Metabolic activation of 4-ipomeanol in human lung, primary pulmonary carcinomas, and established human pulmonary carcinoma cell lines.

4-Ipomeanol (IPO) is a pulmonary-specific toxin that is metabolically activated by a cytochrome P450 pathway in lung tissue. In this study, IPO metabolism, as determined by measurement of [14C]IPO covalent binding, was evaluated in a diverse sampling of 18 established, human lung cancer cell lines as well as in normal lung tissue and primary lung carcinoma tissue obtained at the time of thoracotomy from 56 patients with lung cancer. [14C]IPO covalent binding in lung cancer cell lines ranged from 248 to 1,047 pmol of bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 547 +/- 62.2). IPO metabolism in normal lung tissue ranged from 12 to 2,007 pmol of covalently bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 549 +/- 60). In lung cancer tissue, values ranged from 0 to 2.566 pmol of covalently bound [14C]IPO per milligram of protein per 30 minutes (mean +/- SE = 547 +/- 60, P greater than .3). When patients were divided into smokers and current non-smokers (no tobacco products smoked for greater than 6 mo), no effects of cigarette smoking were observed for either normal lung tissue or lung tumor tissue (P greater than .1 in all instances). A wide range of IPO metabolic activity was observed among different histological classifications of lung cancer cell lines and of fresh lung cancer tissues. IPO metabolism was simultaneously compared in normal lung tissue and lung cancer tissue from individual patients, but no positive correlation was observed (r = .10; P greater than .30). The results clearly demonstrate a wide range of IPO metabolism in both normal and lung cancer cells and indicate that a wide diversity of human lung cancers possess the metabolic enzyme system(s) necessary for the bioactivation of IPO to a potentially cytotoxic intermediate. Therefore, the continued exploration for any possible therapeutic potential of IPO in patients with lung cancer appears warranted.

Expression of CYP1A1 gene in patients with lung cancer: evidence for cigarette smoke-induced gene expression in normal lung tissue and for altered gene regulation in primary pulmonary carcinomas.

The major polycyclic aromatic hydrocarbon inducible-cytochrome P4501A1 gene (CYP1A1) is presumed to be important in pulmonary carcinogenesis and toxicology because its product, the cytochrome P4501A1-dependent (CYP1A1-dependent) monooxygenase, transforms selected xenobiotics (including polycyclic aromatic hydrocarbon procarcinogens in cigarette smoke) to potent carcinogenic metabolites. CYP1A1 messenger RNA (mRNA) expression has not, however, been previously demonstrated in human pulmonary tissue. This report defines CYP1A1 gene expression in normal lung tissue and primary pulmonary carcinoma tissue obtained at thoracotomy from 56 patients with lung cancer. When Northern blot hybridization analyses were performed, 17 of 19 (89%) and zero of five (0%) samples of normal lung tissue from active cigarette smokers and nonsmokers, respectively, expressed the normal 2.8-kilobase CYP1A1 mRNA. In addition, a time-dependent decrease in expression of the CYP1A1 gene was noted in normal lung tissue from individuals who were former smokers, with a decrease in expression occurring as early as 2 weeks following cessation of cigarette smoking. Expression became undetectable in all patients who had stopped smoking more than 6 weeks prior to study. When CYP1A1 gene expression was evaluated in lung cancers, mRNA levels were detectable in one of four (25%) tumors from nonsmokers; two of 24 (8%) tumors from former smokers; and seven of 15 (47%) tumors from cigarette smokers. In addition, an approximately 10-kilobase CYP1A1 RNA species, which was not detectable in normal lung tissue, was observed in five of ten (50%) of the lung cancers that expressed the CYP1A1 gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Profiles of prostaglandin biosynthesis in normal lung and tumor tissue from lung cancer patients.

prostaglandin (PG) biosynthetic profiles from endogenous arachidonic acid were determined by capillary gas chromatography-mass spectrometry in matched fresh normal lung (NL) and lung cancer (LC) tissue fragments obtained from 42 individual LC patients at the time of diagnostic thoracotomy. The histological diagnoses represented were squamous cell carcinoma (N = 20), adenocarcinoma (N = 7), small cell carcinoma (N = 4), mixed cell carcinoma (N = 2), bronchioloalveolar cell carcinoma (N = 2), large cell undifferentiated carcinoma (N = 3), bronchial carcinoid (N = 1), and metastatic tumors (N = 3). When PG biosynthesis was determined in NL tissue separately, low mean levels of PGE2 and PGF2 alpha (less than 2 pmol/mg protein/15 min), intermediate levels of PGD2 and 6-keto-PGF1 alpha (6KPGF1 alpha) (2-7 pmol/mg protein/15 min), and high levels of thromboxane B2 (TXB2) (greater than 7 pmol/mg protein/15 min) were observed. There was no particular correlation with cigarette smoking history and PG biosynthesis in NL. When PG production in LC tissue was evaluated separately, high levels of PGE2, PGF2 alpha, and 6KPGF1 alpha as well as TXB2 and low levels of PGD2 were noted. In addition, LC tissue from cigarette smokers demonstrated elevated levels of PGE2, 6KPGF1 alpha, and TXB2 when compared to current nonsmokers with LC (P less than 0.05 in all instances). Simultaneous comparison of PG production in matched LC and NL tissue from individual patients indicated increased biosynthesis of PGE2 and PGF2 alpha and low levels of PGD2 in LC compared to NL tissue (P less than 0.05 in all instances; paired, two-tailed, Student's t test). Individual comparison of PG biosynthesis according to LC histological cell type revealed that PGE2 and PGF2 alpha were consistently elevated in all four common primary LC histological cell types, the only exception being large cell undifferentiated carcinoma. Interestingly, this latter LC histological cell type presented a unique profile with lower levels of PGE2 and PGD2 in LC than in NL tissue (P less than 0.05 in both instances). In addition, the biosynthesis of all 5 PGs studied was consistently higher in primary than metastatic adenocarcinomas of the lung (P less than 0.05 in all instances). No differences were observed in NL and LC tissue for the major LC histological cell types when PGD2, TXB2, or 6KPGF1 alpha biosyntheses were compared. These findings indicate that the profiles of PG biosynthesis in LC and NL tissue from individual patients may differ substantially. These differences may reflect, in part, contributions to the PG biosynthetic profile unique to malignant cells.