Effects of smoking and Helicobacter pylori on prostaglandin concentrations in gastric and duodenal mucosa of patients with duodenal ulcer and duodenitis.

The aim of this study was to determine the level of endogenous prostaglandin E2 (PGE2), prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TXB2) in the gastric and duodenal mucosa of patients with duodenal ulcer and duodenitis. Besides, the investigation aimed at determining the effect of smoking and infection by Helicobater pylori on prostaglandin synthesis. The investigation comprised 62 patients with duodenal ulcer, 46 patients with duodenitis and 44 controls. The results of our investigation indicate that the decreased prostaglandin synthesis in gastric and duodenal mucosa determined in patients with duodenal ulcer may have a considerable role in development of duodenal ulcer. Furthermore, the harmful effects of smoking on the gastric and duodenal mucosa may be mediated by the decreased prostaglandin synthesis in the gastric and duodenal mucosa. However, Helicobacter pylori seems to affect the development of duodenal ulcer through other mechanisms.

Arachidonic acid metabolites and sinonasal polyposis. I. Possible prognostic value.

PURPOSE: The etiology of sinonasal polyps is sometimes obscure. This study was undertaken to evaluate the potential role of arachidonic acid metabolites (AAm) on recurrent polyposis. MATERIALS AND METHODS: Tissue production of prostaglandin E2 (PGE2), 6-keto-prostaglandin F1-alpha (PGI2), thromboxane A2 (TxA2), and leukotriene C4 (LTC4) by nasal mucosa was determined by radioimmunoassay in 27 patients with sinonasal polyposis (SNp) and in 10 volunteers. RESULTS: The group of patients with SNp with the evidence of recurrences in postoperative period (Group 1) showed significantly lower PGE2 concentrations than group of patients with SNp recurrences (Group 2). The differences in concentrations of PGI2 in mentioned groups were insignificant. In comparison with other groups, a group of patients who underwent surgery several times for SNp (Group 4) had a higher mean TxA2 concentration. The LTC4 concentrations were the highest in groups of patients where SNp recurrences were observed. When the incidence of polyposis recurrences (within 18 months after surgery) was correlated with the level of LTC4 production at the time of surgery, the rate of recurrence was significantly higher in patients with increased LTC4 level than in those with normal LTC4 levels. CONCLUSIONS: LTC4 might have a prognostic value. The possible role of AAm in occurrence of SNp is apparent and suggests possible role for medical intervention.

Effect of cyclophosphamide on tumor cell sensitivity to the action of immunological effectors.

A single sublethal dose of cyclophosphamide (CY) given to mice with Ehrlich ascites carcinoma (EAC) kills tumor cells and inhibits tumor growth for the first five days after its administration. From day 7 on, treated tumor cells reassume their growth, but their transplantability in normal recipients is greatly reduced for further three weeks more. On the other hand, the transplantability of untreated (control) and CY-treated cells in T cell-deficient mice is similar. Experiments with criss-cross immunization and challenge have shown that CY-treated cells are equally, or even less, immunogenic than un-treated cells. On the other hand, CY-pretreated cells are several times more sensitive to immunological attack of passively transferred immune spleen cells. These data show that CY does not increase the tumor cell immunogenicity but only increases its sensitivity to immunological attack.

Gonadectomy abrogates sex differences in the effectiveness of chemical carcinogenesis in mice.

Sham-gonadectomized and gonadectomized male and female mice were given methylcholanthrene s.c. to assess the influence of sex hormones on carcinogenesis. Gonadectomy decreased the concentration of the respective sex hormone and increased the concentration of the opposite sex hormone. The results showed that androgens enhanced the effectiveness of carcinogenesis, while estrogens had the opposite effect. Gonadectomy effectively abrogated the sex differences in tumor induction.

Effect of three biological response modifiers on chemical carcinogenesis in mice.

The modulation of chemical carcinogenesis by three biological response modifiers was assessed in a mouse model. CBA mice given 20-methylcholanthrene s.c. were treated with peptidoglycan monomer, azure B and indomethacin for one month, either from day 0 or 75 after methylcholanthrene injection to assess their effects on tumor incidence (on days 150 and 300), time of tumor appearance, time of death, and duration and dynamics of tumor growth. All three agents significantly influenced some of the parameters of tumor growth, except tumor incidence on day 300. Highly significant sex differences in tumor appearance and growth were observed. Tumors with late appearance grew faster in comparison to tumors with early appearance. The data presented indicate that the effectiveness of anti-cancer body defense mechanisms can be best defined by the time of tumor appearance.

Lipid-bound sialic acid, prostaglandin E and histamine in head and neck cancer.

Blood concentration of lipid-bound sialic acid (LBSA), prostaglandin E (PGE) and histamine were determined in 37 patients with carcinoma of hypopharynx and larynx (supraglottic and glottic), in 12 non-cancer patients and in 10 healthy subjects. The concentration of LBSA was significantly increased in 94.4% cancer patients preoperatively and fell to somewhat lower levels within 1 month after tumour resection. In patients with complete tumour resection and no tumour recurrences within 2 years, it steadily decreased thereafter, reaching normal levels within 6-24 months after surgery, whereas in patients with tumour recurrences or incomplete tumour resection it rose again within 6 months after tumour resection. Similarly, the concentration of PGE was significantly increased in about two thirds of cancer patients (67.6%) preoperatively, dropped significantly within 1 month after tumour resection and rose again in patients with tumour recurrences. Preoperative histamine concentration was decreased in 24.3% of cancer patients and postoperatively it rose both in patients with or without tumour recurrences.

The influence of cyclophosphamide on antitumor immunity in mice bearing late-stage tumors.

Spleen cells from mice bearing late-stage methylcholanthrene-induced tumor did not show any tumor activity when mixed with tumor cells in Winn's assay. Treatment of these mice with cyclophosphamide (CY) induced a tumor-inhibitory activity in spleen, occurring on day 7 after treatment, reaching its maximum on day 11 and disappearing by day 21. This antitumor activity could not be induced in control, tumor-free or T-deficient tumor-bearing mice. CY-induced tumor-inhibitory activity was immunologically specific, and mediated by Thy-1+, L3T4-, Ly-2+ cells. Contrary to spleen cells from untreated tumor-bearing mice, spleen cells from CY-treated tumor-bearing mice did not suppress the antitumor activity of immune spleen cells in Winn's assay. However, in contrast to immune spleen cells, CY-induced tumor-inhibitory cells did not manifest antitumor activity when transferred systemically (i.v.) into T-cell-deficient tumor-bearing mice. Even more, spleen cells from CY-pretreated mice, harvested 7-15 days after the drug administration, partially suppressed the antitumor activity of concomitantly transferred spleen cells from specifically immune mice. Nevertheless, CY-pretreated mice manifested concomitant immunity, i.e. these mice exhibited higher resistance to a second inoculum of the same tumor than did nontreated mice or even mice with excised primary tumor.

Production of prostaglandin E by squamous carcinoma of the head and neck and adenocarcinoma of gastrointestinal tissue.

The production of prostaglandin E ex vivo was studied in samples of 31 squamous cell carcinomas of the head and neck (SCCHN) and 12 adenocarcinomas of gastrointestinal tract (ACGI). As a control, the PGE production was measured in 22 samples of noninvolved mucosa in patients with SCCHN and 12 samples of gastrointestinal mucosas. The mean PGE production by SCCHN was significantly higher than in normal mucosa. Furthermore, the PGE production by tumors which recurred or spread to regional lymph node within 18 months after surgery was higher than in tumors which did not recur within that interval. Also, production of PGE by noninvolved mucosa was significantly higher in patients in which tumor recurred after surgery than in patients which were tumor free. On the other hand, the mean production of PGE by ACGI was not different from that of normal mucosa. These data show that determination of PGE production might have prognostic significance in SCCHN.

Prognostic significance of plasma prostaglandin E concentration in patients with head and neck cancer.

Plasma prostaglandin E (PGE) levels were determined by radioimmunoassay in 53 patients with various stages (II, III, and IV) of hypopharyngeal and laryngeal squamous cell carcinoma, in 12 non-cancer patients and in 10 healthy volunteers. The mean PGE concentration was somewhat higher in non-cancer patients (mean +/- SD = 34.6 +/- 5.37 pg/ml) than in healthy subjects (28.1 +/- 4.96 pg/ml). In spite of a high data variability, the mean preoperative PGE levels in cancer patients were proportional to the stage of the disease and higher than in non-cancer patients (41.2 +/- 19.7 pg/ml, 52.8 +/- 26.7 pg/ml and 82.0 +/- 34.9 pg/ml in stages II, III and IV respectively). The mean plasma PGE concentration significantly decreased for all tumour stages 15-30 days after surgical removal of the tumour, but rose again in some patients within 6-18 months after surgery. The incidence of tumour recurrences 6 and 18 months after surgery was significantly higher in patients with an increased preoperative PGE level (greater than 43.3 pg/ml) than in those patients with a PGE level within the normal range (less than 43.3 pg/ml). The mortality was also higher in the former group, but the difference did not reach the level of significance. Similarly, the mean preoperative and most postoperative concentrations of PGE were significantly higher in patients in whom tumour recurred within 18 months than in tumour-free patients.

Anti-tumoral and anti-inflammatory effects of biological stains.

The biological stains, methylene blue and its metabolite azure B, were evaluated as anti-tumor and anti-inflammatory agents. Azur B, administered in drinking water to tumor-bearing mice, inhibited the growth of transplanted tumors and the growth of primary tumors induced by methylcholanthrene. Inhibition of growth of primary tumors was observed only in female mice. Azure B also reduced the wet weight of carrageenin-induced granulomas in rats. Azure B, given intravenously to BCG-sensitized mice 15 minutes prior to challenge with lipopolysaccharide, decreased TNF production (to 10% of control values) and prevented death from endotoxic shock. Methylene blue decreased TNF production (to 50% of control values) but did not protect the animals from endotoxic shock. Our results suggest that some of the effects previously ascribed to methylene blue are probably mediated via its metabolite, i.e. azure B. Low toxicity and easy administration of the dyes explain their use in clinical settings.

[Histamine levels in the blood in patients with malignant tumors]. / Razina histamina u krvi kod bolesnika s malignim tumorom.

The concentration of histamine in blood was determined in 22 patients with solid malignant tumors, 16 hospitalized non-cancer patients and 9 healthy subjects. Patients with cancer (mainly carcinomas of the breast and gastrointestinal tract) were divided into two groups: patients with resected primary tumor without known metastases (group I) and patients with present primary tumor with or without metastases (group II). In comparison with the healthy subjects (histamine concentration 69.0 +/- 6.03 ng.ml-1), cancer patients in both groups had significantly decreased levels of histamine in blood. Also, the concentration of histamine in patients with present tumor (group II; 40.1 +/- 3.48 ng.ml-1) vas significantly lower than in patients with resected primary tumor (49.9 +/- 3.14 ng.ml-1). Furthermore, hospitalized non-cancer patients had lower, but not statistically significant, concentration of histamine (59.7 +/- 6.13 ng.ml-1) than healthy subjects. These findings, together with similar data of other authors, suggest that decreased level of histamine in blood might be a good nonspecific marker for onset and progression of solid malignant tumors.

The effectiveness of intravenously administered immune lymphoid cells against intraperitoneally growing tumor correlates with their homing in the recipients' lymphoid organs.

Intraperitoneally growing Ehrlich ascites tumor (EAT) was eradicated by both i.p. and i.v. injection of serum, and by i.p. injection of spleen cells from mice immune to EAT. However, the i.v. injected immune spleen cells were completely ineffective unless the recipients had been pretreated with cyclophosphamide. The analysis of immune response in mice cured by the combination of cyclophosphamide and cell transfer revealed that they developed a humoral-type immunity to EAT and that the transferred spleen cells did not penetrate into their abdominal cavity. The effect of cyclophosphamide correlated with the extent of seeding of the donor-type cells in the recipients' lymphoid organs. Inasmuch as homing in cyclophosphamide-pretreated mice surpassed that in normal mice three to four times, it appeared that the beneficial effect of cyclophosphamide was primarily founded on its enhancement of seeding of the transferred lymphoid cells, implying that homing of these cells is a prerequisite for their anti-tumor activity.

In vivo and in vitro effect of progesterone on the growth of some mouse and human tumours.

The effect of progesterone on the growth of tumours of different morphological and cytokinetic characteristics and origin has been investigated, such as mammary aplastic carcinoma, Ehrlich ascitic and solid tumour, fibrosarcoma, melanoma B-16, myeloid leukaemia and three cell lines, HeLa, HEp-2 and L929. The administration of progesterone has been proved to stimulate the growth of aplastic carcinoma of the breast in vivo. Directly implemented into cell culture of the same tumour it increased the incorporation of 3H-thymidine into DNA. In HeLa and HEp-2 cell cultures progesterone stimulated the population growth of these cells. However, progesterone has shown no effect at all on the growth of fibrosarcoma, melanoma, Ehrlich tumour, myeloid leukaemia and L929 cells, fibroblasts of C3H mice.

Interference of anti-tumor and immunosuppressive effects of cyclophosphamide in tumor-bearing rats. Analysis of factors determining resistance or susceptibility to a subsequent tumor challenge.

Adult rats were given 10(5) or 10(6) Yoshida ascites sarcoma (YAS) cells IP and were treated with cyclophosphamide (CY) given IP in single doses of 20 mg/kg or 100 mg/kg, 2 or 5 days after YAS inoculation. Both the curative effect of CY and subsequent resistance to tumor challenge in rats that survived depended on the dose of injected tumor cells and on the dose and time of administration of CY. These three factors determined whether the host's immune response to tumor antigens would develop and contribute to the overall anti-tumor effects of the chemotherapy. The curative effects of CY were significantly less pronounced in T-cell-deficient than in normal rats. Anti-tumor and immunosuppressive activities of CY exerted opposite influences on the ultimate result of the chemotherapy. Adverse immunosuppressive effects prevailed when the drug was administered early (2 days) after YAS inoculation. In this case the chemotherapy was less efficient and the surviving rats were susceptible to a subsequent tumor challenge. Further analysis showed that the injection of CY 2 days after inoculation of YAS antigens induced strong and specific immunologic tolerance to the tumor. In contrast, when a sufficient amount of tumor antigens (higher dose of tumor cells injected and CY injection delayed) elicited an anti-YAS immune response that was not suppressed by early injection of CY (CY administered 5 days after the tumor) effective eradication of tumor cells and anti-YAS resistance in cured animals were observed.

Treatment of tumours with the combination of WR-2721 and cis-dichlorodiammineplatinum (II) or cyclophosphamide.

The ability of WR-2721 [S-2(3-aminopropylamino)ethyl-phosporothioic acid] to selectively protect the host against the toxic effects of multiple doses of cis-dichlorodiammineplatinum [cis-Pt] or cyclophosphamide [CY] has been studied in mice and rats bearing 3 different tumours. Selective protection against cis-Pt induced nephrotoxicity has been demonstrated under all conditions studied, with the extent of protection being inversely related to the size of the cis-Pt dose. For example, pre-treatment with 200 mg/kg of WR-2721 30 min before each weekly dose of 2 mg/kg of cis-Pt allows the administration of this cytotoxic agent for 3 times longer before nephrotoxic injury. In none of these studies was there tumour protection. The same pattern was observed with CY, but quantitation of the extent of marrow protection was not possible for the multiple treatment studies, due to the longer latent period between induced and observed death with this drug. We conclude, therefore, that for both of these drugs, selective protection of the kidney and marrow is not only maintained under conditions of multiple treatment, but actually enhanced due to the need for smaller doses of cytotoxic agents in these protocols.

Selective inhibition of the nephrotoxicity of cis-dichlorodiammineplatinum(II) by WR-2721 without altering its antitumor properties.

Injection of 200 mg/kg of body weight of WR-2721 30 minutes before graded doses of cis-dichlorodiammineplatinum(II) (cisplatin) increased the resistance of Fischer 344 rats to cisplatin-induced nephrotoxicity by a factor of 1.7, but did not alter the sensitivity of three different transplanted tumors to cisplatin-induced growth delay. As a consequence, it was possible to administer doses of cisplatin which would have been lethal in the absence of WR-2721 injection, resulting in a proportionally greater tumor response. WR-2721 can, therefore, increase the effectiveness of cisplatin therapy through selective protection against the toxic side effects of chemotherapy.

Multicellular tumour spheroids: a model for combined in vivo/in vitro assay of tumour immunity.

Multicellular tumour spheroids (MTS) from 4 mouse tumours (Line 1 lung carcinoma; a fibrosarcoma, FSA; a mammary carcinoma, MCa-11; and SV40-transformed fibroblasts, SV-A31) WEre injected into the abdominal cavity of normal, immunized or tumour-bearing syngeneic mice, recovered after 4-48 h, and their growth measured in vitro for 7-16 days. Both normal and immunized mice inhibited MTS growth, but there was no correlation between the two types of inhibition, suggesting that different immunological processes were involved. For example, the greatest inhibition by normal mice was seen for the weakly immunogenic MCa-11, and the highly immunogenic tumour, SV-A31, was only moderately inhibited. However, the summed inhibition of MTS growth in normal and sensitized hosts corresponded to the behaviour of tumours as s.c. transplants; i.e., was inversely related to the malignancy of the same tumours. The inhibition of MTS by mice bearing identical early tumours (FSA or MCa-11) was comparable to that in immunized mice. Histological sections of SV-A31 MTS in normal or immunized hosts revealed the infiltration of MTS by various types of host cells, mostly polymorphonuclears, macrophages and lymphocytes.

The role of WR-2721 in radiotherapy and/or chemotherapy.

This report summarizes the present status of the proposed use of WR-2721 (S-2-(3-aminopropylamino)-ethylphosphorothioic acid) acid) in radiotherapy and/or chemotherapy. This drug selectively concentrates in normal tissues, both in vivo and in vitro, but is passively absorbed by virtually all of the solid tumors which have been studied. In vivo this drug can increase the resistance to radiation or alkylating agents (nitrogen mustard, cis-platinum, cyclophosphamide, and L-phenylalamine mustard) by factors of up to 3, while leaving the solid tumors to suffer the full effects of either treatment.