James L. Mulshine

Bio: James L. Mulshine is an academic researcher from Rush University. The author has contributed to research in topics: Lung cancer & Cancer. The author has an hindex of 64, co-authored 271 publications receiving 17467 citations. Previous affiliations of James L. Mulshine include University of Texas MD Anderson Cancer Center & National Institutes of Health.

The pharmacology of monoclonal antibodies.

Abstract: We are entering an era in which biological macromolecules can be designed to order and genetically or synthetically produced. If the experience with classical low molecular weight drugs is any guide, it will be possible in fact, easy to produce many more such agents than can be tested for effect in animals, let alone in humans. Predictive criteria are required for the process of rational design, and these must be based on an understanding of fundamental physiological and pharmacological principles. Monoclonal antibodies illustrate the point. Hundreds of new monoclonal reagents with possible clinical use are being developed every year. Each of them could be administered as whole antibody, F(ab')*, or Fab. Each could be conjugated to a toxin, a drug, a radionuclide, or a liposome containing one of those agents. Each could be class-switched to change effector functions or could be mutated in its binding site. As noted previously,' the combinatorial aspects of trying every possibility are out of the question even before one has considered such current and likely future developments as ( I ) chimeric molecules combining mouse variable and human constant domains; (2) Fv (variable domain) fragments; (3) recombinants consisting of murine hypervariable segments and human variable domain framework; (4) conjugates formed by genetically grafting a linker peptide onto the molecule; and (5) enzyme-antibody or toxin-antibody chimeras. At the end of this developmental process will be ligand molecules consisting of antibody-derived binding sites grafted onto molecules designed de novo. A predictive pharmacology of biologicals must be based on theoretical and experimental information from several hierarchical levels: global (whole body), regional, local, cellular, and molecular. Here we will focus on one study of whole body pharmacokinetics, one development in regional delivery, and one issue at the local, or tissue, level.

Bombesin-like peptides can function as autocrine growth factors in human small-cell lung cancer.

Abstract: The autocrine hypothesis proposes that a cell produces and secretes a hormone-like substance that can interact with specific membrane receptors on its surface to induce effects such as proliferation. Thus, a cancer cell could act to stimulate its own growth. Bombesin and bombesin-like peptides (BLPs) such as gastrin-releasing peptide (GRP) cause various physiological responses in mammals, including stimulation of proliferation of 3T3 mouse fibroblasts and normal human bronchial epithelial cells in vitro and induction of gastrin cell hyperplasia and increased pancreatic DNA content in vivo in rats. Human small-cell lung cancer (SCLC) cell lines produce and secrete BLPs and can express a single class of high-affinity receptors for BLPs. Exogenously added BLPs can also stimulate the clonal growth and DNA synthesis of SCLC in vitro. These findings suggest that BLPs function as autocrine growth factors for this tumour. One way to test this hypothesis is to interrupt the function of the endogenously produced BLPs. Here, we demonstrate that a monoclonal antibody to bombesin binds to the C-terminal region of BLPs, blocks the binding of the hormone to cellular receptors and inhibits the clonal growth of SCLC in vitro and the growth of SCLC xenografts in vivo. These results demonstrate that BLPs can function as autocrine growth factors for human SCLC.

Clinical practice. Lung cancer screening.

Abstract: A 60-year-old woman who quit smoking 20 years earlier comes for a routine visit. She previously smoked one pack of cigarettes a day for 10 years. Her medical history is otherwise unremarkable. She feels well and exercises regularly. Her husband smoked one pack of cigarettes per day for at least 30 years but stopped smoking a decade ago. She asks whether she and her husband should undergo computed tomographic (CT) scanning to screen for lung cancer. What do you advise?

Patterns of Cancer Incidence, Mortality, and Prevalence Across Five Continents: Defining Priorities to Reduce Cancer Disparities in Different Geographic Regions of the World

Abstract: Efforts to reduce global cancer disparities begin with an understanding of geographic patterns in cancer incidence, mortality, and prevalence. Using the GLOBOCAN (2002) and Cancer Incidence in Five Continents databases, we describe overall cancer incidence, mortality, and prevalence, age-adjusted temporal trends, and age-specific incidence patterns in selected geographic regions of the world. For the eight most common malignancies-cancers of lung, breast, colon and rectum, stomach, prostate, liver, cervix, and esophagus-the most important risk factors, cancer prevention and control measures are briefly reviewed. In 2002, an estimated 11 million new cancer cases and 7 million cancer deaths were reported worldwide; nearly 25 million persons were living with cancer. Among the eight most common cancers, global disparities in cancer incidence, mortality, and prevalence are evident, likely due to complex interactions of nonmodifiable (ie, genetic susceptibility and aging) and modifiable risk factors (ie, tobacco, infectious agents, diet, and physical activity). Indeed, when risk factors among populations are intertwined with differences in individual behaviors, cultural beliefs and practices, socioeconomic conditions, and health care systems, global cancer disparities are inevitable. For the eight most common cancers, priorities for reducing cancer disparities are discussed.

Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

Abstract: The doxorubicin-selected lung cancer cell line H69AR is resistant to many chemotherapeutic agents. However, like most tumor samples from individuals with this disease, it does not overexpress P-glycoprotein, a transmembrane transport protein that is dependent on adenosine triphosphate (ATP) and is associated with multidrug resistance. Complementary DNA (cDNA) clones corresponding to messenger RNAs (mRNAs) overexpressed in H69AR cells were isolated. One cDNA hybridized to an mRNA of 7.8 to 8.2 kilobases that was 100- to 200-fold more expressed in H69AR cells relative to drug-sensitive parental H69 cells. Overexpression was associated with amplification of the cognate gene located on chromosome 16 at band p13.1. Reversion to drug sensitivity was associated with loss of gene amplification and a marked decrease in mRNA expression. The mRNA encodes a member of the ATP-binding cassette transmembrane transporter superfamily.

Epidermal growth factor receptor mutations in lung cancer

Abstract: The development and clinical application of inhibitors that target the epidermal growth factor receptor (EGFR) provide important insights for new lung cancer therapies, as well as for the broader field of targeted cancer therapies. We review the results of genetic, biochemical and clinical studies focused on somatic mutations of EGFR that are associated with the phenomenon of oncogene addiction, describing 'oncogenic shock' as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors. Understanding the genetic heterogeneity of epithelial tumours and devising strategies to circumvent their rapid acquisition of resistance to targeted kinase inhibitors are essential to the successful use of targeted therapies in common epithelial cancers.