Drug resistance, which so often accompanies tumor progression, has been shown to be related to changes in membrane properties which may result in decreased drug accumulation in the tumor cell. A correlation between sensitivity to thermochemotherapy and degree of malignancy was found in the AKR lymphoma system. Hyperthermia increased adriamycin (ADR) uptake and concomitantly its cytotoxicity to AKR lymphoma cells. Moreover, these effects were more pronounced on a variant of high malignancy (HM) than on a low malignancy (LM) one. Fluorescent microscopy, as well as cytofluorometry, indicated that lymphoma cells treated by ADR at 43 degrees C were more permeable to the cytotoxic agent than those exposed to the chemotherapeutic substance at 37 degrees C. Cytofluorometry indicated the presence of a minor cell subpopulation with low ADR uptake in the HM variant, not found in the LM one. Fluorocytometry also showed that the temperature-dependent increased ADR uptake was more marked in the HM than in the LM variant, explaining the differential effect of thermochemotherapy on the two lymphoma variants. However, correlation between degree of malignancy and sensitivity to thermochemotherapy is not a general feature. In contrast to the results obtained in the AKR lymphoma system, in the B16 melanoma the low malignancy variant, F1, was more markedly affected by the combined treatment than the F10 variant. The increased cytotoxic effect of ADR by supranormal temperatures in the F1 variant was shown to be due to an augmented drug uptake. The results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane. However, the data also indicate the necessity of assaying cancer treatment modalities, including those designed to circumvent drug resistance, on various tumor system models.

Animals↗

PubMedDate not supplied

[Drug addiction prevention in the workplace--feasibility study in a company from the chemical industry].

INTRODUCTION: In recent years drug prevention at the place of work has became increasingly important for programmes focussing on health promotion at the place of work. Drug prevention programmes aim at reducing cost and protecting the employees from physical harm. There are virtually no reliable figures from surveys in companies. To date intervention programme in companies have hardly been verified. In this feasibility study we intended to examine the practicability of an evaluation of an intervention programme in a large chemical company by means of questionnaires and we present preliminary intervention effects. METHODS: In the context of a pilot study we conducted and evaluated a drug prevention programme at the place of work. Focus was on illegal designer drugs. The programme was conducted as a one-day workshop for trainers in superior management positions. We used a feedback form and a detailed questionnaire on drug prevention in the working place. 41 trainers who participated in the seminar were compared with a control group of 12 trainers who did not participate. RESULTS: The intervention programme was well accepted by the participants. Follow-up data demonstrated, that participants in the seminar had far better knowledge of the employment agreement on addiction and drugs and of the possible ways to get help and they were far more active in realising the employment agreement. CONCLUSION: To achieve a long-term improvement of drug abuse in companies it is not enough to include and implement a passage on drug abuse and addiction in the employment agreement. Well-instructed trainers talk far often with colleagues displaying abnormal or addictive behaviour, resulting in more rapid therapeutic interventions.

Chemical Industry↗

PubMedDate not supplied

Second-line treatment with high-dose 5-fluorouracil and folinic acid in advanced colorectal cancer refractory to standard-dose 5-fluorouracil treatment.

Results with second-line treatment of advanced colorectal cancer are poor. Preliminary phase I/II results suggest encouraging response rates to high-dose 5-fluorouracil (FU) (2,600 mg/m2) combined with folinic acid (FA) in pretreated patients with advanced colorectal cancer. To determine the significance of weekly high-dose FU/FA in colorectal cancer refractory to weekly standard doses of FU/FA, a phase II study was initiated. 69 patients with metastatic colorectal cancer refractory to first-line weekly standard-dose FU/FA were treated with weekly high-dose FU 2,600 mg/m2 combined with FA 500 mg/m2 as a 2-hour infusion prior to FU application. Pretreatment was highly homogenous and consisted of weekly FU 500 mg/m2 combined with FA 500 mg/m2 or FA 20 mg/m2 or the pure stereoisomer of FA (6S-FA) 250 mg/m2. At the time of disease progression under first-line therapy, patients were transferred to high-dose FU/FA within 4 weeks. Treatment was continued until tumor progression under therapy was documented. Of the 69 evaluable patients, 17 (24.6%) achieved partial response (PR), 42 (60.9%) had no change (NC) and 10 (14.5%) had progressive disease under therapy. The median duration of PR was 7 months, the median time to progression of NC was 4 months. Median survival of all patients was 9 months, of patients with PR, 11.5 months. 33/38 patients with tumor-related pain experienced impressive relief under therapy. Prognostic factors for a beneficial outcome were complete response/PR under first-line therapy, a small number of metastatic sites and a good Karnofsky performance status. Moderate toxicity was observed, and the pattern of toxic events and severity did not differ from standard-dose FU regimens.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Combination of 5-fluorouracil, adriamycin, ifosfamide and cisplatin in metastatic adult soft tissue sarcoma: results of a phase II study.

Treatment results of advanced soft tissue sarcomas are still suboptimal. To evaluate the clinical effects of a combination therapy (FADIP) with Adriamycin (ADM), ifosfamide (IFO), cisplatin (DDP) plus continuous infusion of 5-fluorouracil (FU) as a synergistic factor for alkylating agents, a phase II study was initiated in patients with advanced soft tissue sarcomas of different histological subtypes. Fifty-six previously untreated patients with advanced soft tissue sarcomas of different histological subtypes (24 females, 31 males, median age 51.3 years, median Karnofsky performance status 80%) were included in this study. Treatment consisted of ADM 50 mg/m2 i.v. on day 1, IFO 4,000 mg/m2 i.v. on day 1, mesna 800 mg/m2 i.v. 3 x with 8-hour intervals on day 1 starting with IFO administration, FU 500 mg/m2 i.v. as 24-hour infusion on days 1 + 2, DDP 100 mg/m2 i.v. on day 2. This regimen was repeated every 4 weeks for at least 2 cycles. Major WHO grade III/IV hematological toxicity was observed in 35/56 patients. One toxic death due to severe neutropenia and fungal pneumonia occurred. Granulocyte colony-stimulating factor was administered in 8/35 neutropenic patients. Time to recovery was significantly reduced and no infectious complication was observed. WHO grade III/IV toxic diarrhea was observed in 8 patients requiring intravenous fluid replacement. WHO grade III/IV nausea occurred in 11 patients, 9/11 responded to symptomatic treatment with ondansetron alone. The overall response rate was 30.3%. The median duration of response (complete/partial response, CR/PR) was 18.1 months, the median progression-free interval was 4.5 months. The median survival time of all patients was 11.8 months, and 18.1 months in responding patients (CR/PR). Tumor-related pain was effectively reduced in 15/31 patients under treatment. FADIP produces comparable response rates to other standard treatment regimens in soft tissue sarcomas. Prolonged duration of response and median survival may be due to the use of continuous infusion of FU as a synergistic factor to alkylating agents. Granulocyte colony-stimulating factor is effective in reducing the otherwise observed high rate of WHO grade III/IV hematological toxicity with severe neutropenia.

Antineoplastic Combined Chemotherapy Protocols↗

PubMedDate not supplied

Intraperitoneal infusion of glucose-based dialysate in the rat--an animal model for the study of peritoneal advanced glycation end-products formation and effect on peritoneal transport.

OBJECTIVE: Glucose-based dialysate induces non enzymatic glycation within the peritoneal cavity. To evaluate the relationship between the formation of advanced glycation end-products (AGEs) and peritoneal transfer for small solutes and macromolecules, we developed a model of simulated peritoneal dialysis (PD) in normal rats. METHODS: Male albino rats of the Charles River strain were divided into two sets of 3 groups (15-25 rats in each group). In the experimental (E) group, the rats were intraperitoneally (i.p.) injected daily with a commercially available 4.25% dextrose solution. In the control puncture (CP) group, the peritoneum was punctured daily, but no PD solution infused. In an age-matched control (CC) group, no intervention was given. Two study protocols were used. Protocol A (duration 20 weeks) consisted of a daily i.p. injection of 10 mL PD solution per 100 g body weight. In protocol B, a double volume of PD solution was introduced (20 mL per 100 g body weight). At 9, 16, and 20 weeks in protocol A, and at 9 weeks in protocol B, urea, creatinine, microalbumin [(MAL) measured using specific anti-rat albumin monoclonal antibody], and AGEs (measured by fluorescent assay with excitation at 370 nm and emission at 440 nm) were measured in peritoneal effluent and serum. RESULTS: At no time during the study were AGEs detected in serum from any group in either protocol. In both protocols, no differences were found between the control groups (CP, CC) with respect to all parameters. In protocol A, the dialysate-to-plasma ratio (D/P) of urea was significantly higher in the experimental group as compared with the control groups at 9, 16, and 20 weeks [9 weeks: 0.59 +/- 0.03 (E) vs 0.39 +/- 0.02 (CP) vs 0.46 +/- 0.02 (CC), p < 0.0004 and p < 0.002, respectively; 16 weeks: 0.71 +/- 0.08 (E) vs 0.42 +/- 0.01 (CP) vs 0.46 +/- 0.01 (CC), p < 0.0001 and p < 0.02, respectively; 20 weeks: 0.57 +/- 0.03 (E) vs 0.39 +/- 0.01 (CP) vs 0.41 +/- 0.02 (CC), p < 0.002 and p < 0.004, respectively]. At 16 and 20 weeks, dialysate MAL levels were significantly increased in group E [16 weeks: 354.00 +/- 80.35 microg/mL (E) vs 134.75 +/- 14.36 microg/mL (CP) vs 110.69 +/- 7.83 microg/mL (CC), p < 0.04 and p < 0.03, respectively; 20 weeks: 283.17 +/- 14.71 microg/mL (E) vs 105.14 +/- 12.11 microg/mL (CP) vs 135.50 +/- 19.03 microg/mL (CC), p < 0.00001 and p < 0.0001, respectively]. In protocol B, at completion of the study (week 9), D/P urea, effluent MAL, and AGEs were significantly higher in the experimental group as compared with the control groups [D/P: 0.67 +/- 0.04 (E) vs 0.46 +/- 0.07 (CP) vs 0.41 +/- 0.02 (CC), p < 0.0002 and p < 00001, respectively; MAL: 336.8 +/- 63.30 microg/mL (E) vs 125.71 +/- 16.77 microg/mL (CP) vs 119.00 +/- 39.75 microg/mL (CC), p < 0.008 and p < 0.007, respectively; AGEs: 265.77 +/- 33.49 U/mg creatinine (E) vs 163.10 +/- 21.99 U/mg creatinine (CP) vs 83.17 +/- 22.66 U/mg creatinine (CC), p < 0.02 and p < 0.001, respectively]. Peritoneal effluent AGEs were found to be significantly correlated with D/P urea and dialysate MAL (r = 0.42, p < 0.04, and r = 0.7, p = 0.00001, respectively). CONCLUSIONS: In situ generation of AGEs constitutes the chief origin of peritoneal AGEs. Advanced glycation end-products affect peritoneal permselectivity for both small and large solutes. The rat model of simulated peritoneal dialysis developed in this experiment provides a reliable method for studying peritoneal AGE formation and effect on peritoneal transfer of small solutes and macromolecules.

Animals↗

PubMedDate not supplied

The effect of advanced glycation end-products and aminoguanidine on TNFalpha production by rat peritoneal macrophages.

OBJECTIVE: To evaluate the effect of advanced glycation end-products (AGEs) and the inhibitor of their formation, aminoguanidine, on tumor necrosis factor-alpha (TNFalpha) production (as a functional marker) by rat peritoneal macrophages (PMphi). DESIGN: Charles River rats underwent a daily intraperitoneal injection of peritoneal dialysis solution [(PDS), 4.25 g/dL dextrose; Dialine, Travenol, Ashdod, Israel] for a 2-month period (group E). Another group of rats was subjected to the same protocol with the addition of 25 mg/kg aminoguanidine (group A). Three control groups were utilized: (1) rats that were injected daily with aminoguanidine only (group AO), (2) rats that were injected with Dulbecco's phosphate-buffered saline (group D), and (3) rats in which no intervention was carried out (group C). After 2 months, PMphi were isolated from rat peritoneal effluent and their TNFalpha production measured by ELISA in cell-free culture supernatants, in both the basal state and after 24-hour stimulation with lipopolysaccharide (LPS). The concentrations of AGEs in peritoneal effluent were assayed and correlated to TNFalpha levels. PMphi obtained from normal rats were then incubated for 24 hours with (1) the peritoneal effluent of each of the above respective groups, with or without LPS; (2) increasing concentrations of AGEs (0-250 microg/mL); and (3) increasing concentrations of aminoguanidine (0-7.5 mg/mL), and TNFalpha secretion again determined. RESULTS: After 2 months of daily intraperitoneal injection of PDS, in the basal state, TNFalpha production was significantly higher in PMphi isolated from the peritoneal effluent groups (groups E, A, and AO) compared to controls (group C). Following LPS stimulation, a further increase in TNFalpha secretion was seen, with a significantly greater response in group AO versus groups E, A, and D. Effluent AGEs were markedly elevated only in group E. No correlation was found between TNFalpha secretion by these PMphi and the concentration of AGEs. On incubation with the respective peritoneal effluents (groups E, A, and AO), in both the basal and stimulated state, TNFalpha production by PMphi from normal rats was significantly enhanced compared to group C. Incubation with increasing concentrations of AGEs or aminoguanidine resulted in an increase of TNFalpha secretion by these PMphi. CONCLUSIONS: Following intermittent intraperitoneal administration of glucose-based PDS, rat PMphi are chronically activated, as evidenced by increased basal TNFalpha secretion. The peritoneal effluent of such treated animals is capable of stimulating TNFalpha production by normal rat PMphi. These data suggest that glucose-based PDS acts as a primer of PMphi, which retain their ability to further stimulation by LPS. Although, in vitro, AGEs promote TNFalpha secretion by normal rat PMphi, in vivo, their influence is probably modulated by other factors. Aminoguanidine has a specific inducing effect on rat PMphi, independent of glucose-based PDS.

Animals↗

PubMedDate not supplied

A model for cancer treatment in advanced compared to early cancer.

Loss of sensitivity to drugs following tumor progression constitutes the main reason for failure of treatment in advanced cancer. In view of the dynamic nature of neoplasms, models of tumor progression should be used for the testing of drugs. In the present study, two variants of malignancy of AKR lymphoma were used as a model of tumor progression to test various treatment modalities. The two variants, TAU-39 (of low-malignancy) and TAU-38 (of high-malignancy) differed in the pattern of local tumor growth as well as in the rate of metastatic spread and mice killing capacity. The efficiency of chemotherapy, immunotherapy and hyperthermia on the two variants was compared. The low-malignancy tumor was more sensitive to adriamycin than the high-malignancy one. Administration of levan-activated macrophages at the tumor site inhibited the growth of TAU-39. However, growth of the high-malignancy variant was stimulated by macrophages. Hyperthermic treatment was, in contrast to the other treatments, more effective against the high - than against the low-malignancy tumor. Models of tumor progression used in tests for antitumoral drugs may help in the discovery of treatment modalities effective also for advanced stages of cancer.

Animals↗

PubMedDate not supplied

[Obstructive inflammatory fibroid polyp of the cardia].

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Cardia↗