AL, Calvert AH (1995) Folate-based thymidylate synthase inhibitors as anticancer drugs. Ann Oncol 6:871–881

    PubMed  CAS  Google Scholar 

  87. Galetta D, Giotta F, Rosati G et al (2005) Carboplatin in combination with raltitrexed in recurrent and metastatic head and neck squamous cell carcinoma: a multicentre phase II study of the Gruppo Oncologico Dell’Italia Meridionale (G.O.I.M.). Anticancer Res 25:4445–4449

    PubMed  CAS  Google Scholar 

  88. Curtin NJ, Hughes AN (2001) Pemetrexed disodium, a novel antifolate with multiple targets. Lancet Oncol 2:298–306

    Article  PubMed  CAS  Google Scholar 

  89. Adjei AA (2004) Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 10:4276s–4280s

    Article  PubMed  CAS  Google Scholar 

  90. Argiris A, Karamouzis MV, Gooding WE et al (2011) Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. J Clin Oncol 29:1140–1145

    Article  PubMed  CAS  Google Scholar 

  91. Gangjee A, Jain HD, Kurup S (2007) Recent advances in classical and non-classical antifolates as antitumor and antiopportunistic infection agents: part I. Anticancer Agents Med Chem 7:524–542

    Article  PubMed  CAS  Google Scholar 

  92. Xia W, Low PS (2010) Folate-targeted therapies for cancer. J Med Chem 53:6811–6824

    Article  PubMed  CAS  Google Scholar 

  93. Wouters A, Pauwels B, Lardon F et al (2010) In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells. BMC Cancer 10:441

    Article  PubMed  CAS  Google Scholar 

  94. Avallone A, Di Gennaro E, Bruzzese F et al (2007) Synergistic antitumour effect of raltitrexed and 5-fluorouracil plus folinic acid combination in human cancer cells. Anti-Cancer Drugs 18:781–791

    Article  PubMed  CAS  Google Scholar 

  95. Wilson L, Jordan MA (1995) Microtubule dynamics: taking aim at a moving target. Chem Biol 2:569–573

    Article  PubMed  CAS  Google Scholar 

  96. Caplow M, Fee L (2003) Concerning the chemical nature of tubulin subunits that Cap and stabilize microtubules. Biochemistry 42:2122–2126

    Article  PubMed  CAS  Google Scholar 

  97. Mollinedo F, Gajate C (2003) Microtubules, microtubule-interfering agents and apoptosis. Apoptosis 8:413–450

    Article  PubMed  CAS  Google Scholar 

  98. Mitchison T, Kirschner M (1984) Dynamic instability of microtubule growth. Nature 312:237–242

    Article  PubMed  CAS  Google Scholar 

  99. Waterman-Storer CM, Salmon ED (1997) Microtubule dynamics: treadmilling comes around again. Curr Biol 7:R369–R372

    Article  PubMed  CAS  Google Scholar 

  100. Rapidis A, Sarlis N, Lefebvre J-L et al (2008) Docetaxel in the treatment of squamous cell carcinoma of the head and neck. Ther Clin Risk Manag 4:865–886

    PubMed  CAS  Google Scholar 

  101. Jordan MA, Kamath K (2007) How do microtubule-targeted drugs work? An overview. Curr Cancer Drug Targets 7:730–742

    Article  PubMed  CAS  Google Scholar 

  102. Checchi PM, Nettles JH, Zhou J et al (2003) Microtubule-interacting drugs for cancer treatment. Trends Pharmacol Sci 24:361–365

    Article  PubMed  CAS  Google Scholar 

  103. Singer WD, Jordan MA, Wilson L et al (1989) Binding of vinblastine to stabilized microtubules. Mol Pharmacol 36:366–370

    PubMed  CAS  Google Scholar 

  104. Skoufias DA, Wilson L (1992) Mechanism of inhibition of microtubule polymerization by colchicine: inhibitory potencies of unliganded colchicine and tubulin-colchicine complexes. Biochemistry 31:738–746

    Article  PubMed  CAS  Google Scholar 

  105. Jordan MA, Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4:253–265

    Article  PubMed  CAS  Google Scholar 

  106. Safa AR (2004) Identification and characterization of the binding sites of P-glycoprotein for multidrug resistance-related drugs and modulators. Curr Med Chem Anticancer Agents 4:1–17

    Article  PubMed  CAS  Google Scholar 

  107. Skwarczynski M, Hayashi Y, Kiso Y (2006) Paclitaxel prodrugs: toward smarter delivery of anticancer agents. J Med Chem 49:7253–7269

    Article  PubMed  CAS  Google Scholar 

  108. Kingston DGI (2009) Tubulin-interactive natural products as anticancer agents (1). J Nat Prod 72:507–515

    Article  PubMed  CAS  Google Scholar 

  109. Ndungu JM, Lu YJ, Zhu S et al (2010) Targeted delivery of paclitaxel to tumor cells: synthesis and in vitro evaluation. J Med Chem 53:3127–3132

    Article  PubMed  CAS  Google Scholar 

  110. Makarov AA, Tsvetkov PO, Villard C et al (2007) Vinflunine, a novel microtubule inhibitor, suppresses calmodulin interaction with the microtubule-associated protein STOP. Biochemistry 46:14899–14906

    Article  PubMed  CAS  Google Scholar 

  111. Ma Y, Zhao N, Liu G (2011) Conjugate (MTC-220) of muramyl dipeptide analogue and paclitaxel prevents both tumor growth and metastasis in mice. J Med Chem 54:2767–2777

    Article  PubMed  CAS  Google Scholar 

  112. Burtness BA, Manola J, Axelrod R et al (2008) A randomized phase II study of ixabepilone (BMS-247550) given daily x 5 days every 3 weeks or weekly in patients with metastatic or recurrent squamous cell cancer of the head and neck: an Eastern Cooperative Oncology Group study. Ann Oncol 19:977–983

    Article  PubMed  CAS  Google Scholar 

  113. Lee J-L, Ryu M-H, Chang HM et al (2007) A phase II study of docetaxel as salvage chemotherapy in advanced gastric cancer after failure of fluoropyrimidine and platinum combination chemotherapy. Cancer Chemother Pharmacol 61:631–637

    Article  PubMed  CAS  Google Scholar 

  114. Manning G, Whyte DB, Martinez R et al (2002) The protein kinase complement of the human genome. Science 298:1912–1934

    Article  PubMed  CAS  Google Scholar 

  115. Haroon Z, Peters KG, Greenberg CS et al (1999) Angiogenesis and blood flow in the solid tumors. In: Teicher BA (ed) Antiangiogenic agents in cancer therapy, 1st edn. Humana Press, Totowa, pp 3–22

    Chapter  Google Scholar 

  116. Madhusudan S, Ganesan TS (2004) Tyrosine kinase inhibitors in cancer therapy. Clin Biochem 37:618–635

    Article  PubMed  CAS  Google Scholar 

  117. Shawver LK, Lipson KE, Fong AT et al (2002) Receptor tyrosine kinases in angiogenesis. In: Fan T-PD, Kohn EC (eds) The new angiotherapy. Humana Press, Totowa, pp 409–452

    Google Scholar 

  118. Folkman J (2007) Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov 6:273–286

    Article  PubMed  CAS  Google Scholar 

  119. Rak J, Yu J, Klement G et al (2000) Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Investig Dermatol Symp Proc 5:24–33

    Article  PubMed  CAS  Google Scholar 

  120. Han L, Lorincz AM, Sukumar S (2008) Regulation of angiogenesis in cancer and its therapeutic implications. In: Teicher BA, Ellis LM (eds) Antiangiogenic agents in cancer therapy. Humana Press, Totowa, pp 331–352

    Chapter  Google Scholar 

  121. Cunningham MP, Thomas H, Marks C et al (2008) Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells. Int J Oncol 33:1107–1113

    PubMed  CAS  Google Scholar 

  122. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739

    Article  PubMed  CAS  Google Scholar 

  123. Moyer JD, Barbacci EG, Iwata KK et al (1997) Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res 57:4838–4848

    PubMed  CAS  Google Scholar 

  124. Rusnak DW, Lackey K, Affleck K et al (2001) The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 1:85–94

    PubMed  CAS  Google Scholar 

  125. Wilhelm S, Carter C, Lynch M et al (2006) Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 5:835–844

    Article  PubMed  CAS  Google Scholar 

  126. Liao JJ-L (2007) Molecular recognition of protein kinase binding pockets for design of potent and selective kinase inhibitors. J Med Chem 50:409–424

    Article  PubMed  CAS  Google Scholar 

  127. Huse M, Kuriyan J (2002) The conformational plasticity of protein kinases. Cell 109:275–282

    Article  PubMed  CAS  Google Scholar 

  128. Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, Shewchuk L (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652–6659

    Article  PubMed  CAS  Google Scholar 

  129. Bishop AC (2004) A hot spot for protein kinase inhibitor sensitivity. Chem Biol 11:587–589

    Article  PubMed  CAS  Google Scholar 

  130. Cherry M, Williams D (2004) Recent kinase and kinase inhibitor X-ray structures: mechanisms of inhibition and selectivity insights. Curr Med Chem 11:663–673

    Article  PubMed  CAS  Google Scholar 

  131. Stamos J, Sliwkowski MX, Eigenbrot C (2002) Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 277:46265–46272

    Article  PubMed  CAS  Google Scholar 

  132. Lombardo LJ, Lee FY, Chen P et al (2004) Discovery of N-(2-Chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47:6658–6661

    Article  PubMed  CAS  Google Scholar 

  133. Sharafinski ME, Ferris RL, Ferrone S et al (2010) Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 32:1412–1421

    Article  PubMed  Google Scholar 

  134. Elferink LA, Resto VA (2011) Receptor-tyrosine-kinase-targeted therapies for head and neck cancer. J Signal Transduct 2011:1–11

    Article  CAS  Google Scholar 

  135. Bao L, Gorin MA, Zhang M et al (2009) Preclinical development of a bifunctional cancer cell homing, PKC inhibitory peptide for the treatment of head and neck cancer. Cancer Res 69:5829–5834

    Article  PubMed  CAS  Google Scholar 

  136. Hassoun EA, Cearfoss J, Spildener J (2010) Dichloroacetate- and trichloroacetate-induced oxidative stress in the hepatic tissues of mice after long-term exposure. J Appl Toxicol 30:450–456

    PubMed  CAS  Google Scholar 

  137. Li W, James MO, McKenzie SC et al (2011) Mitochondrion as a novel site of dichloroacetate biotransformation by glutathione transferase zeta 1. J Pharmacol Exp Ther 336:87–94

    Article  PubMed  CAS  Google Scholar 

  138. Warburg O (1956) On the origin of cancer cells. Science 123:309–314

    Article  PubMed  CAS  Google Scholar 

  139. Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994

    Article  PubMed  CAS  Google Scholar 

  140. Fujita K, Sano D, Kimura M et al (2007) Anti-tumor effects of bevacizumab in combination with paclitaxel on head and neck squamous cell carcinoma. Oncol Rep 18:47–51

    PubMed  CAS  Google Scholar 

  141. Chen Y, Cairns R, Papandreou I et al (2009) Oxygen consumption can regulate the growth of tumors, a new perspective on the Warburg effect. PLoS One 4:e7033

    Article  PubMed  CAS  Google Scholar 

  142. Cairns RA, Papandreou I, Sutphin PD et al (2007) Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy. Proc Natl Acad Sci U S A 104:9445–9450

    Article  PubMed  CAS  Google Scholar 

  143. Sun W, Zhou S, Chang SS et al (2009) Mitochondrial mutations contribute to HIF1 accumulation via increased reactive oxygen species and up-regulated pyruvate dehydrogenease kinase 2 in head and neck squamous cell carcinoma. Clin Cancer Res 15:476–484

    Article  PubMed  CAS  Google Scholar 

  144. Dhar S, Lippard SJ (2009) Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Proc Natl Acad Sci U S A 106:22199–22204

    Article  PubMed  CAS  Google Scholar 

  145. dos Santos LV, Carvalho AL (2011) Bcl-2 targeted-therapy for the treatment of head and neck squamous cell carcinoma. Recent Pat Anticancer Drug Discov 6:45–57

    Article  PubMed  Google Scholar 

  146. Kang MH, Reynolds CP (2009) Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res 15:1126–1132

    Article  PubMed  CAS  Google Scholar 

  147. Wang G, Nikolovska-Coleska Z, Yang C-Y et al (2006) Structure-based design of potent small-molecule inhibitors of anti-apoptotic Bcl-2 proteins. J Med Chem 49:6139–6142

    Article  PubMed  CAS  Google Scholar 

  148. Ashimori N, Zeitlin BD, Zhang Z et al (2009) TW-37, a small-molecule inhibitor of Bcl-2, mediates S-phase cell cycle arrest and suppresses head and neck tumor angiogenesis. Mol Cancer Ther 8:893–903

    Article  PubMed  CAS  Google Scholar 

  149. Oltersdorf T, Elmore SW, Shoemaker AR et al (2005) An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 435:677–681

    Article  PubMed  CAS  Google Scholar 

  150. Barelier S, Pons J, Marcillat O et al (2010) Fragment-based deconstruction of Bcl-x L inhibitors. J Med Chem 53:2577–2588

    Article  PubMed  CAS  Google Scholar 

  151. Kutzki O, Park HS, Ernst JT et al (2002) Development of a potent Bcl-x L antagonist based on α-helix mimicry. J Am Chem Soc 124:11838–11839

    Article  PubMed  CAS  Google Scholar 

  152. National Institutes of Health, US National Library of Medicine, US Department of Health and Human Services (2012) Home – ClinicalTrials.gov. http://clinicaltrials.gov/. Accessed 15 Apr 2012

  153. Longo DL (2012) Approach to the patient with cancer. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J (eds) Harrison’s principles of internal medicine, 18th edn. McGraw-Hill, New York, pp 646–654

    Google Scholar 

  154. Gourin C (2011) Taking action-comprehensive treatment considerations. In: Shockney L, Shapiro G (eds) Patients’ guide to head and neck cancer. Jones & Bartlett Learning, Sudbury, pp 41–87

    Google Scholar 

  155. Bernier J, Cooper JS (2005) Chemoradiation after surgery for high-risk head and neck cancer patients: how strong is the evidence? Oncologist 10:215–224

    Article  PubMed  Google Scholar 

  156. Lu C, Kiss M (2004) Systemic therapy for recurrent and metastatic diseases. In: Harrison L, Sessions R, Hong W (eds) Head and neck cancer: a multidisciplinary approach. Lippincott Williams & Wilkins, Philadelphia, pp 919–925

    Google Scholar 

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Authors and Affiliations

  1. Department of Biopharmaceutical Sciences, Roosevelt University College of Pharmacy, Schaumburg, IL, 60173, USA

    Sonali Kurup Ph.D., Kirk E. Dineley Ph.D., Ruth Adewuya M.D. & Lawrence A. Potempa Ph.D.

  2. Department of Anatomy, Midwestern University, Downers Grove, IL, 60515, USA

    Latha M. Malaiyandi Ph.D.

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  1. Sonali Kurup Ph.D.
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    James A. Radosevich

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Kurup, S., Dineley, K.E., Malaiyandi, L.M., Adewuya, R., Potempa, L.A. (2013). Drugs to Treat Head and Neck Cancers: Mechanisms of Action. In: Radosevich, J. (eds) Head & Neck Cancer: Current Perspectives, Advances, and Challenges. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5827-8_28

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