Theodore L. McLemore

Mechanisms of lung injury by systemically administered chemicals

In this paper we will attempt to provide some explanations for the organ selectivity of four different pneumotoxicants (monocrotaline, naphtalene, 3-methylindole, and 4-ipomeanol)

Profiling of prostaglandin biosynthesis in biopsy fragments of human lung carcinomas and normal human lung by capillary gas chromatography-negative ion chemical ionization mass spectrometry.

Methods for the profiling of prostaglandin F2 alpha (PGF2 alpha), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6KPGF1 alpha) biosynthesis in tissue samples of clinical origin by capillary gas chromatography-negative ion chemical ionization mass spectrometry (CGC-NICIMS) are detailed. Aliquots (25 microliter 1) of incubates (1 ml volume) of human lung carcinoma and normal human lung tissue fragments (total protein content = 0.2 to 2.0 mg) were derivatized for vapor phase analysis in the presence of 0.75 to 1.60 ng of tetradeuterated analogs of PGE2, PGF2 alpha and 6KPGF1 alpha without prior extraction and/or chromatography. The derivatized analytes and internal standards were detected by simultaneous monitoring of ions at six different masses characteristic for each of the derivatized prostanoids. The inter-sample and intra-sample coefficients of variation for the assay method were typically less than 12%. The analysis of biological samples was completed with less than 2.5% of each derivatized sample per injection. The samples were of adequate purity for the identification and quantitation of each of the eicosanoids. The methods described in this report are highly selective and highly sensitive with detection limits of 0.1 to 0.2 picograms per injection. The analytical procedures provide the basis for comparisons of the qualitative and quantitative profiles of prostaglandin biosynthesis and should be adaptable for use in a variety of biological and clinical studies.

Human Tumour Xenograft Models for Use with an In Vitro-Based, Disease-Oriented Antitumour Drug Screening Program

Both short-term and long-term xenograft models may be useful in conjunction with an in vitro based disease-oriented drug screening program. Shortterm models may be most valuable in making initial assessments of the potential in vitro drug screening leads for in vivo use. We have previously shown that a substantial number of such leads may be subject to metabolic inactivation (1) and that this may be associated with a lack of therapeutic activity and a relative lack of toxicity in vivo. Certainly, rapid excretion or other pharmacologic factors may also render compounds inactive in vivo. Short-term as says may be very useful for identifying such compounds and thus setting priorities for further testing of in vitro drug leads in more rigorous longer-term models. Rational application of these longer-term models with particular attention to modeling of in situ vascular barriers, tumor microenvironment, and the natural history of the target diseases may facilitate identification and development of new drugs with significant clinical activity against the common adult solid tumors.

Fatty Acid Cyclooxygenase Metabolism of Arachidonic Acid in Human Tumor Cells

The prostaglandins, leukotrienes and related eicosanoids have been implicated as mediators in human malignant disease, particularly in cellular events related to tumor metastasis, cell proliferation, tumor promotion and host immunoregulation (1–23). There is substantial evidence that human tumor cells may synthesize significant quantities of prostaglandins. Elevated production of prostaglandin E2 (PGE2) has been demonstrated in lung cancer patients in vivo (24,25). Other studies have shown that prostanoid biosynthesis is elevated in human tumor tissues in comparison with production in normal human tissues (26–28) and that cultured human tumor cells synthesize significant quantities of prostanoids (29–32). In the present studies, the profiles of prostanoid biosynthesis from endogenous arachidonic acid in 55 established cell lines derived from human tumors of the colon, lung, prostate, ovary, kidney, and the central nervous system were determined. The objective of these studies was the determination of PGH synthase activity in diverse histological classes of human tumor cells in order to discern whether fatty acid cyclooxygenase metabolism of arachidonic acid may be uniquely characteristic of certain histological classes of human tumors.