Biomedical subjects

G A Storme

Publications and source records attributed to G A Storme.

29 records · Page 2Linked to original sources

PubMed1984

Enhanced recovery from growth inhibition in irradiated M04 spheroids invading into embryonic chick heart fragments in organ culture.

We have studied recovery from growth inhibition in irradiated M04 mouse fibrosarcoma spheroids using various post-irradiation culture conditions. Recovery after irradiation with 18 Gy was significantly higher in M04 spheroids confronting fragments of embryonic chick heart in suspension culture as compared to M04 spheroids confronting pieces of Gel-foam in suspension culture (p less than 0.0007) or to M04 spheroids explanted on coverslips in static culture (p less than 0.006). These observations suggest that the normal tissue might contribute to recovery from growth inhibition in irradiated M04 cell populations.

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PubMed1983

Recovery from growth inhibition in irradiated MO4 spheroids: suspension cultures versus explanted cultures.

Spheroids of MO4 mouse fibrosarcoma cells were irradiated with single doses of photons between 1 and 50 Gy. Growth of irradiated spheroids was followed in suspension culture and after explantation on glass. We found that MO4 spheroids recovered from higher doses of irradiation when they were explanted on glass than when they were kept in suspension culture. These results suggest that irradiated MO4 cell populations may become anchorage-dependent for growth.

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PubMed1982

Vinblastine, Vincristine and Vindesine: anti-invasive effect on MO4 mouse fibrosarcoma cells in vitro.

Inhibition of the invasiveness of MO4 mouse fibrosarcoma cells by the vinca alkaloid, vinblastine (VLB), vincristine (VCR) and vindesine (VDS), has been examined in vitro. At doses between 0.006 microgram/ml (minimal effect) and 0.1 microgram/ml (complete inhibition) these drugs interfered with the invasion of MO4 cells from an aggregate confronting a fragment of embryonic chick heart in three-dimensional culture. We have also examined the effect of these drugs on the following activities of MO4 cells: growth, directional migration and assembly of the cytoplasmic microtubule complex. Growth and directional migration were affected by the same doses of vinca alkaloids as invasion. In contrast with the vinca alkaloids, 5-fluorouracil at 1 microgram/ml inhibited growth but allowed directional migration and invasion. At a dose of 0.3 microgram/ml VLB, VCR and VDS interfered with the assembly of cytoplasmic microtubules, as visible after immunocytochemical staining with tubulin antiserum. Ultrastructural analysis demonstrated that inhibition of invasion in three-dimensional culture corresponds with abolishment of the cytoplasmic microtubule complex. Anti-invasive concentrations of VLB, VCR and VDS represent clinically achievable plasma concentrations. We concluded that the anti-invasive effect of the vinca alkaloids may contribute to their antitumor activity.

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PubMedDate not supplied

Invasiveness and tumorigenicity of MO4 mouse fibrosarcoma cells pretreated with microtubule inhibitors.

MO4 cell aggregates with a diameter of 0.3 mm produced invasive fibrosarcomas after s.c. implantation into the pinna of syngeneic mice. Histology of pinnae fixed 10 min to 5 days after implantation of an aggregate suggested that the tumour was produced by the cells that invaded during the first day, and that the cells remaining in the aggregate were eliminated by the reaction of the host. Before implantation we have pretreated MO4 cell aggregates with 1 microgram/ml of the microtubule inhibitors Nocodazole (ND) and vincristine (VCR), known to inhibit both proliferation and invasion, and with 1 microgram/ml 5-fluorouracil (5-FU), known to inhibit proliferation but not invasion. Tumorigenicity was significantly reduced after treatment with ND or VCR, as compared to treatment with 5-FU or to controls. Histology of pinnae fixed 10 min to 3 days after implantation showed absence or scarceness of invasive MO4 cells after pretreatment with ND or VCR, in contrast with controls or with aggregates pretreated with 5-FU. The effect of ND, VCR and 5-FU on the growth of aggregates in culture on gyrotory shaker was reversible within 1 and 2 days respectively. After treatment with ND or VCR slight alterations in the function of the cytoplasmic microtubule complex remained visible during 3 days in cells migrating from an aggregate explanted on glass. Confrontation of pretreated aggregates with fragments of embryonic chick cardiac muscle in three-dimensional culture indicated that the anti-invasive effect of ND or VCR was reversible in vitro. We concluded that a delay of invasiveness caused by pretreatment with ND or VCR provided the host with the opportunity to eliminate MO4 cells implanted s.c. into the pinna.

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PubMedDate not supplied

Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastasis in limited squamous cell lung cancer? A randomized study.

In order to study the usefulness of treatment with vinblastine (VLB) in the prevention of cancer metastasis in squamous cell lung cancer, 50 patients with locoregional disease were randomized to receive either locoregional RT alone (group A) or a weekly intravenous bolus injection of VLB (6 mg/m2) concurrently with and after locoregional radiotherapy (RT) (55 Gy in 6 weeks) until the appearance of metastases (group B). Neither the incidence of death with metastases, metastasis-free survival (MFS) nor overall survival (S) were significantly affected by treatment with the drug. However, due to the limited number of patients in each group, the power of the statistical test was such to allow only the detection of differences in MFS and S to or more than 80 per cent at the P = 0.05 level. Local tumor response was significantly superior in group B (P less than 0.05). Acute toxicity (dysphagia, myelosuppression) during RT was significantly worse in group B. During long-term therapy with VLB, mild polyneuropathy developed in the majority of patients in group B. Furthermore, seven patients discontinued treatment with VLB during maintenance due to compliance (4) and excessive neurotoxicity (3). This treatment schedule with VLB is not recommended for patients with locoregional squamous cell lung cancer as significant toxicity is present during and after RT and significant increase in MFS and S is lacking. Because of an apparent increase in local response, the combination of VLB and RT merits further investigation in those tumors where local tumor control is crucial.

Aged↗

PubMedDate not supplied

An image analysis system for the quantification of invasion in vitro.

We have tested the value of a computer-assisted image analysis program for the quantitative study of invasion in vitro using experiments that were previously described semi-quantitatively. Mouse fibrosarcoma cell (MO4) aggregates were confronted with precultured fragments of embryonic chick heart in organ culture. Confronting pairs were fixed after 1, 2, 3 and 4 days, and processed for paraffin sectioning and immunostaining with an antiserum against chick heart. The image analysis system allowed separate quantification of two aspects of invasion, namely, occupation of the heart tissue by MO4 cells and degeneration of the invaded heart tissue. Complex combination of occupation and invasion added a qualitative aspect of invasion that has not been described previously and that revealed qualitative differences in invasion under various circumstances.

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PubMedDate not supplied

Role of the host tissue in the anti-invasive activity of the alkyllysophospholipid, ET-18-OCH3, in vitro.

The alkyllysophospholipid, racemic-l-O-octadecyl-2-O-methylglycero-3- phosphocholine (ET-18-OCH3) was previously shown to inhibit invasion of malignant cells into precultured heart fragments (PHF) in vitro. In particular, pretreatment of PHF with 10 micrograms ET-18-OCH3 for 48 h was sufficient to induce in the host tissue resistance towards invasion by mouse MO4 cells. Resistance was obvious when MO4 cells were confronted either immediately (the pretreatment experiment) or after withdrawal of the drug 7 days prior to confrontation (the reversibility experiment). In the present study, the survival of PHF cells in the pretreatment and reversibility experiments was similar to that of untreated PHF cells as determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) test and by the PHF explantation test. The effective anti-invasive concentration was 6 micrograms/ml in the pretreatment experiment while 3 micrograms/ml was sufficient to inhibit invasion in the reversibility experiment. Induction of resistance towards invasion in pretreated PHF was shown to occur not only with MO4 cells but also with mouse LLC-H61 Lewis lung carcinoma and mouse BW-O-Li1 T-lymphoma cells. The increase in molecular weight of N-linked cell surface glycosylpeptides (N-GP) of PHF was apparent in the pretreatment experiment and was enhanced in the reversibility experiment. This effect was completely abolished in cells obtained from pretreated PHF which were converted into a cell suspension and further cultured as a monolayer on tissue culture plastic without drug for 7 days. The results reported here provide additional evidence for the causal involvement of N-GP of the PHF host tissue in the anti-invasive activity of ET-18-OCH3 in vitro.

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PubMedDate not supplied

Antiinvasive activity of hexadecylphosphocholine in vitro.

The antiinvasive and related effects of hexadecylphosphocholine (HePC), a newly synthesized antitumor phospholipid, were studied on malignant murine MO4 cells in vitro and compared to the effects produced by racemic - 1 - 0 - octadecyl - 2 - 0 - methylglycero - 3 - phosphocholine (ET-18-OCH3), the prototype of ether lipids. The effects on cell survival produced by both drugs, determined through the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium-bromide test, was moderate at the antiinvasive concentration of 30 micrograms for HePC and 10 micrograms for ET-18-OCH3 per ml. Growth in suspension culture and directional migration from MO4 spheroids explanted on solid substrate was reduced in the presence of 30 micrograms HePC per ml. Invasion of MO4 cells into precultured heart fragments (PHF) was variably inhibited in the presence of 30 micrograms HePC per ml, while the antiinvasive effect on two epithelial lines was more complete. Invasion was also inhibited in PHF pretreated with 30 micrograms HePC and 10 micrograms ET-18-OCH3 per ml for 48 hours followed by confrontation with MO4 spheroids in drug-free medium. This inhibition of invasion was maintained when PHF was pretreated and kept in drug-free medium for 7 days before confrontation with MO4 spheroids. It was our impression that this phenomenon was more obvious with ET-18-OCH3 than with HePC. After pretreatment of PHF followed by 7-day incubation in drug free-medium, a larger shift towards higher molecular weight of the N-linked cell surface glycosylpeptides (N-GP) was observed with ET-18-OCH3 than with HePC. Removal of terminal sialic acid moieties abolished the shift in PHF pretreated with HePC or ET-18-OCH3 followed or not by further incubation in drug-free medium. The antiinvasive effect on the malignant epithelial cells was complete at 30 micrograms HePC per ml. Areas of differentiation in close contact with the PHF were obvious. We concluded that both ET-18-OCH3 and HePC had antiinvasive activity in vitro. For MO4 cells, this antiinvasive activity was less variable with ET-18-OCH3 than with HePC.

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PubMedDate not supplied

Cellular pharmacokinetics of vinblastine and other vinca alkaloids in MO4 cells.

Accumulation of vinblastine has been studied in different types of cancer cells. We measured the intracellular concentration of vinblastine in MO4 cells and compared it to its extracellular concentration in culture medium. We observed that the ratio of accumulation, expressed as the ratio of intracellular over extracellular vinblastine, was dose-dependent. An initial accumulation level was reached within 30 min and a second dose-induced level after 48 hours. This remained constant for another 5 days. Intracellular accumulation was also seen for vincristine and vindesine but here the phenomenon was less dose-dependent and the maximum level was reached after 6 hours. The accumulation ratio of a single vinca alkaloid in MO4 cells is not different from combined simultaneous exposure with 2 or 3 of the drugs. Energy blocking by sodium azide resulted in an inhibition of the supplementary but not the initial level of vinblastine accumulation. After washing out the medium for vinblastine the intracellular concentration remained about 60 micrograms/ml for 1 microgram/ml vinblastine added to the medium. Based on these results, it is concluded that the accumulation of vinblastine is only partially based on an energy mediated mechanism, in which binding of the drug to at least two types of sites may play an important role.

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PubMedDate not supplied

Action mechanisms of anti-invasive agents.

An anti-invasive activity has been observed with a number of agents in confronting cultures between invasive cell populations and embryonic chick heart fragments. Cytochalasins, microtubule inhibitors and dipyridamole act via intracellular targets. Inhibition of glycosylation of proteins, low temperature and alkyl lysophospholipids alter the plasma membrane. Flavonoids aim at extracellular targets. In a unifying hypothesis we postulate that invasion is due to lack of responsiveness to stop signals that normally retain cells within their tissue boundaries. Some of the anti-invasive agents act on cellular activities that are necessary for invasion; others might act on the stop signal, the perception of and/or the response to this signal.

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PubMedDate not supplied

Phase I trial of erbulozole (R55104).

Erbulozole (R55 104) is a water soluble congener of the microtubule inhibitor tubulozole, which has proven to possess anti-invasive, antitumoral and radiosensitizing capacities. A dose-finding study was performed on respectively 9 patients (every three weeks; doses ranging from 20 mg/m2 to 100 mg/m2; maximum 2 cycles per patient) and 6 patients (weekly; doses ranging from 20 mg/m2 to 50 mg/m2; maximum 60 cycles per patient). At all dosages, hematological and biochemical toxicity was very limited. Seven patients complained of pain at the tumor site (grade I to III). Dose limiting toxicity appeared at respectively 100 mg/m2 (one administration every three weeks) and 50 mg/m2 (weekly administration). At this level, 2 patients displayed a dose-limiting Wernicke's encephalopathy-like syndrome. Other secondary effects were headache, fever, exacerbation of dyspnea and moderate nausea and vomiting.

Adult↗