Pharmacokinetics of intraperitoneally administered dipyridamole in cancer patients

The pharmacokinetics of i.p. administered dipyridamole was studied in six patients to explore the feasibility of using this drug as a modulator of antimetabolite activity in extravascular spaces. Infusions of dipyridamole (50 mg/m2 in 2 liters of normal saline) into the peritoneal cavity resulted in peak drug concentrations 5 to 20 times higher in that cavity than in the plasma. The peritoneal decay data for dipyridamole fitted very well to a single compartment open pharmacokinetic model with one exponential term, while the plasma data are adequately described by a single compartment model with two exponentials (a short absorption phase). The mean peritoneal half-life for total extractable dipyridamole was 3.3 +/- 1.9 (SD) h, and the mean peritoneal clearance was 0.4 +/- 0.3 liters/h/m2. The mean plasma half-life of total dipyridamole in our patients was 2.2 +/- 1.2 h, and the mean clearance value was 5.7 +/- 4.7 liters/h/m2. The area under the concentration versus time curve was calculated to be 626 +/- 312 microM-h for the peritoneal cavity and 45 +/- 20 microM-h for the plasma. Using membrane ultrafiltration, we have measured the concentration of free (non-protein bound) dipyridamole in each patient. While the peritoneal clearance values of free and total drug are comparable, the plasma clearance of free dipyridamole was 47 +/- 39 liters/h/m2. This increased plasma clearance resulted in a plasma area under the concentration versus time curve of 8.3 +/- 5.1 microM-h, which suggests minimal systemic exposure. Our data show that instillation of dipyridamole into the peritoneal cavity resulted in much higher local drug exposure than systemic exposure, confirming the feasibility of using this drug to augment antimetabolite activity within the peritoneal cavity. Since dipyridamole is highly protein bound in the plasma but less so in the peritoneal cavity, these data imply that peritoneal exposure to active (free) dipyridamole is far greater than systemic exposure in our patients.     

Adduct formation on DNA and haemoglobin in mice intraperitoneally administered with styrene

Styrene-specific N-7- and O⁶guanine DNA adducts and N-terminalvaline adducts were determined in mice tissues after the intraperitonealadministration of styrene. Blood, liver, lungs and spleen werecollected 3 h after administration of various doses (from 0to 435 mmol/kg b.w.) of styrene. DNA adducts were analysed bythe modified ³²P-postlabelling assay and N-terminal valine adductswere detected by GC-MS according to the modified Edman degradationtechnique. In the dose-range studied, for all adducts a cleardose-response relationship was observed. 7-Alkylguanines andO⁶-styrene guanine adducts were most abundant in lungs,     

Detection of potent mutagens,Trp-P-1 and Trp-P-2, in broiled fish

The potent mutagens Trp-P-1 (3-amino-1, 4-dimethyl-5H-pyrido-[4,3-b]indole) and Trp-P-2 (3-amino-1-methyl-5H-pyrido[4,3-b]indole) are known to be produced by pyrolysis of tryptophan [8]. To determine whether such mutagens are produced by cooking foods, the fractions obtained from broiled sardines cooked in the ordinary was were analysed by gas chromatography/mass spectrometry. The results whowed that 13.3 ng of Trp-P-1 and 13.1 ng of Trp-P-2 were, in fact, present per gram of broiled sardines.     

Effect of intraperitoneal injection volume and antibody protein dose on the pharmacokinetics of intraperitoneally administered IgG2a kappa murine monoclonal antibody in the rat

The i.p. route of antibody administration offers a regional delivery advantage to the peritoneal cavity. In an effort to optimize this method of delivery, the volume of i.p. injection and total protein dose were examined for their effect on the absorption and disposition of an IgG2a kappa murine monoclonal antibody. 5G6.4, administered i.p. Normal rats (Sprague-Dawley) were given one of two protein doses (1-2 or 100 micrograms) of 125I-5G6.4 in a 2.0-ml i.p. injection volume. In both cases the same radiation dose (approximately 20 mu Ci/rat) was administered since only the tracer level (1-2 micrograms) was labeled. Hence, the 100-micrograms dose consisted of approximately 2 micrograms of labeled antibody with 98 micrograms of unlabeled antibody. In a separate experiment, two i.p. injection volumes (2.0 or 20.0 ml) of 125I-5G6.4 (approximately 20 mu Ci/rat) were administered to normal Sprague-Dawley rats. Pharmacokinetic modeling of the whole blood radioactivity levels was undertaken for both groups. The liver, kidney, muscle, lung, diaphragm, and anterior mediastinal lymph nodes were excised upon sacrifice and tissue levels at sacrifice were recorded. The volume of i.p. injection is shown to be a significant factor with respect to i.p. transport. Maximum concentration in the blood, Cmax, was reduced (P less than 0.1) and time of maximum concentration, tCmax was prolonged (P less than 0.05) from 8.4 h (in the 2-ml group) to 14.5 h (in the 20-ml group). Both contribute to a modest reduction in AUC(0----infinity) (P less than 0.15) in which AUC is the area under the concentration-time curve. The increase in blood clearance, Clb, at the higher injection volume (0.287 ml/h for the 20-ml volume and 0.194 ml/h for the 2-ml volume) is presumably due to increased diuresis resulting from autoregulation of fluid removal via lymphatic drainage. Volume of distribution, Vd, is increased since Vd and Clb are functionally proportionate and elimination is assumed constant. Tissue levels at sacrifice, except for the thyroid and anterior mediastinal lymph nodes, were the same. Mean thyroid levels were reduced in the 20-ml group (P less than 0.05) by 22.5%, likely as a result of increased diuresis. Increased nodal uptake (P less than 0.01) can be attributed to the dilution effect of the bolus injection. The rate of mass transfer is greater for the 2-ml group up to 4 h postinjection. Subsequently, the mass transfer rate is greater for the 20-ml group.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of beta-naphthoflavone on the metabolism of aflatoxin B1 in hamsters

The effect of beta-naphthoflavone (BNF) pretreatment of hamsters on the hepatic metabolism of aflatoxin B1 (AFB1) has been examined in studies in vitro and in vivo. Pretreatment with BNF not only increased microsomal cytochrome P-450 by 50-80% but also increased microsome-mediated AFB1 epoxidation as measured by AFB1-DNA binding 2.6 fold without significantly affecting other hydroxylations. Neither cytosolic GSH S-transferases' activities nor AFB1-GSH (AFB1-SG) conjugation were affected. In vivo, hepatic AFB1-DNA binding was also increased about 3-4-fold. These results in contrast to those observed in the rat indicate that induced species of cytochrome P-450 are primarily responsible for higher epoxidation of AFB1 in the hamster.     

Influence of dietary fat on fecal mutagenicity in premenopausal women

A dietary intervention study was conducted on 31 premenopausal women (age: 20-40 years) to investigate the relationship between dietary fat and fecal mutagenicity. After a free-living period (baseline) of one menstrual cycle, the subjects were placed on a high-fat diet (40% calories from fat) for 4 menstrual cycles, followed by a low-fat diet (20% calories from fat) for 4 menstrual cycles. One-half of the subjects were randomly assigned throughout the study to a diet with a P:S ratio of 1.0 while the other half was assigned to one with a P:S ratio of 0.3; body weight by group remained constant. Three-day stool samples were collected at the mid-follicular period during the free-living phase and during the 4th menstrual cycle of each of the 2 controlled diet periods. Mutagenicity was assayed by the SOS chromotest. Reduction of dietary fat was accompanied by a significant decrease in fecal mutagenicity in both P:S groups. Combined values, i.e., both P:S groups, were 20.3 units for high-fat diets vs. 8.78 for low-fat diets.     

Effect of intraperitoneally administered plant lectins on leukocyte diapedesis and visceral organ weight in rats and mice

The effects of intraperitoneally administered plant lectins were examined in rats and mice. Intraperitoneally injected ConA transiently decreased the leukocyte count in the peritoneal cavity, due to the agglutination and attachment of cells to the peritoneal lining. Subsequently the total cell count was increased for hours, exceeding initial values. Peritoneal fluid aspartate transaminase (AST) concentration showed little change during the accumulation of ascitic fluid. The most marked histological alterations were found when wheat germ lectin was injected ip. (WGA, 10 mg/kg, 6 h). Neutrophil granulocytes migrated across the wall of both arterioles and venules, but the response was highly variable among adjacent vessels. The wall of the arterioles may have impeded the migration of neutrophil granulocytes, resulting in their accumulation in the muscular layer. Granulocyte accumulation was also observed in patches under the mesothelium and in other sites of the interstitium. Marked dilatation and thrombosis of a few venules were also observed. Kidney bean lectin (PHA) induced similar but less pronounced changes. The neutrophil diapedesis suggests the release of mediator(s) from mesothelial cells and/or peritoneal white cells. The cytokine-induced neutrophil chemoattractant CINC-1, injected as control, resulted in the diapedesis of predominantly mononuclear cells in the omentum within 40 minutes. In rats ip. injected ConA increased the wet weight of spleen and liver within 6 and 10 h, respectively, but kidney weight did not change. Intravascular clumping of red blood cells, thrombosis and organ weight changes also suggest the absorption of ConA into the circulation. The experiments show that plant lectins, used as models of bacterial lectins, can reproduce some aspects of peritonitis.     

Comparative brain tissue distribution of camptothecin and topotecan in the rat

Purpose: The primary objective of this investigation was to compare the extent of brain distribution of the lactone and the carboxylate forms of camptothecin (CPT) and topotecan (TPT) in awake freely moving rats. Methods: The plasma concentration-time profiles of the lactone and the carboxylate forms of CPT and TPT were determined simultaneously after a single i.v. administration of the lactone form of each drug. Also, the brain extracellular fluid (ECF) concentration-time profiles were characterized utilizing the microdialysis technique. This technique allowed serial sampling of the brain ECF in awake rats. Results: CPT-lactone in plasma declined biexponentially with a terminal half-life of 102 ± 25.2 min. During the elimination phase, the plasma concentration of CPT-carboxylate was approximately ten times the concentration of CPT-lactone. The brain ECF to plasma distribution ratio measured as the ratio of the AUC in the brain ECF to the AUC in plasma was 0.51 ± 0.08 for CPT-lactone, and 0.26 ± 0.21 for CPT-carboxylate. The terminal half-life for TPT-lactone was 64.0 ± 9.4 min. During the elimination phase, the TPT-carboxylate concentration was higher than that of TPT-lactone but the carboxylate to lactone concentration ratio was much lower than that of CPT. The brain ECF to plasma distribution ratio was 0.38 ± 0.12 for TPT-lactone, and 0.21 ± 0.06 for TPT-carboxylate. Conclusions: CPT and TPT are distributed to the brain ECF most probably by passive diffusion across the blood-brain barrier. Although the brain ECF to plasma distribution ratio for CPT-lactone was higher than that for TPT-lactone, the brain ECF concentrations of TPT-lactone were significantly higher than the CPT-lactone brain ECF concentrations. The relatively high brain ECF to plasma distribution ratio of these two drugs makes them potential candidates for first-line treatment of CNS tumors. Received: 4 May 1998 / Accepted: 5 August 1998     

Effects of various dietary staples on esophageal carcinogenesis induced in rats by subcutaneously administered N-nitrosomethylbenzylamine

Previous epidemiologic studies associated large differences of esophageal cancer risk with the nature of the staple diet. In this study, various cereals and dietary staples were fed to inbred BD IX rats for 7 months or longer. N-Nitrosomethylbenzylamine [(MBN) CAS:937-40-6] was given five times subcutaneously between the 45th and 58th day. The percentage of rats with tumors and the mean number of tumors per esophagus were similar when corn, wheat, commercial bird-resistant sorghum, bananas, and polished rice were fed but were strikingly lower when the basis of the diets was millet, red sorghum, brown rice, or potatoes. The number of esophageal tumors was significantly related to the dietary concentration of some minerals and vitamins. Supplementing marginally deficient corn or wheat diets with various combinations of nicotinic acid, riboflavin, zinc, magnesium, molybdenum, and selenium significantly reduced the numbers of esophageal tumors. When the feeding of protective cereals or nutrients was commenced only 150 days after MBN was given, a marked inhibitory effect on the progression of tumors was still observed.     

Phase I clinical and pharmacokinetic study of thiotepa administered intraperitoneally in patients with advanced malignancies

An important subset of malignancies arising in the ovary or digestive organs remains confined to the peritoneal cavity throughout its natural course. These tumors constitute appropriate targets for loco-regional therapy. With this rationale a clinical phase I and pharmacokinetic study of intraperitoneally administered N, N', N' triethylenethiophosphoramide (thiotepa), an alkylating agent with activity against ovarian carcinoma, was initiated with the objectives of determining the systemic and local toxicities, maximum-tolerated dose, and pharmacokinetic advantage associated with using the drug in this manner. A total of 13 patients received 15 courses of intraperitoneal thiotepa at doses ranging from 30 mg/m2 to 60 mg/m2. The only important systemic toxicity observed was myelosuppression. At 50 mg/m2 two patients developed Eastern Cooperative Oncology Group (ECOG) grade III myelosuppression. At 60 mg/m2, the maximum-tolerated dose, the mean nadir WBC and platelet counts were 2.7 X 10(3)/microliter and 110 X 10(3)/microliter, respectively. There were no instances of vomiting, stomatitis, or alopecia. Pharmacokinetic studies performed in nine patients revealed that thiotepa was rapidly lost from the peritoneal cavity in a biexponential fashion with a mean t1/2 alpha of 0.26 +/- 0.08 hour and a mean t1/2 beta of 2.13 +/- 0.52 hour. Concomitant with the rapid loss of drug from the peritoneal cavity was the rapid rise in drug levels in the plasma, with peak plasma values approaching those associated with intravenous administration. Peritoneal exposure to thiotepa expressed as the area under the curve (AUC)peritoneal fluid was 7 to 34 micrograms/mL X hour. Systemic exposure expressed as the AUCplasma ranged between 0.95 and 7.71 micrograms/mL X hour. The observed pharmacokinetic advantage of intraperitoneal administration calculated as AUCperitoneal fluid/AUCplasma was 4.3 +/- 0.6. This relatively small advantage, combined with our observation of rapid appearance of the active metabolite, tepa, into the plasma argue against an important role for intraperitoneal administration of thiotepa.     

Effects of dietary fish oil and corn oil on protein kinase C distribution in the rat colon with and without 1,2 dimethylhydrazine treatment and in rat colonic adenocarcinoma

The activity and subcellular distribution of Protein Kinase C (PKC) was determined in the colons of Sprague-Dawley rats that were fed either a low fat rat chow or rat chow supplemented with 17% corn oil (40% ingested calories as fat). Rats given the high fat diets were either given no carcinogen or treated prior to or subsequent to the initiation of the test diets with 1,2 dimethylhydrazine (DMH). Rats were sacrificed and PKC activity determined in the soluble and particulate fractions of the colonic tissue 13 weeks after the initiation of the diets or DMH treatment, which was before tumor induction. In addition several rats were maintained on their diets until colon tumor formation occurred and PKC activity determined in the colonic tumor and compared to age matched control colonic tissue. In the absence of DMH, fish oil and corn oil equally augmented PKC activity and decreased the ratio of soluble/particulate PKC. With DMH treatment, corn oil augmented PKC as above, but fish oil supplementation resulted in a pattern of PKC activity and distribution more typical of a low fat diet, particularly when fish oil supplementation preceded DMH treatment. PKC activity in DMH induced colonic carcinomas was markedly depressed regardless of the fat source in the diet, when compared to colonic tissue from a non-DMH treated age matched low fat control.     

Effect of rat liver cytosolic enzymes and cofactors on mutagenicity of 1-amino-8-nitropyrene

1-Amino-8-nitropyrene (1,8-ANP), a product of 1,8-dinitropyrene metabolism by either bacterial or mammalian enzymes, is weakly mutagenic to the 'classical nitroreductase'-deficient Salmonella tester strain TA98NR. The addition to the test system of rat liver cytosol without cofactors did not produce any effect on the 1,8-ANP mutagenic response toward TA98NR strain. Conversely, when both rat hepatic cytosol and NADPH (1 mM) were added to the mutagenicity assay, a 10-fold increase in 1,8-ANP mutagenic activity was observed. This suggests the involvement of rat hepatic cytosolic NADPH-dependent nitroreductase(s) in 1,8-ANP mutagenic activation. The addition to the mutagenesis assay of pentachlorophenol, an inhibitor of O-acetyltransferase and sulfotransferase, produced a dose-dependent decrease of 1,8-ANP mutagenic activation, whereas 2,6-dichloro-4-nitrophenol, a more specific inhibitor of sulfotransferase than O-acetyltransferase, did not affect the activation of 1,8-ANP to a mutagen at concentrations that selectively inhibit only bacterial sulfotransferase. This indicates that bacterial O-acetyltransferase but not sulfotransferase plays a role in the mutagenic activation of 1,8-ANP. Addition of acetyl co-enzyme A (AcCoA) and adenosine 3'-phosphate 5'-phosphosulfate (PAPS), cofactors for O-acetyl-transferase and sulfotransferase respectively, to the test system caused a dose-dependent inhibition of 1,8-ANP mutagenic activation by rat liver cytosol and NADPH, probably due to the formation of highly reactive O-acetoxy and N-sulfate ester derivatives of 1,8-ANP, which react with nucleophilic sites before reaching bacterial DNA. This hypothesis was confirmed by DNA covalent binding in in vitro experiments showing that both the cofactors AcCoA and PAPS enhanced the NADPH/rat liver cytosol-mediated covalent binding of 1,8-ANP to DNA from calf thymus 10- and 3-fold respectively. It seems likely that rat hepatic cytosolic nitroreductases activate 1,8-ANP to an N-hydroxyarylamine derivative which can be further metabolized to mutagenic species by either bacterial or mammalian O-acetyltransferase.     

2-Nitrofluorene metabolism in the rat lung. Pharmacokinetic and metabolic effects of beta-naphthoflavone treatment

Absorption, metabolism and DNA binding of 2-nitrofluorene (NF) was studied in isolated, perfused and ventilated rat lungs and in lung microsomal incubations. Comparisons were made between control animals and animals treated with beta-naphthoflavone (BNF), a 2,3,7,8-tetrachlorodibenzo(rho)dioxin (TCDD) receptor ligand and inducer of cytochrome P450IA1. Clearance of NF increased significantly in the isolated, perfused and ventilated lungs after BNF dosage, from 0.55 +/- 0.06 ml/min to 2.37 +/- 0.62 ml/min (P less than 0.05, n = 5-6). As a consequence of this, the mean residence time (MRT) for NF decreased when NF was dosed directly to the perfusion buffer, from 213 +/- 23 min (n = 6) to 48 +/- 9 min (n = 6), and after intratracheal dosage from 289 +/- 101 min (n = 5) to 135 +/- 72 min (n = 5). Irreversible binding of NF metabolites to DNA increased 2-fold after treatment with BNF when NF was dosed to the lung perfusion buffer. Treatment with BNF increased the rate of lung microsomal NF metabolism significantly, from 54 +/- 5 to 106 +/- 11 pmol/min/mg protein (P less than 0.05, n = 6-12). Formation of the monohydroxylated metabolite X-OHNF was inhibited in vitro by addition of alpha-naphthoflavone (50 microM), by 89 and 98% with lung microsomal fractions from control and BNF-treated rats respectively. In contrast, proadifen (50 microM) preferentially inhibited formation of 9-OHNF, by 42 and 33% in incubations with lung microsomal fractions from control and BNF-treated animals. Anti-P450IIB1-IgG inhibited formation of 9-OHNF by 96 and 45% with lung microsomes from control and BNF-treated rats respectively. Formation of X-OHNF was unaffected by addition of anti-P-450IIB1-IgG in both cases. These results show that both constitutive and inducible microsomal rat lung enzymes metabolize NF. A constitutive enzyme, most likely cytochrome P450IIB1, catalyzes metabolic attack on NF with high preference for the 9-position. A BNF-inducible microsomal enzyme, most likely cytochrome P450IA1, catalyzes hydroxylation of NF both in the 9-position and in other positions. Increased metabolic clearance, metabolism and DNA binding of NF after BNF treatment suggest that the level and specificity of cytochrome P450 isozymes may be important determinants for toxicity and availability of NF in the rat lung.     

Effects of dietary compounds on alpha-hydroxylation of N-nitrosopyrrolidine and N'-nitrosonornicotine in rat target tissues

Male F344 rats were pretreated with various dietary compounds, and the effects of pretreatment on the in vitro alpha-hydroxylation of N-nitrosopyrrolidine or N'-nitrosonornicotine were determined in assays with liver microsomes or cultured esophagus, respectively. Dietary compounds included phenols, cinnamic acids, coumarins, indoles, and isothiocyanates. Pretreatments were carried out either by administering the compound by gavage 2 hr prior to sacrifice (acute protocol) or by adding the compound to the diet for 2 weeks (chronic protocol). Acute pretreatment with benzyl isothiocyanate, allyl isothiocyanate, phenethyl isothiocyanate, phenyl isocyanate, and benzyl thiocyanate but not sodium thiocyanate inhibited formation of alpha-hydroxylation products of both nitrosamines. When the chronic pretreatment protocol was used, only phenyl isothiocyanate and sodium thiocyanate inhibited formation of alpha-hydroxylation products of both nitrosamines. Pretreatments with butylated hydroxyanisole, p-methoxyphenol, or N-acetylcysteine had little, if any, effect on the alpha-hydroxylation of N-nitrosopyrrolidine or N'-nitrosonornicotine. Chronic pretreatment with p-hydroxycinnamic acid, 4-hydroxy-3- methoxycinnamic acid, coumarin, umbelliferone, limetine , indole, indole-3-carbinol, indole-3-acetonitrile, and L-tryptophan induced activity for the alpha-hydroxylation of N-nitrosopyrrolidine. The results of this study indicate that isothiocyanates are possible candidates for further study as potential inhibitors of carcinogenesis by N-nitrosopyrrolidine and N'-nitrosonornicotine.     

Improvement of the antitumor activity of intraperitoneally and orally administered 5,6-dimethylxanthenone-4-acetic acid by optimal scheduling.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), a new anticancer drug that has recently completed Phase I clinical trial, is effective against transplantable murine tumors with established vasculature. We wished to determine the relationship between administration schedule and antitumor activity. EXPERIMENTAL DESIGN: C57Bl/6 mice with s.c. implanted Colon 38 tumors were used for determination of maximal tolerated doses and tumor growth delay. Plasma and tissue DMXAA concentrations were measured by high-performance liquid chromatography. RESULTS: Continuous infusion (30 mg/kg/day for 3 days) and daily i.p. administration schedules (7.5 mg/kg) were ineffective. A pharmacokinetically guided schedule was developed to increase tumor tissue drug concentrations without increasing the maximal plasma concentration. A schedule comprising a loading dose (25 mg/kg, i.p.) followed by supplementary doses (5 mg/kg after 4 and 8 h) provided a 1.6-fold increase in tumor tissue area under the concentration-time curve, no increased toxicity, and superior antitumor activity (100% cure rate, as compared with 55% for a single i.p. dose of 25 mg/kg). A similar strategy was developed for oral administration with a loading dose (30 mg/kg) and supplementary doses (15 mg/kg after 4 and 8 h). It provided a 90% cure rate, in contrast to a single oral dose (0% cure rate). CONCLUSIONS: The antitumor action of DMXAA is schedule dependent, and the achievement of an adequate tumor tissue DMXAA concentration above a threshold value appears to be critical for activity. The use of a pharmacokinetically guided schedule provides excellent oral activity against Colon 38 tumors and provides a basis for developing more effective administration schedules in clinical trials.     

Effects of dietary fats and soybean protein on azaserine-induced pancreatic carcinogenesis and plasma cholecystokinin in the rat

Both dietary unsaturated fat and raw soybean products are known to enhance pancreatic carcinogenesis when fed during the postinitiation phase. A comparison of these two dietary components was made to evaluate the relative potency of each ingredient for enhancing pancreatic carcinogenesis and to determine if this enhancement was correlated with an increase in plasma cholecystokinin (CCK) levels. Male Wistar rats were initiated with a single dose of azaserine (30 mg/kg body weight) at 14 days of age. The rats were weaned to test diets formulated from purified ingredients. Dietary protein at 20% by weight was either casein or soy protein isolate (heat treated or raw). Corn oil was the unsaturated fat of major interest and it was fed at either 5 or 20% by weight. Pancreases were quantitatively evaluated for carcinogen-induced lesions at 2- and 4-month postinitiation. In a second experiment designed to closely mimic the above experiment, rats were implanted with cannulae which allowed plasma to be repetitively sampled over a 2.5-week period during which the test diets were fed. Plasma was collected both prior to introduction of the test diets and afterwards. Plasma CCK was measured by a specific radioimmunoassay. Both the 20% corn oil diet and the raw soy protein isolate diet enhanced pancreatic carcinogenesis. The effects of the raw soy protein isolate on the growth of the carcinogen-induced lesions were significantly greater than the effects of the 20% corn oil diet. Plasma CCK values were not elevated in the rats fed the 20% corn oil diet, but they were significantly elevated in the rats fed the raw soy protein isolate. Heat-treated soy protein isolate neither enhanced carcinogenesis nor elevated the plasma CCK level. This study demonstrates that certain plant proteins enhance the growth of carcinogen-induced pancreatic foci and that this effect is considerably greater than the enhancement by high levels of dietary unsaturated fat. Furthermore, the enhancement by the raw soy protein isolate may be mediated by CCK; but this does not appear to be the mechanism by which the unsaturated fat, corn oil, enhances pancreatic carcinogenesis.     

Effects of dietary lipids on lactogenic hormone receptor binding in rat mammary tumors

Both epidemiologic studies in humans and experiments in laboratory animals have indicated that high-fat (HF) diets promote mammary tumor growth; however, the biochemical mechanisms responsible for this accelerated tumor growth are poorly understood; thus this study was designed to determine whether diet-induced alterations in the lipid composition of mammary tumor cell membranes were associated with differences in lactogenic hormone binding capacity. Mammary tumors were induced with N-methyl-N-nitrosourea in 50-day-old female inbred Buffalo rats that were maintained on either HF or low-fat (LF) diets composed of either 20% corn oil or 0.5% corn oil, respectively. The microsome-membrane fractions of these tumors were then analyzed for specific lactogenic hormone binding with the use of 125-I-labeled human growth hormone. Methylated extracts of these same membrane fractions were also subjected to gas-liquid chromatography. Our results demonstrated that the mammary tumor membranes of the HF group did have a significantly greater lactogenic binding capacity than those of the LF group and that these differences in hormone binding were accompanied by significant alterations in the membrane qualitative fatty acid profiles of each group. Therefore, one way in which dietary lipids may be able to influence mammary tumor growth is by modification of the lactogenic hormone binding capacity of tumor cell membranes.