Treatment of advanced colorectal cancer with doxorubicin combined with two potential multidrug-resistance-reversing agents: high-dose oral tamoxifen and dexverapamil.

On the basis of the overexpression of the MDR1 gene in human colorectal cancer, which may constitute a molecular basis for intrinsic drug resistance that can be reversed, and because of the limited therapeutic value of conventional cytotoxic treatment in this common disease, the present phase II study of P-glycoprotein-directed double modulation was initiated. Fifteen patients with measurable metastatic colorectal cancer, all of whom were refractory to first-line chemotherapy with 5-fluorouracil/leukovorin, were entered in this trial. Treatment consisted of 80 mg tamoxifen twice daily on days 1-9, oral dexverapamil every day on days 7-9, and 60 mg/m2 doxorubicin given by intravenous bolus injection on day 8. Courses were repeated every 4 weeks. After a median of three (between one and six) courses, none of the 14 evaluable patients had objective response, and 4 had stable disease. Adverse reactions consisted mainly of myelosuppression (WHO grade IV granulocytopenia was noted in 40%), and mild and reversible dexverapamil-related cardiovascular side-effects, specifically hypotension (47%). Our results suggest that, despite the histological demonstration of high levels of P-glycoprotein in colorectal cancer and administration of two potentially synergistic chemosensitizers, we were unsuccessful in circumventing its primary resistance to chemotherapy.

Phase I/II trial of dexverapamil, epirubicin, and granulocyte-macrophage-colony stimulating factor in patients with advanced pancreatic adenocarcinoma.

BACKGROUND: The purpose of this study was to determine the maximum tolerated dose (MTD) of a cytotoxic regimen consisting of the second-generation chemosensitizer dexverapamil (DVPM), high dose epirubicin, and recombinant human granulocyte-macrophage-colony stimulating factor (GM-CSF) in pancreatic carcinoma. PATIENTS AND METHODS: Twenty-eight previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were studied. Treatment consisted of oral DVPM at a dose of 1000-1200 mg/day for 3 days, epirubicin administered as an intravenous bolus injection on Day 2 with an initial dose of 90 mg/m2, and a dose of GM-CSF of 400 micrograms administered subcutaneously from Day 5s through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of four to eight patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. RESULTS: Hematologic toxicity, specifically granulocytopenia, constituted the dose-limiting toxicity with an MTD of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, four, two, and five patients experienced Grade 4 granulocytopenia during their first two treatment courses at levels 105, 120, and 135 mg/m2, respectively. Grade 4 granulocytopenia was observed in two, three, and one additional patients during subsequent courses with these levels. Nonhematologic toxicity was uncommon, generally modest, and did not correlate clearly with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Nine of 28 patients achieved partial responses to this therapy. Stable disease was observed in nine patients, and tumor progress occurred in 10. CONCLUSION: The MTD of epirubicin for this regimen with DVPM and GM-CSF was 120 mg/m2 every 3 weeks. Though it remains uncertain whether the encouraging response activity observed in this disease-oriented Phase I study was, in fact, due to successful modulation of multidrug resistance, these results suggest that this regimen is likely to be an effective and tolerable treatment strategy for patients with pancreatic cancer, which should be evaluated further.

Phase I/II trial of dexverapamil, epirubicin and granulocyte/macrophage-colony-stimulating factor in patients with advanced pancreatic adenocarcinoma.

A group of 28 previously untreated patients with locally advanced or metastatic adenocarcinoma of the pancreas were entered in this phase I/II study. Treatment consisted of oral dexverapamil 1000-1200 mg/day for 3 days, epirubicin given as an intravenous bolus injection on day 2 with a starting dose of 90 mg/m2, and 400 micrograms granulocyte/macrophage-colony-stimulating factor (GM-CSF) administered subcutaneously from day 5 through 14. Epirubicin dose escalation levels were 90, 105, 120 and 135 mg/m2. Consecutive cohorts of 4-8 patients were planned at each dose level. Treatment cycles were repeated every 3 weeks. Haematological toxicity, specifically granulocytopenia constituted the dose-limiting toxicity with a maximum tolerated dose of 120 mg/m2 for epirubicin. Despite routine supportive therapy with GM-CSF, 4, 2, and 5 patients experienced grade 4 granulocytopenia during their first two treatment courses at levels of 105, 120, and 135 mg/m2 respectively. Non-haematological toxicity was uncommon, generally modest, and did not demonstrate a clear relationship with the anthracycline dose. Dexverapamil-related cardiovascular symptoms occurred frequently, but they never resulted in serious toxicity requiring active medical intervention or permanent discontinuation of therapy. Of the 28 patients, 9 achieved partial reponses to this therapy. The recommended dose of epirubicin for this regimen with dexverapamil and GM-CSF is 120 mg/m2 every 3 weeks. Therapeutic results suggest this regimen to be an effective and tolerable treatment strategy in pancreatic cancer, which should be evaluated further.

Sister-chromatid exchange induction by metabolically activated retinoids in human diploid fibroblast cultures.

13-cis-Retinoic acid, retinyl-mthyl-ether, retinyl-phenyl-ether, retinyl-thio-ether and axerophthene each induced dose-dependent sister-chromatid exchanges (SCE) in human diploid fibroblasts. The functional relationship between retinoid concentration and SCE rate was similar in each of the 5 retinoids tested. The relationship reached a plateau at concentrations exceeding 8 micrograms/ml. alpha-Naphthoflavone (ANF), an inhibitor of P448-dependent mono-oxygenase, prevented the retinoid-induced increase of the SCE rate, but had no inhibitory effect in the presence of 4-nitroquinoline-1-oxide, an ultimate carcinogen. ANF did not reduce the spontaneously increased SCE rate in fibroblasts of patients with Bloom's syndrome. Retinoids failed to induce SCE in V79 Chinese hamster cells, which lack mono-oxygenase. Thus, we conclude that the retinoid-induced SCE rate increases independently of structural changes in the molecular side-chain ad that a metabolic activation of retinoids is required for SCE induction by cytochrome P448-dependent mono-oxygenase.

["Hair-spray lung". Clinical and morphological findings]. / "Haarspray-Lunge". Klinische und morphologische Befunde.

We present two cases of an uncommon lung disease. The considerable decrease in respiratory function was in sharp contrast with the moderate changes seen in the lung. Whereas the radiographs only revealed a milky and a slightly reticular cloudiness of the lungs, pulmonary vital capacity and compliance were reduced to one half of the standard value. Open lung biopsies were performed. Histological examination showed a fibrosing alveolitis with considerable response and foreign body reaction of the alveolar and interstitial macrophages. Intraalveolar and interstitial granulomas included macrophages and multinucleated giant cells of the foreign body type. They frequently enclosed PAS-positive material. Ultrastructural examination revealed distinct lysosomal inclusions in the macrophages and giant cells. Similar inclusions were induced in guinea pigs by hair-spray components. These findings led to the diagnosis of an exogenous thesaurosis of the lung. Prolonged and excessive exposure to hair-sprays could be established in both cases. Upon termination of the exposure, a marked improvement occurred in both patients within half a year. Extreme exposure to hair-spray may cause alterations of the lung parenchyma, including a so-called "hair-spray lung". The present report is directed towards a better understanding of this particular disease which is one of the numberous conditions induced by the increasing air pollution.

Alveolitis due to hair-spray. Ultrastructural observations in two patients and the results of experimental investigations.

Observation of two patients with hair-spray induced lung disease have prompted us to study the ultrastructure of the lung lesion. We have compared the results with experimental lesions in animals injected with hair-spray extracts and with human monocyte cell cultures exposed to hair-spray. The lungs show a chronic alveolitis with a striking granulomatous reaction including macrophages and multinucleated giant cells of the foreign body type. The intraalveolar and interstitial macrophages and the giant cells all contain PAS-positive material. Ultrastructurally distinct lamellar inclusions are found in the secondary lysosomes of the macrophages and giant cells. Identical structures can be produced in animals injected with hair-spray extracts and with polyvinyl-pyrrolidone and -acetate (PVP/PVA), which are regular ingredients of hair-sprays. Large, presumeably polymeric particles (PVP/PVA) are ingested by giant cells. This "gigantophagocytosis" is associated with the fusion of mononuclear phagocytes and leads to the genesis of giant cells. In cell cultures of human blood monocytes hair-spray extracts and PVP/PVA induce maturation and aggregation of these cells, with PAS-positive cytoplasmatic inclusions. The development of multinuclear giant cells in these monocyte cell cultures is also seen. These observations suggest that hair-spray induced lung disease is caused by the prolonged and extensive body response of the local mononuclear phagocyte system (MPS). Overstimulation of the MPS leads to a quantitative and qualitative change which is followed by a partial blockade of this system. The alveolitis is a consequence of the foreign body response to inhaled hair-spray substances.

[Lymphocytic and non-lymphocytic dysplasia, carcinoma in situ and infiltrating squamous cell carcinoma of the cervix (author's transl)]. / Lymphozytäre und nichtlymphozytäre epitheliale Tumoren der Portio.

The degree of lymphocytic infiltration in 490 cases of infiltrating squamous cell carcinoma, carcinoma in situ, and dysplasias of the cervix was studied. 204 cases did not show any lymphocytic infiltration at the site of dysplasias, carcinoma in situ, and infiltrating squamous cell carcinoma. The degree of lymphocytic infiltration was furthermore not related to the grade of dysplasia. Taking into account all cases it was found that 75% of carcinoma in situ and infiltrating squamous cell carcinoma remained without or with only sparse lymphocytic infiltrations.