Do you want to buy antibiotics online without prescription? http://buyantibiotics24h.com/ - This is pharmacy online for you!

Doi:10.1016/s0305-7372(03)00116-6

CANCER TREATMENT REVIEWS 2003; 29: 515–523doi:10.1016/S0305-7372(03)00116-6 Classification of anticancer drugs—a newsystem based on therapeutic targets Enrique Espinosa, Pilar Zamora, Jaime Feliu andManuel Gonza´lez Baro´n Servicio de Oncologı´a Me´dica, Hospital La Paz, Madrid, Spain The arrival of a great number of new antineoplastic agents has made it necessary to reclassify all of them. Anticancer drugsmay act at different levels: cancer cells, endothelium, extracellular matrix, the immune system or host cells. The tumour cellcan be targeted at the DNA, RNA or protein level. Most classical chemotherapeutic agents interact with tumour DNA,whereas monoclonal antibodies and small molecules are directed against proteins. The endothelium and extracellular matrixmay be affected also by specific antibodies and small molecules.
2003 Elsevier Ltd. All rights reserved.
Key words: Antineoplastic drugs; chemotherapy; classification; monoclonal antibodies; new drugs; small molecules.
therapy. A global view is important to remember the drugs and their mechanism of action and also forteaching purposes. On the other hand, multidrug Most patients with advanced solid tumours still die regimens usually include drugs belonging to differ- of their disease. For this reason, new effective drugs ent groups to increase efficacy and decrease toxicity, are needed and, in fact, new agents appear every at least whenever classical chemotherapy is con- few months. The last years have witnessed the ap- pearance of a great number of anticancer drugs, We hereby propose a new drug classification many of which cannot be included in a simple based on the kind of target. Drugs may be directed at classification. Classically, anticancer drugs were tumour cells or other elements involved in carcino- grouped as chemotherapy, hormonal therapy and genesis, i.e., the endothelium and extracellular ma- immunotherapy. Chemotherapy included a number trix, and the immune system. Potential host cells a families defined by both their chemical structure such as the bone may also be targeted. Table 2 shows and mechanism of action: alkylating agents, antibi- all these groups. The target may be located at the otics, antimetabolites, topoisomerase I and II inhib- DNA, RNA or protein level. In general, chemother- itors, mitosis inhibitors, platinum compounds and apy acts at the DNA level in tumour cells, whereas others (Table 1). However, the group ‘‘others’’ has monoclonal antibodies and small molecules interact expanded so much that this classification is no with proteins, either in the tumour cells or in other elements. Antisense oligonucleotides are the main A drug classification serves two main objectives: the achievement of a comprehensive view of the It is beyond our scope to describe the mechanism available drugs and the design of combination of action of every drug in detail. In some cases, theprecise mechanism is still uncertain. Besides, someof the compounds we shall mention may not go Correspondence to: Enrique Espinosa, Servicio de OncologııaMedica, Hospital La Paz, Po de la Castellana, 261-28046 Madrid, beyond phase III trials. We would like to offer a useful tool to classify both available and forthcoming 0305-7372/$ - see front matter C 2003 ELSEVIER LTD. ALL RIGHTS RESERVED.
Classical classification of anticancer drugs The drugs may act on DNA either by breaking the helix itself, interfering with DNA-related proteins, or modifying the expression of specific genes. Most classical anticancer agents have one of these mech- anism of action, and new drugs are being incorpo- rated every year (Tables 3a and 3b).
Anti-estrogensAnti-androgensLH–RH analogsAnti-aromatase agents Alkylating agents were the first compounds identi- fied to be useful in cancer. They form a variety ofinterstrand cross-links called adducts, that alterDNA structure or function. The most common site ofalkylation is the N-7 position of guanine, but it anticancer drugs, even when a global classification varies depending on the family of drugs. Alkylators might have some exceptions or could be very sche- belong to one of several families: nitrogen mustards, matic in some instances. We have restricted the in- nitrosoureas, triazenes, platinum compounds and clusion of new compounds to those under clinical Non-specificDNA break: chemotherapyDNA-related proteins: chemotherapySpecificHormonal therapy, retinoidsInterferon aGene therapy Membrane receptorsExtracellular domain: MoAbIntracellular domain: small moleculesCytoplasmIntracellular pathways: small moleculesTubulin: chemotherapy * In this group, antisense therapy might also be developed in the future.
MoAb, monoclonal antibodies and MMPs, metalloproteinases.
C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Drugs directed against tumour DNA: chemotherapy Cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine Anthracyclines: doxorubicin, epirubicin, idarubicin, mitoxantrone Fluoropyrimidines (5FU, ftorafur, capecitabine) and raltitrexed Adenosine analogs: deoxycoformycin, cladribine Topo, topoisomerase; DHFR, dihydrofolic reductase; TS, thymidilate synthase; FTRG, formyltransferase ribonucleotide glycinamide;RR, ribonucleotide reductase; £, inhibition.
Drugs directed against tumour DNA: modifiers of specific genes Union to specific receptors, transcriptional Antiestrogens: tamoxifen, fulvestrantAntiandrogens: flutamide, There are some new experimental agents among the alkylators, such as bendamustine or tira- compound, has activity in lymphomas (2–4). Tira- Topoisomerase I and II inhibitors, antimetabolites pazamine is activated in hypoxic cells and en- and ecteinascidin could be grouped together as hances the cytotoxicity of radiation, cisplatin and drugs directed at protein–DNA complexes, because the taxanes (5,6). It has been used for the treatment they do not bind directly to DNA (1).
of non-small cell lung cancer and head and neck The anthracyclines (doxorubicin and their analogs epirubicin and idarubicin) inhibit topoisomerase II Some antibiotics also belong to the group of al- and form free radicals. Mitoxantrone, although kylators: bleomycin and mitomycin C. The anthra- synthetic, can be regarded as an anthracycline. The cyclines have a different mechanism of action and main epipodophillotoxin, etoposide, also inhibits Topoisomerase I transiently breaks a single strand specific genes does not mean that this activity is re- of DNA during DNA replication, thereby reducing torsional strain. Inhibitors of this enzyme derive Gene therapy also targets specific genes, but in from camptothecin. This family has grown rapidly this case the mechanism of action differs substan- in recent years. In addition to topotecan and irino- tially from that of the hormones. Genes are intro- tecan, new experimental agents could join the family duced in vectors to either repair or block specific in the near future, for instance rubitecan (7,8), lur- On the other hand, antimetabolites interfere with enzymes that contribute to DNA synthesis. In this group we have antifolates, fluoropyrimidines, ral-titrexed, cytarabine, gemcitabine, and adenosineanalogs A number of anticancer drugs such as the fluoro- Pemetrexed has recently been incorporated to the pyrimidines and platinum compounds interfere clinic. This drug shows activity in non-small cell with RNA synthesis. However, they mainly act by lung cancer, breast cancer, mesothelioma and head binding to DNA. The major representatives in this and neck tumours (13–15). Table 3a indicates the group are antisense oligonucleotides. These mole- target enzyme for each antimetabolite.
cules are directed against specific mRNAs. The A marine derivative, ecteinascidin or ET-743, has mRNAs of bcl-2, myb, p53, mdm2, Her-2 and a unique mechanism of action. Formerly thought to methyltransferase-1 have been targeted with these be an alkylator, recent investigations have shown oligonucleotides (19–25). The synthesis of antisense that it blocks transcriptional factors—such as TC- oligonucleotides is complex and improved methods NER or Sp1—and seems to affect RNA polymerase to deliver the compound in the target are needed II-mediated gene transcription (16). Ecteinascidin (25–27). These problems are delaying the develop- has been used in patients with refractory sarcomas ment of antisense therapy. Another drug in this group is angiozyme, which blocks the mRNA of thevascular endothelial growth factor (28,29).
The classical representatives in this group are hor- monal agents. Steroids, antihormones and retinoidsshare a common mechanism of action because they In the last decade, a great number of compounds modify the expression of specific genes (Table 3b).
have joined this group, mainly monoclonal anti- Steroid hormones, such as glucocorticoids, bind to bodies and small molecules. They are all very spe- receptor proteins in the cytoplasm or nucleus to cific and their effect is cytostatic rather than form a hormone–receptor complex. This complex cytotoxic. They can bind to membrane receptors or has the capacity to activate regulatory sequences in DNA. Antioestrogens and antiandrogens block re-ceptors of oestrogens and androgens, respectively.
These receptors are ligand-regulated transcriptionfactors located in the nucleus. The antiaromatase agents anastrozole, letrozole and exemestane act inthe cytoplasm, mainly in tumour cells but also in Two groups may be distinguished: monoclonal an- tibodies and small molecules. The former block the LH–RH analogs bind to a specific membrane re- extracellular domain of the receptor, whereas the ceptor linked to a G protein in the hypothalamus.
latter cross the membrane and inhibit the intracel- However, the ultimate effect takes place in the tu- lular domain, usually a tyrosin-kinase (Table 4). The mour cell, and for this reason the analogs should be term ‘‘small molecule’’ may be misleading, because grouped together with the other hormones (Table 2).
classical chemotherapy compounds are also small in The antitumour activity of interferon a appears to size, but it allows the distinction with monoclonal be due to a combination of direct antiproliferative as well as indirect immune-mediated effects. It has also The first antitumour antibodies were directed antiangiogenic effects mediated through interferon against lymphoid antigens, such as CD20 and CD52.
gamma (18). Thus, this drug may appear in several Some of them combine the antibody with an isotope groups in our classification. Activity over some to increase efficacy (30–34). These highly active C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Drugs directed against the membrane receptors of one of the most active drugs in chronic myeloidleukaemia and in gastrointestinal stromal tumours.
Other drugs are aimed at the ras or the phosphati- compounds have expanded the possibilities of dyl-inositol pathways, as well as the proteasome and treatment in patients with refractory lymphomas the cyclin-dependent kinases. With few exceptions, and are now being evaluated in first- line therapy.
these agents are now in the first steps of clinical New antibodies are under investigation at this mo- development. Table 5A includes some of them.
ment: the anti-CD33 gemtuzumab and the anti-CD22 Ras is activated by farnesyl transferase. Once ac- tivated, the ras protein activates raf and MEK.
The main antibodies for carcinomas are trast- Farnesyl-transferase inhibitors act as false metabo- uzumab (37,38) and cetuximab (39,40). Trastuzumab lites of this enzyme, for instance, lonafarnib and is available for the treatment of Her-2 positive breasttumours, either alone or in combination with che-motherapy, and new possible indications are being Drugs acting in the cytoplasm of the tumour cell studied. On the other hand, an anti-MUC antibody (A) Inhibitors of intracellular pathways in tumour cells could be used in the future as a vaccine in patients Small molecules bind to receptors of the epider- mal growth factor family. Some of them are specific for EGFR (Her-1), such as gefitinib (ZD-1839) (42–43) or OSI- 774 (44). Gefitinib is the only member of the group that has been tested in phase III trials so far. Itobtains responses as single agent in non-small cell lung cancer and head and neck tumours. PKI-166 inhibits both Her-1 and Her-2 (45). CI-1033 is an ir- reversible inhibitor of all the epidermal growth fac- Cyclin-dependent kinasesFlavopiridol, CYC-202 A number of metabolic pathways carry proliferationsignals to the nucleus. Although we shall comment on them separately, all of them are interrelated.
These pathways are activated by growth factors and a few of them have been targeted with specific drugs. Figure 1 shows a scheme of the pathways that are being used in cancer therapeutics. The better known drug in this group is imatinib, which inhibits the tyrosine kinase of bcr/abl and c-kit (47,48). It is R115,777 (49,50). There are also inhibitors of raf Drugs directed against the endothelium and the (BAY 43-9006) and MEK (CI-1040) (51,52).
The phosphatidyl-inositol pathway starts with the serin threonine PI-3K, which is connected with mTOR through PKB/Akt. MTOR controls apoptosis and is related to the balance between cellular ca- tabolism and anabolism. Specific drugs in this pathway are rapamycin derivatives such as CCI-779, which inhibits mTOR (53). PI-3K is also connectedwith protein-kinase C, a family of enzymes that ac- tivate the transcription factor NF-jB. Protein-kinase C is inhibited by bryostatin (54,55) and PKC-412 (56).
The proteasome—a group of enzymes that de- grade proteins—is inhibited by PS-341 (57,58). On the other hand, the chaperones exert the oppositefunction, i.e., they protect proteins from degrada-tion. Geldanamycin derivatives such as 17-AAG in-crease the degradation of one of the main chaperones, heat shock protein 90 (59,60).
Finally, flavopiridol and CYC-202 (a roscovitine The main endothelial growth factors—vascular en- derivative) inhibit cyclin-dependent kinases (61,62).
dothelial growth factor (VEGF)and basic fibroblast The staurosporin compound UCN-01 inhibits CDK-2 growth factor (bFGF)—are inhibited by thalido- mide (68,69). Another inhibitor specific for VEGF iscarboxyamido-triazole (70,71). Interferon a also re-duces VEGF synthesis in tumour cells, but this effectseems to be mediated through interferon gamma (18,72,73). Cyclo-oxygenase 2 may stimulate endo-thelial growth, hence one of the possible mecha- Tubulin contributes to the maintenance of cell shape, nisms of action of COX-2 inhibitors (74,75).
intracellular transport and mitosis, so drugs inter- With regard to VEGF receptors, the monoclonal fering with tubulin are grouped here in the present antibody bevacizumab binds to all of these receptors classification. The vinca alkaloids bind to specific (70,76,77). SU-5416 is a small molecule binding to the sites on tubulin and prevent polymerization of tu- tyrosine kinase of VEGFR-1 and VEGFR-2 (70,78). It bulin dimers, thereby disrupting the formation of also binds to platelet derived growth factor receptor microtubules. The taxanes have a different binding and c-kit. Clinical trials with SU-5416 in haemato- site and stabilize microtubules: this unusual stability logical malignancies and colorectal cancer have been inhibits the normal reorganization of the microtu- initiated. Another small molecule, SU-6668, binds to bule network. Oral formulations of taxanes will VEGFR, bFGFR and platelet derived growth factor improve convenience if they prove to be as active as the parent drugs (65). The epothilones are a new Finally, combretastatin inhibits the mitotic spin- group of tubulin-stabilizing agents. Preclinical dle in the endothelium and induces apoptosis studies have shown promising activity of these compounds, but the results of phase II and III clin-ical trials are not still available (66,67). Table 5Bshows all these drugs.
Activation of MMPs in tumours facilitates invasionand is an essential step in angiogenesis. MMPs may also stimulate the release of VEGF, bFGF and insulin growth factor. A number of MMP inhibitors arecurrently under clinical investigation (83). Most of Compounds directed against the endothelium in- them are synthetic inhibitors of the enzyme activity, hibit either endothelial growth factors or the recep- such as marimastat (84–86), prinomastat or BAY 12- tors of such factors. On the other hand, most drugs 9566 (83). Tetracycline derivatives such as neovastat acting in the extracellular matrix inhibit metallo- also down regulate the production, inhibit the acti- proteinases (MMPs). They all have antiangiogenic vation and increase the degradation of MMPs C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S Apart from MMPs, other elements of the extra- 7. Giovanella BC, Stehlin JS, Hinz HR, Kozielski AJ, Harris NJ, cellular matrix could be targeted as a form of anti- Vardeman DM. Preclinical evaluation of the anticancer cancer therapy, for instance, integrin, endothelin and (Rubitecan). Int J Oncol 2002; 20(1): 81–88.
8. Schoffski P, Herr A, Vermorken JB, Van den Brande J, Beijnen pharmacological evaluation of rubitecan in non-pretreatedpatients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecinanalogue. Eur J Cancer 2002; 38(6): 807–813.
Some drugs are directed to organs that may harbour 9. Emerson DL, Bendele R, Brown E, Chiang S, Desjardins JP, Dihel LC, et al. Antitumor efficacy, pharmacokinetics, and tumour cells. At present, these only relate to agents biodistribution of NX 211: a low-clearance liposomal that inhibit bone cell function and the bone micro- formulation of lurtotecan. Clin Cancer Res 2000; 6(7): environment, such as bisphosphonates (91,92), os- teoprotogerin (93) and PTHRP antibodies. In the 10. Kehrer DF, Bos AM, Verweij J, Groen HJ, Loos WJ, future, more drugs could be developed to target Sparreboom A, et al. Phase I and pharmacologic study ofliposomal lurtotecan, NX 211: urinary excretion predicts hematologic toxicity. J Clin Oncol 2002; 20(5): 1222–1231.
Finally, cytokines such as interferon and inter- 11. Giles FJ, Cortes JE, Thomas DA, Garcia-Manero G, Faderl S, leukin 2 enhance the antitumour activity of the im- Jeha S, et al. Phase I and pharmacokinetic study of DX-8951f mune system and are already well known.
(exatecan mesylate), a hexacyclic camptothecin, on a daily-times-five schedule in patients with advanced leukemia. ClinCancer Res 2002; 8(7): 2134–2141.
12. Minami H, Fujii H, Igarashi T, Itoh K, Tamanoi K, Oguma T, et al. Phase I and pharmacological study of a newcamptothecin derivative, exatecan mesylate (DX-8951f),infused over 30 min every three weeks. Clin Cancer Res 2001; A great number of anticancer agents are under clinical investigation at this moment. Some of them 13. Calvert H, Bunn Jr PA. Future directions in the development belong to classic groups of chemotherapy, but others of pemetrexed. Semin Oncol 2002; 29(2 Suppl 5): 54–61.
14. Novello S, le Chevalier T. ALIMTA (pemetrexed disodium, are the first of new families of drugs. For clinicians, it LY231514, MTA): clinical experience in non-small cell lung is important to have the main groups in mind and, cancer. Lung Cancer 2001; 34(Suppl 4): S107–S109.
for this reason, we propose a classification that is 15. Pivot X, Raymond E, Laguerre B, Degardin M, Cals L, based on the target. The target may be located in the Armand JP, et al. Pemetrexed disodium in recurrent locally tumour cell or in other elements that interact with advanced or metastatic squamous cell carcinoma of the headand neck. Br J Cancer 2001; 85(5): 649–655.
the tumour cells (endothelium, extracellular matrix, 16. Scotto KW. ET-743: more than an innovative mechanism of immune system, host cells). We hope that this clas- action. Anticancer Drugs 2002; 13(Suppl 1): S3–S6.
sification will be able to incorporate new drugs 17. Delaloge S, Yovine A, Taamma A, Riofrio M, Brain E, Raymond E, et al. Ecteinascidin-743: a marine-derivedcompound in advanced, pretreated sarcoma patients—preliminary evidence of activity. J Clin Oncol 2001; 19(5):1248–1255.
18. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, andtoxicities. Oncologist 2001; 6(1): 34–55.
1. Hurley LH. DNA and its associated processes as targets for 19. Tolcher AW. Preliminary phase I results of G3139 (bcl-2 cancer therapy. Nat Rev Cancer 2002; 2(3): 188–200.
antisense oligonucleotide) therapy in combination with 2. Bremer K. High rates of long-lasting remissions after 5-day docetaxel in hormone-refractory prostate cancer. Semin bendamustine chemotherapy cycles in pre-treated low-grade Oncol 2001; 28(4 Suppl 15): 67–70.
non-Hodgkin’s-lymphomas. J Cancer Res Clin Oncol 2002; 20. Del Bufalo D, Cucco C, Leonetti C, Citro G, D’Agnano I, Benassi M, et al. Effect of cisplatin and c-myb antisense 3. Aivado M, Schulte K, Henze L, Burger J, Finke J, Haas R.
phosphorothioate oligodeoxynucleotides combination on a Bendamustine in the treatment of chronic lymphocytic human colon carcinoma cell line in vitro and in vivo. Br J leukemia: results and future perspectives. Semin Oncol 2002; 21. Strasberg Rieber M, Zangemeister-Wittke U, Rieber M. p53- 4. Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Independent induction of apoptosis in human melanoma Hoelzer D, et al. Bendamustine is effective in relapsed or cells by a bcl-2/bcl-xL bispecific antisense oligonucleotide.
refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol Clin Cancer Res 2001; 7(5): 1446–1451.
22. Wang H, Nan L, Yu D, Lindsey JR, Agrawal S, Zhang R. Anti- 5. Gandara DR, Lara Jr PN, Goldberg Z, Le QT, Mack PC, Lau tumor efficacy of a novel antisense anti-MDM2 mixed- DH, et al. Tirapazamine: prototype for a novel class of backbone oligonucleotide in human colon cancer models: therapeutic agents targeting tumor hypoxia. Semin Oncol p53-dependent and p53-independent mechanisms. Mol Med 6. Peters KB, Brown JM. Tirapazamine: a hypoxia-activated 23. Rait AS, Pirollo KF, Rait V, Krygier JE, Xiang L, Chang EH.
topoisomerase II poison. Cancer Res 2002; 62(18): 5248–5253.
Inhibitory effects of the combination of HER-2 antisense oligonucleotide and chemotherapeutic agents used for the metastatic breast cancer patients immunized with a synthetic treatment of human breast cancer. Cancer Gene Ther 2001; MUC1 peptide. Int J Cancer 1998; 76(6): 817–823.
42. Herbst RS, Kies MS. ZD1839 (Iressa) in non-small cell lung 24. Funato T, Kozawa K, Fujimaki S, Miura T, Kaku M. Increased cancer. Oncologist 2002; 7(Suppl 4): 9–15.
sensitivity to cisplatin in gastric cancer by antisense inhibition 43. Ranson M. ZD1839 (Iressa): for more than just non-small cell of the her-2/neu (c-erbB-2) gene. Chemotherapy 2001; 47(4): lung cancer. Oncologist 2002; 7(Suppl 4): 16–24.
44. Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, 25. Goffin J, Eisenhauer E. DNA methyltransferase inhibitors- Takimoto C, et al. Phase I and pharmacologic study of OSI- state of the art. Ann Oncol 2002; 13(11): 1699–1716.
774, an epidermal growth factor receptor tyrosine kinase 26. Henry SP, Geary RS, Yu R, Levin AA. Drug properties of inhibitor, in patients with advanced solid malignancies. J Clin second-generation antisense oligonucleotides: how do they measure up to their predecessors? Curr Opin Investig Drugs 45. Baker CH, Kedar D, McCarty MF, Tsan R, Weber KL, Bucana CD, et al. Blockade of epidermal growth factor receptor 27. Jansen B, Zangemeister-Wittke U. Antisense therapy for signaling on tumor cells and tumor-associated endothelial cancer—the time of truth. Lancet Oncol 2002; 3(11): 672–683.
cells for therapy of human carcinomas. Am J Pathol 2002; 28. Sandberg JA, Parker VP, Blanchard KS, Sweedler D, Powell JA, Kachensky A, et al. Pharmacokinetics and tolerability of 46. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW.
an antiangiogenic ribozyme (ANGIOZYME) in healthy Potential benefits of the irreversible pan-erbB inhibitor, CI- volunteers. J Clin Pharmacol 2000; 40(12 Pt 2): 1462–1469.
1033, in the treatment of breast cancer. Semin Oncol 2002; 29(3 29. Weng DE, Usman N. Angiozyme: a novel angiogenesis inhibitor. Curr Oncol Rep 2001; 3(2): 141–146.
47. Cohen MH, Moses ML, Pazdur R. Gleevec for the treatment 30. Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, of chronic myelogenous leukemia: US. Food and Drug Czuczman MS, Link BK, et al. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin’s lymphoma: approval, and orphan drug status. Oncologist 2002; 7(5): safety and efficacy of re-treatment. J Clin Oncol 2000; 18(17): 48. Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, 31. Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford Demetri G. Management of malignant gastrointestinal JA, et al. Multicenter phase II study of iodine-131 stromal tumours. Lancet Oncol 2002; 3(11): 655–664.
tositumomab for chemotherapy-relapsed/refractory low- 49. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming grade and transformed low-grade B-cell non-Hodgkin’s STI571 resistance with the farnesyl transferase inhibitor lymphomas. J Clin Oncol 2000; 18(6): 1316–1323.
SCH66336. Blood 2002; 100(3): 1068–1071.
32. Iodine-131 tositumomab (Bexxar) in relapsed/refractory non- 50. Karp JE, Kaufmann SH, Adjei AA, Lancet JE, Wright JJ, End Hodgkin’s lymphoma: Update from the 2001 American DW. Current status of clinical trials of farnesyltransferase Society of Hematology Meeting. Clin Lymphoma 2002; 2(4): inhibitors. Curr Opin Oncol 2001; 13(6): 470–476.
51. Hotte SJ, Hirte HW. BAY 43-9006: early clinical data in 33. Rai KR, Freter CE, Mercier RJ, Cooper MR, Mitchell BS, patients with advanced solid malignancies. Curr Pharm Des Stadtmauer EA, et al. Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received 52. Dancey JE. Agents targeting ras signaling pathway. Curr fludarabine. J Clin Oncol 2002; 20(18): 3891–3897.
34. Lundin J, Kimby E, Bjorkholm M, Broliden PA, Celsing F, 53. Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs 2002; 3(8): Hjalmar V, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first- 54. Brockstein B, Samuels B, Humerickhouse R, Arietta R, Fishkin line treatment for patients with B-cell chronic lymphocytic P, Wade J, et al. Phase II studies of bryostatin-1 in patients leukemia (B-CLL). Blood 2002; 100(3): 768–773.
with advanced sarcoma and advanced head and neck cancer.
35. Roboz GJ, Knovich MA, Bayer RL, Schuster MW, Seiter K, Invest New Drugs 2001; 19(3): 249–254.
Powell BL, et al. Efficacy and safety of gemtuzumab 55. Pfister DG, McCaffrey J, Zahalsky AJ, Schwartz GK, Lis E, ozogamicin in patients with poor-prognosis acute myeloid Gerald W, et al. A phase II trial of bryostatin-1 in patients with leukemia. Leukemia Lymphoma 2002; 43(10): 1951–1955.
metastatic or recurrent squamous cell carcinoma of the head 36. Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, and neck. Invest New Drugs 2002; 20(1): 123–127.
Sievers EL, et al. Antibody-targeted chemotherapy of older 56. Virchis A, Ganeshaguru K, Hart S, Jones D, Fletcher L, Wright patients with acute myeloid leukemia in first relapse using F, et al. A novel treatment approach for low grade Mylotarg (gemtuzumab ozogamicin). Leukemia 2002; 16(9): lymphoproliferative disorders using PKC412 (CGP41251), an inhibitor of protein kinase C. Hematol J 2002; 3(3): 131–136.
57. Adams J. Preclinical and clinical evaluation of proteasome combinations in metastatic breast cancer. Semin Oncol 2002; inhibitor PS-341 for the treatment of cancer. Curr Opin Chem 38. McKeage K, Perry CM. Trastuzumab: a review of its use in 58. Orlowski R, Stinchcombe E, Mitchell B, Shea T, Baldwin A, the treatment of metastatic breast cancer overexpressing Stahl S, et al. Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin 39. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer 2001; 37(Suppl 4): S16–S22.
59. Neckers L, Schulte TW, Mimnaugh E. Geldanamycin as a 40. Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, et al. Phase I study of anti-epidermal growth biochemical activity. Invest New Drugs 1999; 17(4): 361–373.
factor receptor antibody cetuximab in combination with 60. Nimmanapalli R, O’Bryan E, Bhalla K. Geldanamycin and its radiation therapy in patients with advanced head and neck analogue 17-allylamino-17-demethoxygeldanamycin lowers cancer. J Clin Oncol 2001; 19(13): 3234–3243.
Bcr-Abl levels and induces apoptosis and differentiation of 41. Reddish M, MacLean GD, Koganty RR, Kan-Mitchell J, Jones Bcr-Abl-positive human leukemic blasts. Cancer Res 2001; V, Mitchell MS, et al. Anti-MUC1 class I restricted CTLs in C L A S S I F I C A T I O N O F A N T I C A N C E R D R U G S 61. Schwartz GK, O’Reilly E, Ilson D, Saltz L, Sharma S, Tong W, monoclonal antibody bevacizumab. Oncology (Huntingt) 2001; et al. Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with 78. Stopeck A, Sheldon M, Vahedian M, Cropp G, Gosalia R, advanced solid tumors. J Clin Oncol 2002; 20(8): 2157–2170.
Hannah A. Results of a Phase I dose-escalating study of the 62. McClue SJ, Blake D, Clarke R, Cowan A, Cummings L, antiangiogenic agent, SU5416, in patients with advanced Fischer PM, et al. In vitro and in vivo antitumor properties of malignancies. Clin Cancer Res 2002; 8(9): 2798–2805.
the cyclin dependent kinase inhibitor CYC202 (R-roscovitine).
79. Fabbro D, Manley P. Su-6668. SUGEN. Curr Opin Investig Int J Cancer 2002; 102(5): 463–468.
63. Koh J, Kubota T, Migita T, Abe S, Hashimoto M, Hosoda Y, et 80. Hoekman K. SU6668, a multitargeted angiogenesis inhibitor.
al. UCN-01 (7-hydroxystaurosporine) inhibits the growth of Cancer J 2001; 7(Suppl 3): S134–S138.
human breast cancer xenografts through disruption of signal 81. Dowlati A, Robertson K, Cooney M, Petros WP, Stratford M, transduction. Breast Cancer 2002; 9(1): 50–54.
Jesberger J, et al. A phase I pharmacokinetic and translational 64. Senderowicz AM. The cell cycle as a target for cancer therapy: study of the novel vascular targeting agent combretastatin a-4 basic and clinical findings with the small molecule inhibitors phosphate on a single-dose intravenous schedule in patients flavopiridol and UCN-01. Oncologist 2002; 7(Suppl 3): 12–19.
with advanced cancer. Cancer Res 2002; 62(12): 3408–3416.
65. Rose WC, Long BH, Fairchild CR, Lee FY, Kadow JF.
82. Ohno T, Kawano K, Sasaki A, Aramaki M, Tahara K, Etoh T, Preclinical pharmacology of BMS-275183, an orally active et al. Antitumor and antivascular effects of AC-7700, a taxane. Clin Cancer Res 2001; 7(7): 2016–2021.
combretastatin A-4 derivative, against rat liver cancer. Int J 66. Lee FY, Borzilleri R, Fairchild CR, Kim SH, Long BH, Reventos-Suarez C, et al. BMS-247550: a novel epothilone 83. Hoekstra R, Eskens FA, Verweij J. Matrix metalloproteinase analog with a mode of action similar to paclitaxel but inhibitors: current developments and future perspectives.
possessing superior antitumor efficacy. Clin Cancer Res 2001; 84. Bramhall SR, Hallissey MT, Whiting J, Scholefield J, Tierney 67. Stachel SJ, Biswas K, Danishefsky SJ. The epothilones, G, Stuart RC, et al. Marimastat as maintenance therapy for eleutherobins, and related types of molecules. Curr Pharm patients with advanced gastric cancer: a randomised trial. Br J 68. Neben K, Moehler T, Egerer G, Kraemer A, Hillengass J, 85. Bramhall SR, Schulz J, Nemunaitis J, Brown PD, Baillet M, Benner A, et al. High plasma basic fibroblast growth factor Buckels JA. A double-blind placebo-controlled, randomised concentration is associated with response to thalidomide in progressive multiple myeloma. Clin Cancer Res 2001; 7(9): gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002; 87(2): 69. Raje N, Anderson KC. Thalidomide and immunomodulatory drugs as cancer therapy. Curr Opin Oncol 2002; 14(6): 635–640.
86. Groves MD, Puduvalli VK, Hess KR, Jaeckle KA, Peterson P, 70. Figg WD, Kruger EA, Price DK, Kim S, Dahut WD. Inhibition Yung WK, et al. Phase II trial of temozolomide plus the matrix of angiogenesis: treatment options for patients with metalloproteinase inhibitor, marimastat, in recurrent and metastatic prostate cancer. Invest New Drugs 2002; 20(2): progressive glioblastoma multiforme. J Clin Oncol 2002; 20(5): 71. Waselenko JK, Shinn CA, Willis CR, Flinn IW, Grever MR, 87. Batist G, Patenaude F, Champagne P, Croteau D, Levinton C, Byrd JC. Carboxyamido-triazole (CAI)—a novel ‘‘static’’ Hariton C, et al. Neovastat (AE-941) in refractory renal cell signal transduction inhibitor induces apoptosis in human B- carcinoma patients: report of a phase II trial with two dose cell chronic lymphocytic leukemia cells. Leukemia Lymphoma levels. Ann Oncol 2002; 13(8): 1259–1263.
88. Falardeau P, Champagne P, Poyet P, Hariton C, Dupont E.
72. Dreau D, Foster M, Hogg M, Swiggett J, Holder WD, White RL. Angiogenic and immune parameters during recombinant antiangiogenic drug, in phase III clinical trials. Semin Oncol interferon-a2b adjuvant treatment in patients with melanoma.
89. Gutheil JC, Campbell TN, Pierce PR, Watkins JD, Huse WD, 73. Kawano Y, Matsui N, Kamihigashi S, Narahara H, Miyakawa Bodkin DJ, et al. Targeted antiangiogenic therapy for cancer I. Effects of interferon-gamma on secretion of vascular using Vitaxin: a humanized monoclonal antibody to the endothelial growth factor by endometrial stromal cells. Am J integrin avb3. Clin Cancer Res 2000; 6(8): 3056–3061.
Reprod Immunol 2000; 43(1): 47–52.
90. Patel SR, Jenkins J, Papadopolous N, Burgess MA, Plager C, 74. Leahy KM, Ornberg RL, Wang Y, Zweifel BS, Koki AT, Gutterman J, et al. Pilot study of vitaxin—an angiogenesis Masferrer JL. Cyclooxygenase-2 inhibition by celecoxib inhibitor—in patients with advanced leiomyosarcomas.
reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 2002; 62(3): 625–631.
91. Coleman RE. Treatment of skeletal complications of cancer 75. Wang Z, Fuentes CF, Shapshay SM. Antiangiogenic and with zoledronic acid. Semin Oncol 2002; 29(Suppl 21): 1–49.
chemopreventive activities of celecoxib in oral carcinoma cell.
92. Body JJ, Mancini I. Bisphosphonates for cancer patients: why, Laryngoscope 2002; 112(5): 839–843.
how, and when? Support Care Cancer 2002; 10: 399–407.
76. Bevacizumab. Anti-VEGF monoclonal antibody, avastin, 93. Body JJ, Greip P, Coleman RE, et al. A phase I study of rhumab-VEGF. Drugs R D 2002; 3(1): 28–30.
AMGN-0007, a recombinant osteoprotegerin construct, in 77. Chen HX, Gore-Langton RE, Cheson BD. Clinical trials patients with multiple myeloma or breast carcinoma related referral resource: Current clinical trials of the anti-VEGF bone metastases. Cancer 2003; 97(Suppl 3): 887–892.

Source: http://farbodm.ir/download/articles/3.pdf

Yafsoanite

Catalogue of Type Mineral Specimens Yafsoanite Kim AA, Zayakina NV, Lavrentev YuG: ZVMO,(1982) 111, 118-121 Russia - Yakutiya-SW - Central Aldan - Kuranakh gold deposit Yakhontovite Postnikova VP, Isipursky SI, Sidorenko GA, Mokhov AV: Mineral.Zhurnal,(1986) 8, n6, 80-84 Russia - Khabarovsk - Komsomol'sk region - Pridorochnoye deposit Supergene Yanomamite Botelho NF, R

Hup1804.vp

HUMAN PERFORMANCE, 18 (4), 331–341Copyright © 2005, Lawrence Erlbaum Associates, Inc. The key to success in business is money and people. Personality psychology isabout people—it’s about the nature of human nature. Some understanding of hu-man nature—and the ability to measure its key components—would seem to offera huge advantage to applied psychologists. Despite its practical signif

Copyright © 2010-2014 Medical Pdf Finder