daunorubicinol and Stomach-Neoplasms

In order to study a model that maximizes gastric cancer tissue and lymph node exposure to antineoplastic drugs while simultaneously reducing their systemic bioavailability, we implemented a preliminary investigation of the disposition of a daunorubicin liposomal preparation (D) in gastric cancer patients by means of gastric submucosa injection.. After a dose finding study, 12 patients (candidates for gastric resection because of gastric cancer) were studied by administering two doses of 50 mg of D (the highest tolerated dose) 1 week before surgery.. Mean tissue concentrations at surgery were higher in cancer, normal non-injected peritumoral mucosa, and lymph node tissues than in serum or urine, in which there were only trace concentrations. While epigastric pain and histological modifications (inflammation and thickening of the gastric layers) were manifest in patients treated with 75 mg doses in the dose finding session, no clinical signs or symptoms of toxicity were recorded in those administered with 50 mg doses.. Local administration of D may allow it to reach high concentrations in normal non-injected peritumoral mucosa, and lymph nodes, while simultaneously avoiding significant systemic exposure and toxicity. This procedure could merit further investigation, in view of a possible use of anthracyclines against metastatic diffusion through the lymphatic system in gastric cancer patients who are candidates for gastric resection.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Daunorubicin; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Gastroscopy; Humans; Injections; Injections, Intralesional; Liposomes; Lymph Nodes; Male; Middle Aged; Prospective Studies; Stomach Neoplasms; Tissue Distribution

A resistant descendant of the human stomach carcinoma cell line EPG85-257 was selected in the presence of increasing concentrations of daunorubicin (DRC). To avoid the expression and activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), cells were cultured in the presence of verapamil. The resulting cells were used to evaluate an induced carbonyl reduction as a new determinant in DRC resistance. The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium bromide) toxicity assay was performed to estimate sensitivity to DRC in both cell lines. IC50 values of DRC increased almost 8-fold in the resistant descendants compared to the parental cell line. P-gp transcripts were detectable in both cell lines at only very low levels, and no significant alterations between sensitive and resistant cells were observed. MRP mRNA expression was markedly higher compared to P-gp mRNA, but, as was the case with P-gp, MRP mRNA levels in sensitive and resistant cells showed no alteration. This was probably due to the effect of the presence of verapamil during cell selection. Another known drug resistance factor, the lung resistance-related protein (LRP), was not at all detectable. Interestingly, resistant cells possessed 6-fold higher levels of DRC carbonyl-reducing activity, leading to the less toxic 13-hydroxy metabolite daunorubicinol (DRCOL). The 6-fold higher DRCOL formation roughly parallels the 8-fold increase in DRC IC50 values during cell selection, and therefore may account for DRC resistance in these cells. The determination of specific carbonyl reducing enzymes, known to be involved in DRC detoxification, revealed that mRNA expression of carbonyl reductase (EC 1.1.1.184), aldose reductase (EC 1.1.1.21), and dihydrodiol dehydrogenase 2 (EC 1.3.1.20) increased in the resistant descendant. In contrast, the phase II-conjugating enzyme activities of glutathione S-transferases were significantly lower in resistant than in sensitive cells, whereas those of glucuronosyl transferase were not detectable in either cell line. Apparently, conjugating enzymes are not involved in DRC resistance in human stomach carcinoma cells. These studies indicate that DRC resistance in human stomach carcinoma cells may appear as a result of an induction of metabolic DRC inactivation via carbonyl reduction to the less active 13-hydroxy metabolite DRCOL.

Topics: Alcohol Oxidoreductases; Antibiotics, Antineoplastic; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Daunorubicin; Drug Resistance, Neoplasm; Gene Expression; Humans; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Oxidation-Reduction; RNA, Messenger; Stomach Neoplasms; Tumor Cells, Cultured; Vault Ribonucleoprotein Particles