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(Chest. 2000;117:163S-168S.)
© 2000 American College of Chest Physicians

New Therapeutic Strategies for Lung Cancer*

Biology and Molecular Biology Come of Age

Paul A. Bunn, Jr., MD; Ariel Soriano, MD; Gary Johnson, PhD and Lynn Heasley, PhD

* From the Lung Cancer Program, University of Colorado Cancer Center, Denver, CO.

Correspondence to: Paul A. Bunn, Jr., MD, University of Colorado Cancer Center, Box B-188, 4200 East 9th Ave, Denver, CO 80262; e-mail: paul.bunn{at}uchsc.edu


   Abstract
TOP
 Abstract
Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
 References
 
The current understanding of the biology and molecular biology of lung cancer pathogenesis and progression is reviewed. Awareness of the influence of growth factors, oncogenes, and tumor suppressor genes as well as signal transduction and angiogenesis pathways on the natural history of cancer cells has led to attempts to develop new therapeutic strategies directed at interrupting tumor cell growth. Treatments utilizing monoclonal antibodies, matrix metalloproteinase inhibitors, and gene transfer and alteration are currently being investigated. The rationale and effectiveness of these treatments in early trials are explored, and recommendations for future directions in cell biology research are presented. Interest in the biology and molecular biology of tumor cells has led to some important findings that may provide opportunities for new treatments. Several of these new directions for anticancer therapy are already being examined in phase I clinical trials.

Key Words: angiogenesis • apoptosis • growth factor • lung cancer • oncogene • receptors • suppressor gene


   Introduction
TOP
 Abstract
 Introduction
Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
 References
 
There has been an explosion in our understanding of the biology and molecular biology of lung cancer over the past decade.1 This understanding has enabled the development of new strategies for the treatment and chemoprevention of lung cancer. This article outlines some of the biological and molecular changes contributing to the pathogenesis of lung cancer, and indicates how recognition of these events is being translated into phase I and II studies with new compounds.


   Lung Cancer Growth Factors
TOP
 Abstract
 Introduction
 Lung Cancer Growth Factors
Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
 References
 
In the late 1970s, Sporn and Todaro2 postulated that the pathogenesis and progression of many solid tumors, including lung cancers, are driven by local paracrine and autocrine growth factors. Subsequent studies identified epidermal growth factor (EGF) as a major growth factor for many non-small cell lung cancers (NSCLCs), especially those of squamous histology.3 4 5 6 EGF is believed to be involved in the pathogenesis of lung cancer, as overexpression of the EGF receptor is evident in most squamous dysplasias, including squamous cell lung cancer.4 5 There are multiple to ways to interrupt this pathway, including use of monoclonal antibody to EGF or EGF receptor3 6 ; recombinant immunotoxins, such as EGF-diphtheria toxin (DAB389EGF, Seragen; Hopkington, MA)7 ; specific tyrosine kinase inhibitors, which prevent EGF activation8 ; and receptor-targeted immunotoxins (Table 1 ).9 Antibodies to EGF receptor and EGF-diphtheria toxin are currently being evaluated in phase I clinical trials. Other receptor tyrosine kinases of the EGF family also are overexpressed in NSCLC, and are being examined as potential prognostic markers and therapeutic targets as well.10 11


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  		Table 1. New Agents for Lung Cancer Prevention and Therapy Based on Biological Abnormalities*

 
Insulin-like growth factor 1 and nerve growth factor have been reported to be growth factors for NSCLC12 ; insulin-like growth factor 1 also plays a role in small cell lung cancer (SCLC).12 Platelet-derived growth factor does not appear to have a major influence in either NSCLC or SCLC.

Peptide growth factors, including gastrin-releasing peptide, bradykinin, arginine, vasopressin, cholecystokinin, and others, are major growth factors for nearly all SCLCs and some large-cell carcinomas and adenocarcinomas.13 14 15 Although the majority of these tumors produce peptides and express peptide receptors, there is considerable heterogeneity with respect to the specific receptors expressed.13 14 For this reason, specific peptide receptor antagonists do not appear to be as effective as broad-spectrum antagonists in inhibiting lung cancer cell growth. One such broad-spectrum antagonist, a substance P derivative, is in phase I clinical trials in the United Kingdom.15 16 17 Recent studies in the United States showed that a substance P derivative causes a discordant cell signaling, which stimulates apoptosis in addition to inhibiting tumor cell growth.17 18 Other agents with this effect, including bradykinin antagonist dimers, are in preclinical development.17

The intracellular pathway by which peptides exert their proliferative and apoptotic effects is being elucidated. Peptide receptors are seven–membrane-spanning receptors coupled to G proteins of both the G{alpha}q and G{alpha}12,13 classes.18 19 20 Figure 1 provides a schematic representation of the intracellular pathway. Peptide-receptor binding leads to activation of G{alpha}q, which then activates, in a sequential manner, phospholipase Cß, diacylglycerol, and inositol triphosphate and leads to increased intracellular calcium, protein kinase C (PKC) activation, and increased cytoplasmic phospholipase A2. The activated proteins stimulate proliferation. Activation of G{alpha}12,13 proteins sequentially activates mitogen-activated kinases and JUN kinases, as indicated in Figure 1 . When the activation of this pathway is unbalanced, apoptosis occurs.17 18 19 20



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  		Figure 1. Schematic representation of the signal pathways induced by peptide-receptor binding and activation. Activation of the seven–membrane-spanning receptor leads to activation of both G{alpha}q11 and G{alpha}12,13 heterotrimeric G proteins. Downstream events are summarized. PLCß = phospholipase Cß; IP3 = inositol triphosphate; DAG = diacylglycerol; MAPK =mitogen-activated protein kinase; MEK = mitogen-activated protein kinase kinases; MEKK = mitogen-activated protein kinase kinase kinases; JNK = janus kinase; JNKK = janus kinase kinases. Reproduced with permission.53

 
Many nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effects by inhibiting the cyclooxygenase (COX) and lipoxygenase enzymes involved in arachadonic acid metabolism.21 These NSAIDs have been shown to be potentially useful for the prevention of colon and breast cancers,22 23 and to inhibit the growth of lung cancer cells in vitro and in athymic mouse models.24 Sulindac sulfone (Exisulind; Cell Pathways; Philadelphia, PA), a metabolite of sulindac sulfide,25 26 induces apoptosis in lung, breast, and colon cancer cells without inhibiting COX-2.26 Thus, it lacks the GI toxicities of the parent compound. This compound is in phase I trials of NSCLC patients to determine if it will induce tumor regression and/or regression of premalignant lesions, and to identify the optimal dose.


   Inhibitors of Invasion and Metastases
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 Abstract
 Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
 References
 
Lung cancers and other solid tumors have a great propensity for early invasion and metastasis. The matrix metalloproteinases (MMPs) are enzymes used by tumor cells to invade and destroy the basement membrane of normal cells.27 MMPs also may promote metastases through a number of other mechanisms.27 Lung cancer cells can both produce MMPs and induce neighboring normal cells to secrete MMPs. A number of MMP inhibitors that inhibit growth of both SCLC and NSCLC tumors in animal models have been developed (Table 1 ).28 29 Three such MMP inhibitors, marimastat (British Biotech; Larden, United Kingdom), Ag 33340 (Agouron Pharmaceuticals; La Jolla, CA), and Bay 12–9566 (Bayer Corporation; West Haven, CT), are undergoing phase III clinical testing in SCLC and/or NSCLC. In these studies, patients in complete remission after induction chemotherapy are randomized to receive placebo treatment or the MMP inhibitor. Ag 33340 also is being combined with paclitaxel and carboplatin to treat patients with NSCLC in phase I clinical trials.

There is increasing evidence that MMP inhibitors also may inhibit angiogenesis as part of their antitumor effect.30 Primary tumors and their metastases require new blood vessel formation (angiogensis) for growth and survival.31 There are a number of natural promoters and inhibitors of angiogenesis, including vascular endothelial growth factor (VEGF), which stimulates endothelial cell growth. Inhibitors of VEGF, such as anti-VEGF antibodies, inhibit blood vessel growth, angiogensis, and tumor growth.32 Because lung cancers may be associated with increased VEGF expression, anti-VEGF antibodies (Genentech; San Francisco, CA) are entering clinical trials designed to assess their role in the treatment of this disease. Endostatin and angiostatin are natural inhibitors of angiogenesis that have been shown to inhibit the growth of a number of human malignancies.33 To our knowledge, they have not yet been evaluated in lung cancer. Thalidomide is a pharmacologic inhibitor of angiogenesis, and is being examined in clinical trials for its effect against lung cancer, brain tumors, and other malignancies.

Inhibitors of PKC
Activation of PKC is a common step in the intracellular signal transduction pathway of many growth factors.34 Recent studies suggest that PKC activation may also inhibit apoptosis.35 A number of PKC inhibitors, such as bryostatin and dolostatin (National Cancer Institute; Bethesda, MD), have been developed. In preclinical studies, these compounds inhibit the growth of human cancers in vitro and in vivo. Phase I and II clinical trials are now ongoing with several PKC inhibitors.36


   Tumor Suppressor Genes in Lung Cancer
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 Abstract
 Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
Dominant Oncogenes in Lung...
 Conclusion
 References
 
There is frequent loss of tumor suppressor genes during the pathogenesis and progression of lung cancers, as in many epithelial cancers (Table 2 ).37 p53 is perhaps the most frequently lost tumor suppressor gene in all epithelial and lung cancers. p53 mutations are present in about 80% of lung cancers,37 and may be related to tobacco smoke, which causes specific p53 mutations and results in inactive gene products. Both copies of tumor suppressor genes are usually lost or mutated in the cancer phenotype.37 These mutations also are observed in 50 to 80% of severe dysplasias and carcinoma in situ lesions.5 Several investigators have shown that gene replacement therapy with wild-type p53 inhibits lung cancer growth in vitro,38 and that p53 gene therapy delivered with retroviral or adenoviral vectors inhibited the growth of p53-mutated human lung tumors in athymic nude mice.39 40 The growth inhibition was much more striking when the animals were also treated with cisplatin, suggesting that p53 increases the apoptotic effects induced by cisplatin.40 These studies led to phase I trials in humans in which the p53 gene sectors were directly injected into subcutaneous metastatic lesions by needle injection or into obstructing intrabronchial lesions via a bronchoscope.41 Despite some tumor regression, systemic delivery of gene therapy remains a major obstacle to widespread use of this approach.


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  		Table 2. Molecular Targets for New Lung Cancer Therapies

 
Other tumor suppressor genes involved in the regulation of the cell cycle also are dysregulated in lung cancer cells (Table 2) . The retinoblastoma (Rb) gene protein is activated when phosphorylated.37 42 43 The activated protein inhibits the progression from the G0/G1 phase to the S phase of the cell cycle. SCLC cells are uniformly deficient in the expression of functional Rb protein.37 42 43 Several studies showed that transfection of functional Rb into SCLC cells inhibits their growth in vitro and in vivo.44

NSCLC cells have normal expression of Rb protein.42 43 However, their cell cycle regulation at the G0/G1 to S phase checkpoint is altered by other mechanisms preventing phosphorylation (activation) of Rb.42 43 Thus, Rb is unable to inhibit progression to the S phase. These mechanisms include overexpression of cyclin D1 and lack of expression of p16 (Fig 2 ). As shown in Figure 2 , cyclin D1 overexpression leads to Rb inactivation by binding to cyclin–cyclin-dependent kinase complexes (CDC) 4 and 6 that inhibit Rb phosphorylation. The tumor suppressor gene, p16, ordinarily inhibits CDC 4 and 6 activation, which subsequently prevents phosphorylation of Rb and loss of control at the G0/G1 to S checkpoint. When p16 function is lost through gene loss, gene mutation, or gene silencing by methylation, CDC 4 and 6 fail to phosphorylate Rb, which leads to inactive Rb and subsequent unchecked cell cycle progression to the S phase. There have been several studies designed to evaluate the growth inhibiting effect of p16 gene transfection on NSCLC cells in vitro and in vivo.45 Investigators from University of Texas MD Anderson Cancer Center have shown that direct injection of p16 gene vectors can inhibit the growth of NSCLC cells in athymic nude mice.45



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  		Figure 2. Dysregulation of all cycle control in lung cancer (adapted from Biology of Lung Cancer 1998; 122:378). SCLCs uniformly have low or absent expression of Rb, which allows unchecked transition from G1 to S phase. In NSCLCs, functional Rb is lost by overexpression of cyclin D1 and lack of expression of p16, p21, and p27. CDK = cyclin-dependent kinase; CDI = cyclin-dependent kinase inhibitors. Adapted and reproduced with permission.53

 
bcl-2 is a tumor oncogene that inhibits apoptosis and can be overexpressed by gene activation or amplification.37 In follicular lymphomas, bcl-2 is overexpressed due to the translocation of the gene to the heavy chain gene promoter that is active in B cells. In lung cancers, bcl-2 is often overexpressed through several different mechanisms. Overexpression is associated with a poor prognosis and drug resistance and is a logical therapeutic target.


   Dominant Oncogenes in Lung Cancer
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 Abstract
 Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
Conclusion
 References
 
Overexpression of dominant oncogenes plays a role in lung cancer progression.37 Overexpression of these genes appears to be a late event in lung cancer pathogenesis. The most commonly overexpressed oncogenes are the myc family of genes in SCLC and the ras, HER-1, and HER-2/neu oncogenes in NSCLC (Table 2) .37 46 47 48 Overexpression of cyclin D1 also is common in NSCLC, and this leads to a loss of the G0/G1 to S checkpoint, as discussed above. Cyclin D1 expression can be reduced by antisense constructs and phosmidosine, a nucleotide antibiotic.49

The myc family of oncogenes produces proteins that, when expressed in the nucleus, lead to cell proliferation.37 myc overexpression occurs in the vast majority of SCLCs but is rare in NSCLC. In preclinical models, myc can be inhibited by antisense oligonucleotides and by transfection of mutant myc genes.50 To our knowledge, there are no ongoing clinical trials evaluating this approach, however, largely due to the difficulties with systemic gene delivery discussed previously.

The ras oncogene is mutated in 20 to 40% of adenocarcinomas of the lung but rarely in other cell types.46 Mutations in ras genes are associated with a poor prognosis.46 Mutant ras expression can be inhibited by antisense constructs and by drugs that inhibit ras activation.47 Farnesylation is required for ras to translocate from its inactive state in the cytoplasm to its active membrane state; and, therefore, several farnesylation inhibitors have undergone preclinical evaluation and are entering clinical trials.51 Again, antisense constructs suffer from the problems of systemic delivery described above.

HER-2/neu is more often expressed in breast cancer than in lung cancer, but a considerable fraction of adenocarcinomas of the lung overexpress HER-2/neu.37 48 Clinical trials involving patients with breast cancer showed that patients with HER-2/neu overexpression have a worse prognosis and a lower response rate to chemotherapy.52 A recombinant anti-HER-2/neu monoclonal antibody (Herceptin; Genentech; South San Francisco, CA) increases the response to standard chemotherapy in patients with breast cancer.52 Clinical trials are needed to explore the effect of this antibody in combination with chemotherapy against adenocarcinomas of the lung in patients with overexpressed HER-2/neu.


   Conclusion
TOP
 Abstract
 Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
References
 
Advances in the understanding of the molecular and biological basis of lung cancer suggest optimism for the future of lung cancer therapy in the new millennium. There currently are more effective chemotherapeutic agents than ever before, and a number of new agents based on the biology and molecular biology of lung cancer hold promise for further progress in the future.


   Footnotes
 
Abbreviations: CDC = cyclin–cyclin-dependent kinase complexes; COX = cyclooxygenase; EGF = epidermal growth factor; MMP = matrix metalloproteinase; NSAID = nonsteroidal anti-inflammatory drug; NSCLC = non-small cell lung cancer; PKC = protein kinase C; Rb = retinoblastoma; SCLC = small cell lung cancer; VEGF = vascular endothelial growth factor

Supported in part by National Cancer Institute grants P50 CA58187 and P30 CA46934.


   References
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 Abstract
 Introduction
 Lung Cancer Growth Factors
 Inhibitors of Invasion and...
 Tumor Suppressor Genes in...
 Dominant Oncogenes in Lung...
 Conclusion
 References
 

  1. Kane, M, Bunn, PA, Jr (1998) Biology of lung cancer. (vol 122). Marcel Dekker New York, NY.
  2. Sporn, MB, Todaro, GJ (1985) Autocrine growth factors and cancer. Nature 313,747-751[CrossRef]
  3. Masui, H, Kawamoto, T, Sato, JD, et al (1984) Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 44,1002-1007[Abstract/Free Full Text]
  4. Cerny, T, Barnes, DM, Hasleton, PS, et al (1986) Expression of epidermal growth factor receptor (EGF-R) in human lung tumors. Br J Cancer 54,265-269[ISI][Medline]
  5. Rusch, V, Klimstra, D, Linkov, I, et al (1995) Aberrant expression of p53 and the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res 55,1365-1372[Abstract/Free Full Text]
  6. Bos, M, Mendelsohn, J, Bowden, D, et al (1996) Phase I studies of anti-epidermal growth factor receptor (EGFR) chimeric monoclonal antibody C225 in patients with EGFR overexpressing tumors [abstract 1381]. Proc Am Soc Clin Oncol 15,443
  7. Shaw, JP, Akiyoshi, DE, Arrijo, DA, et al (1991) Cytotoxic properties of DAB486EGF and DAB389EGF, epidermal growth factor (EGF) receptor-targeted fusion toxins. J Biol Chem 51,2118-2124
  8. Bos, M, Mendelsohn, J, Kim, YM, et al (1997) PD 153035, a tyrosine kinase inhibitor, prevents epidermal growth factor receptor activation and inhibits growth of cancer cells in a receptor number-dependent manner. Clin Cancer Res 3,2099-2106[Abstract]
  9. Vollman, AM, Banker, DE, Mendelsohn, J, et al (1987) Toxicity of ligand and antibody-directed ricin A chain conjugates recognizing the epidermal growth factor receptor. J Cell Physiol 131,418-425[CrossRef][ISI][Medline]
  10. Sherwin, SA, Minna, JD, Gazdar, AF, et al (1981) Expression of epidermal and nerve growth factor receptors and soft aganose growth factor production by human lung cancer cells. Cancer Res 41,3538-3542[ISI]
  11. Fontanini, G, DeLaurentis, M, Vignati, S, et al (1998) Evaluation of epidermal growth factor-related growth factors and receptors and of neoangiogenesis in completely resected stage I-IIIA non-small cell lung cancer: amphiregulin and microvessel count are independent prognostic indicators of survival. Clin Cancer Res 4,241-249[Abstract]
  12. Nakanishi, Y, Mulshine, J, Kasprzyk, PG, et al (1988) Insulin like growth factor-1 can mediate autocrine proliferation of human small cell lung cancer cell lines in vitro. J Clin Invest 82,354-359
  13. Bunn, PA, Jr, Dienhard, DG, Chan, D, et al (1990) Neuropeptide stimulation of calcium flux in human lung cancer cells: delineation of alternative pathways. Proc Natl Acad Sci USA USA 87,2162-2166[Abstract/Free Full Text]
  14. Bunn, PA, Jr, Chan, D, Stewart, J, et al (1994) Effects of neuropeptides analogs on calcium flux and proliferation in lung cancer cell lines. Cancer Res 54,3602-3610[Abstract/Free Full Text]
  15. Woll, PJ, Rozengurt, E (1988) A neuropeptide antagonist that inhibits the growth of small cell lung cancer in vitro. Cancer Res 48,4783-4789[Abstract/Free Full Text]
  16. Everand, MJ, Macaulay, VM, Millar, JL, et al (1993) [D-arg1, D-Phe5, D-Trp7,9, Leu11] Substance P inhibits the growth of human small cell lung cancer xenografts in vivo. Eur J Cancer 29A,1450-1453[CrossRef]
  17. Mitchell, FM, Heasley, LE, Qian, N-X, et al (1995) Differential modulation of bombesin-stimulated phospholipase Cb and mitogen-activated protein kinase activity by [D-arg1, D-Phe5, D-Trp7,9, Leu11] substance P. J Biol Chem 270,8623-8628[Abstract/Free Full Text]
  18. Dhanasekaran, N, Heasley, LE, Johnsen, GL (1995) G-protein-coupled receptor systems involved in cell growth and oncogenesis. Endocr Rev 16,259-270[CrossRef][ISI][Medline]
  19. Mukai, H, Munekata, E, Higashijima, T (1992) G-protein antagonists. J Biol Chem 267,16237-16243[Abstract/Free Full Text]
  20. Heasley, LE, Zamarripa, J, Storey, B, et al (1996) Discordant signal transduction and growth inhibition of small cell lung carcinomas induced by expression of GTPase deficient Ga16. J Biol Chem 271,349-356[Abstract/Free Full Text]
  21. Sano, H, Kawakito, Y, Wilder, RL, et al (1995) Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res 55,3785-3789[Abstract/Free Full Text]
  22. Rao, CV, Rivenson, A, Simi, B, et al (1995) Chemoprevention of colon carcinogenesis by sulindac, a non-steroidal anti-inflammatory agent. Cancer Res 55,1464-1472[Abstract/Free Full Text]
  23. Thompson, HJ, Briggs, S, Paranka, N, et al (1995) Inhibition of mammary carcinogenesis in rats by sulfone metabolite of sulindac. J Natl Cancer Inst 87,1259-1260
  24. Soriano, A, Chan, D, Helfrich, B, et al (1998) Non-steroidal anti-inflammatory drugs (NSAIDS) inhibit the in vitro and in vivo growth of human lung cancer. Proc Am Assoc Cancer Res 39,1336
  25. Piazza, G, Rahm, AK, Finn, TS, et al (1997) Apoptosis primarily accounts for the growth inhibitory properties of sulindac metabolites and involves a mechanism that is independent of cyclooxygenase inhibition, cell cycle arrest, and p53 induction. Cancer Res 57,2452-2459[Abstract/Free Full Text]
  26. Piazza, GA, Kulchak-Rahm, AL, Krutzsch, M, et al (1995) Antineoplastic drugs sulindac sulfide and sulindac sulfane inhibit cell growth by inducing apoptosis. Cancer Res 55,3110-3116[Abstract/Free Full Text]
  27. Chambers, AF, Matrisian, LM (1997) Changing views of the role of matrix metalloproteinases in metastases. J Natl Cancer Inst 89,1260-1270[Abstract/Free Full Text]
  28. Sledge, GWJ, Qulali, M, Gailet, R, et al (1995) Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastases in athymic mice. J Natl Cancer Inst 87,1546-1550[Abstract/Free Full Text]
  29. Davies, B, Brown, PO, East, N, et al (1993) A synthetic matrix metalloproteinase inhibitor decreases tumor burden and prolongs survival of mice bearing human ovarian carcinoma xenografts. Cancer Res 53,2087-2091[Abstract/Free Full Text]
  30. Moses, MA, Langer, RA (1991) A metalloproteinase inhibitor as an inhibitor of neovascularization. J Cell Physiol 47,230-235
  31. Folkman, J (1995) Clinical application of research on angiogenesis. N Engl J Med 333,1757-1763[Free Full Text]
  32. Presta, LG, Chen, H, O’Connor, SJ, et al (1997) Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 57,4593-4599[Abstract/Free Full Text]
  33. O’Reilly, MS, Goehm, T, Shing, Y, et al (1997) Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88,277-285[CrossRef][ISI][Medline]
  34. Levesque, L, Dean, NM, Sasmor, H, et al (1997) Antisense oligonucleotides targeting human protein kinase C-alpha inhibit phorbolester-induced reduction of bradykinin-evoked calcium mobilization in A549 cells. Mol Pharmacol 51,209-216[Abstract/Free Full Text]
  35. Grant, S, Jarvis, WD (1996) Modulation of drug-induced apoptosis by interruption of the protein kinase C signal transduction pathway: a new therapeutic strategy. Clin Cancer Res 2,1915-1920[ISI][Medline]
  36. Prendiville, J, Crowther, D, Thatcher, N, et al (1993) A phase I study of intravenous bryostatin I in patients with advanced cancer. Br J Cancer 68,418-424[ISI][Medline]
  37. Johnson, BE, Kelley, MJ (1993) Overview of genetic and molecular events in the pathogenesis of lung cancer. Chest 103,15-35
  38. Fujiwara, T, Grimm, EA, Mukhopadhyay, T, et al (1993) A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res 53,4029-4123
  39. Roth, JA, Nguyen, P, Lawrence, DD, et al (1996) Retroviral-mediated wild type p53 gene transfer to tumors of patients with lung cancer. Nat Med 2,985-991[CrossRef][ISI][Medline]
  40. Fujiwara, T, Grimm, EA, Mukhopadhyay, T, et al (1994) Induction of chemosensitivity in human lung cancer cells in vivo by adenovirus-mediated transfer of the wild-type p53 gene. Cancer Res 54,2287-2291[Abstract/Free Full Text]
  41. Tursz, T, de Cisne, A, Baldeyrou, P, et al (1996) Phase I study of a recombinant adenovirus-mediated gene transfer in lung cancer patients. J Natl Cancer Inst 88,1857-1863[Abstract/Free Full Text]
  42. Schauer, IE, Siriwardana, S, Langan, TA, et al (1994) Cyclin D1 overexpression vs retinoblastoma inactivation: implications for growth control evasion in non-small cell and small cell lung cancer. Proc Natl Acad Sci USA USA 91,7827-7831[Abstract/Free Full Text]
  43. Kelly, MJ, Nakagawa, K, Steinberg, SM, et al (1995) Differentiated inactivation of CDKN2 and Rb proteins in non-small cell and small cell lung cancer cell lines. J Natl Cancer Inst 87,756-761[Abstract/Free Full Text]
  44. Ookawa, K, Shiseki, M, Takahashi, R, et al (1993) Reconstitution of the Rb gene suppresses the growth of small cell lung carcinoma cells carrying multiple genetic alterations. Oncogene 8,2175-2182[ISI][Medline]
  45. Jiu, X, Nguyen, D, Zhang, WW, et al (1995) Cell cycle arrest and inhibition of tumor cell proliferation by the p16INK4 gene mediated by an adenovirus vector. Cancer Res 55,3250-3253[Abstract/Free Full Text]
  46. Slebos, RJC, Kibbelaar, RE, Dalesio, O, et al (1991) K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323,1353-1362[ISI][Medline]
  47. Mukhopadhyay, T, Tainsky, M, Cavander, AC, et al (1991) Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res 51,1744-1748[Abstract/Free Full Text]
  48. Kern, JA, Schwartz, DA, Nordberg, JE, et al (1990) p185 neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res 50,5184-5191[Abstract/Free Full Text]
  49. Kakeya, H, Onose, R, Lui, PCC, et al (1998) Inhibition of cyclin D1 expression and phosphorylation of retinoblastoma protein by phosmidosine a nucleotide antibiotic. Cancer Res 58,704-710[Abstract/Free Full Text]
  50. Robinson, LA, Smith, LJ, Fontaine, MP, et al (1995) C-myc antisense oligodeoxyribonucleotides inhibit proliferation of non-small cell lung cancer. Ann Thorac Surg 60,1583-1591[Abstract/Free Full Text]
  51. Gibbs, JB, Oliff, A, Kohl, NE (1994) Farnesylation inhibitors: ras research yields a potential cancer therapeutic. Cell 77,175-178[CrossRef][ISI][Medline]
  52. Baselga, J, Tripathy, D, Mendelsohn, J, et al (1996) Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14,737-744[Abstract/Free Full Text]



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