Citations

ABSTRACT: Lung cancer is the second most common form of cancer in the United States, and although it accounts for 15% of all cancers, it is the most lethal, accounting for approximately 28% of cancer deaths. In 2002, it is estimated that 177,000 new cases of lung cancer will be diagnosed in the United States, and an estimated 160,000 men and women will die from the disease. This mortality rate is greater than that attributable to colorectal, breast, and prostate cancer combined. Systemic treatments for lung cancer with standard chemotherapy agents are still relatively ineffective. Agents targeting novel proliferative and survival pathways in lung cancer are needed to improve treatment outcomes. In recent years, numerous agents inhibiting aberrant processes in tumor cells have undergone clinical evaluation. This review is the first of a two-part series that summarizes pertinent preclinical and clinical information on novel drugs that target critical abnormalities in lung cancer. In this article, agents inhibiting growth factor receptors and various molecules downstream of activated signaling cascades, such as cytoplasmic second messengers, are described.

ABSTRACT: Lung cancer is the second most common form of cancer in the United States, and although it accounts for 15% of all cancers, it is the most lethal, accounting for approximately 28% of cancer deaths. In 2002, it is estimated that 177,000 new cases of lung cancer will be diagnosed in the United States, and an estimated 160,000 men and women will die from the disease. This mortality rate is greater than that attributable to colorectal, breast, and prostate cancer combined. Systemic treatments for lung cancer with standard chemotherapy agents are still relatively ineffective. Agents targeting novel proliferative and survival pathways in lung cancer are needed to improve treatment outcomes. In recent years, numerous agents inhibiting aberrant processes in tumor cells have undergone clinical evaluation. This review is the second of a two-part series that summarizes pertinent preclinical and clinical information on novel drugs that target critical abnormalities in lung cancer. In this article, agents that were developed to inhibit various aspects of tumor protein trafficking and protein degradation, cell cycle regulation, angiogenesis, and antigenicity are described. Future approaches to treatment are suggested.

Wilms’ tumor is the most common pediatric primary renal cancer and is highly responsive to surgery and chemotherapy. The role of radiotherapy has evolved in the last three decades from the use of stepwise incremental doses in all patients to the current concept of added radiotherapy in advanced cases or in those with unfavorable pathology. To the authors’ knowledge, this is the first case of a young woman with prior history of Wilms’ tumor and significant weight loss due to radiation arteritis involving the abdominal vasculature. A 31-year-old woman presented with a history of weight loss and severe malnutrition. An angiogram revealed that the aorta was occluded below the renal artery. The celiac artery and the superior mesenteric artery were occluded at the origin, and large intercostal collaterals reconstituted the pelvic circulation. She was initially treated with total parenteral nutrition (TPN) and underwent an infrarenal aortic bypass surgery. Histopathology of the aorta revealed intimal fibrocalcific thickening and changes consistent with radiation-induced arteritis. Later, she was readmitted with progressive hepatic insufficiency. Despite intensive medical therapy, she died of multi-organ failure.

PURPOSE: This trial was prompted by uncertainty about the need for breast irradiation after lumpectomy in node-negative women with invasive breast cancers of ≤ 1 cm, by speculation that tamoxifen (TAM) might be as or more effective than radiation therapy (XRT) in reducing the rate of ipsilateral breast tumor recurrence (IBTR) in such women, and by the thesis that both modalities might be more effective than either alone. PATIENTS AND METHODS: After lumpectomy, 1,009 women were randomly assigned to TAM (n = 336), XRT and placebo (n = 336), or XRT and TAM (n = 337). Rates of IBTR, distant recurrence, and contralateral breast cancer (CBC) were among the end points for analysis. Cumulative incidence of IBTR and of CBC was computed accounting for competing risks. Results with two-sided P values of .05 or less were statistically significant. RESULTS: XRT and placebo resulted in a 49% lower hazard rate of IBTR than did TAM alone; XRT and TAM resulted in a 63% lower rate than did XRT and placebo. When compared with TAM alone, XRT plus TAM resulted in an 81% reduction in hazard rate of IBTR. Cumulative incidence of IBTR through 8 years was 16.5% with TAM, 9.3% with XRT and placebo, and 2.8% with XRT and TAM. XRT reduced IBTR below the level achieved with TAM alone, regardless of estrogen receptor (ER) status. Distant treatment failures were infrequent and not significantly different among the groups (P = .28). When TAM-treated women were compared with those who received XRT and placebo, there was a significant reduction in CBC (hazard ratio, 0.45; 95% confidence interval, 0.21 to 0.95; P = .039). Survival in the three groups was 93%, 94%, and 93%, respectively (P = .93). CONCLUSION: In women with tumors ≤ 1 cm, IBTR occurs with enough frequency after lumpectomy to justify considering XRT, regardless of tumor ER status, and TAM plus XRT when tumors are ER positive.

In contrast to oncoretroviruses, lentiviruses such as human immunodeficiency virus 1 (HIV-1) are able to integrate their genetic material into the genome of nonproliferating cells that are metabolically active. Likewise, vectors derived from HIV-1 can transduce many types of nonproliferating cells, with the exception of some particular quiescent cell types such as resting T cells. Completion of reverse transcription, nuclear import, and subsequent integration of the lentivirus genome do not occur in these cells unless they are activated via the T-cell receptor (TCR) or by cytokines or both. However, to preserve the functional properties of these important gene therapy target cells, only minimal activation with cytokines or TCR-specific antibodies should be performed during gene transfer. Here we report the characterization of HIV-1–derived lentiviral vectors whose virion surface was genetically engineered to display a T cell-activating single-chain antibody polypeptide derived from the anti-CD3 OKT3 monoclonal antibody. Interaction of OKT3 IgGs with the TCR can activate resting peripheral blood lymphocytes (PBLs) by promoting the transition from G0 to G1 phases of the cell cycle. Compared to unmodified HIV-1–based vectors, OKT3-displaying lentiviral vectors strongly increased gene delivery in freshly isolated PBLs by up to 100-fold. Up to 48% transduction could be obtained without addition of PBL activation stimuli during infection. Taken together, these results show that surface-engineered lentiviral vectors significantly improve transduction of primary lymphocytes by activating the target cells. Moreover these results provide a proof of concept for an approach that may have utility in various gene transfer applications, including in vivo gene delivery.

In a phase 2 study, 23 patients with myelofibrosis with myeloid metaplasia were treated with imatinib mesylate at a constant dose of 400 mg/d. Treatment was held in 16 patients (70%), after 1 to 12 weeks, because of side effects (neutropenia, 6 patients; musculoskeletal pain, 5 patients; thrombocytosis, 4 patients; edema, 3 patients; diarrhea and hyperbilirubinemia, 1 patient). Including patients in whom retreatment at a reduced dose was possible, 11 patients (48%) were able to continue treatment beyond 3 months. None of the patients experienced a response in anemia, and only 2 had partial responses in splenomegaly. A greater than 50% increase in platelet count was documented in 11 (48%) patients, but not in those with baseline platelet counts of less than 100 × 109/L. In vitro, imatinib mesylate caused variable degrees of growth suppression of myeloid and erythroid progenitors that unfortunately did not translate into clinical benefit.

This article describes the electrical characterization of live and heat-inactivated micro-organisms within microstructures. Electrophoretic movement of live and heat-inactivated Listeria innocua on interdigitated fingered electrodes confirmed the presence of negative charges on the live micro-organisms and demonstrated positive or neutral charges on the heat-inactivated micro-organisms. A micropore was fabricated in an oxide coated silicon diaphragm, which was placed between two chambers containing ionic buffer solutions. When the micro-organism electrophoretically traversed the pore, the background ionic current was blocked and a decrease in the current was observed. As an initial test case, negatively charged polystyrene beads, which were 2.38 μm in diameter, were electrophoretically driven across the pore. Then, Listeria innocua, suspended in tris-glycine buffer, were also moved through the pore and their electrophoretic mobility was determined. In addition, the values of mobility of the micro-organisms through the micropore were found to be about 3 orders of magnitude smaller than their mobility without the pore, which can be explained by the higher hydrostatic pressures experienced by the micro-organisms when traversing through the pore.

ABSTRACT Members of the transforming growth factor pβ (TGF‐β) superfamily‐namely, TGF‐β and BMP2—applied to undifferentiated murine embryonic stem cells up‐regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C). Embryoid bodies generated from stem cells primed with these growth factors demonstrated an increased potential for cardiac differentiation with a significant increase in beating areas and enhanced myofibrillogenesis. In an environment of postmitotic cardiomyocytes, stem cells engineered to express a fluorescent protein under the control of a cardiac promoter differentiated into fluorescent ventricular myocytes beating in synchrony with host cells, a process significantly enhanced by TGF‐β or BMP2. In vitro, disruption of the TGF‐β/BMP signaling pathways by latency‐associated peptide and/or noggin prevented differentiation of stem cells. In fact, only host cells that secrete a TGF‐β family member induced a cardiac phenotype in stem cells. In vivo, transplantation of stem cells into heart also resulted in cardiac differentiation provided that TGF‐β/BMP2 signaling was intact. In infarcted myocardium, grafted stem cells differentiated into functional cardiomyocytes integrated with surrounding tissue, improving contractile performance. Thus, embryonic stem cells are directed to differentiate into cardiomyocytes by signaling mediated through TGF‐β/BMP2, a cardiac paracrine pathway required for therapeutic benefit of stem cell transplantation in diseased heart.—Behfar, A., Zingman, L. V., Hodgson, D. M., Rauzier, J.‐M., Kane, G. C., Terzic, A., Pucéat, M. Stem cell differentiation requires a paracrine pathway in the heart. FASEB J . 16, 1558–1566 (2002)