Hans Peter Rutz

Modification of radiosensitivity and recovery from X ray damage in vitro by retinoic acid

We studied the effects of all-trans retinoic acid (RA) combined with X-irradiation on confluent cultures of human breast cancer (MCF-7) and melanoma (C-143) cell lines, as well as in a normal human diploid fibroblast strain (AG 1522). RA in non-cytotoxic concentrations was a potent inhibitor of confluent holding recovery of potentially lethal damage (PLD repair) for all three cell types. A complete inhibition of recovery was observed at lower RA concentrations in the tumor lines than in the fibroblast strain. Exposure to RA prior to and during irradiation resulted in a radiosensitizing effect that was similar in MCF-7 and AG 1522 cells. The implications of these findings are discussed in terms of the potential value of retinoids as biological response modifiers for the clinical radiotherapy of cancer.

Dexamethasone-induced enhancement of resistance to ionizing radiation and chemotherapeutic agents in human tumor cells

Background: Dexamethasone-induced changes in radioresistance have previously been observed by several authors. Here, we examined effects of dexamethasone on resistance to ionizing radiation in 10 additional human cell lines and strains, and on resistance to carboplatin and paclitaxel in 13 fresh tumor samples.nn Material and Methods: Eight human carcinoma cell lines, a glioblastoma cell line and a strain of normal human diploid fibroblasts were arbitrarily chosen for these in-vitro studies. Effects on radiosensitivity were assessed using a conventional colony formation assay. Effects on resistance to the drugs were investigated prospectively (ATP cell viability assay) using 13 fresh tumor samples from consecutive patients operated for ovarian cancer within the context of a Swiss nation-wide randomized prospective clinical trial (SAKK 45/94)nn Results: Dexamethasone promoted proliferation of 1 of the cell lines without affecting radiosensitivity, while it completely inhibited proliferation of another cell line (effects on radiosensitivity could thus not be examined). Furthermore, dexamethasone induced enhanced radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance in 1 of the 8 carcinoma cell lines examined. In the glioblastoma cell line, there was no effect on growth or radioresistance, nor in the fibroblasts. Treatment with dexamethasone enhanced resistance of the malignant cells to carboplatin in 4 of the 13 fresh tumor samples examined, while no enhancement in resistance to paclitaxel was observed.nn Conclusions: In agreement with previous reports, we found that dexamethasone may induce radioresistance in human carcinoma cells. Including the published data from the literature, dexamethasone induced enhancement in radioresistance in 4 of 12 carcinoma cell lines (33%), but not in 3 glioblastoma cell lines, nor in 3 fibroblast strains. Dexamethasone also induced enhanced resistance to carboplatin with a similar probability in fresh samples of ovarian cancer evaluated prospectively (in 4 of 13 samples; 31%). We worry that induction of resistance by corticosteroids given to patients undergoing either radiotherapy or chemotherapy with agents causing DNA damage might be associated with a reduced clinical responsiveness in a significant fraction of patients with a carcinoma.Hintergrund: In der Literatur gibt es verschiedene Berichte über eine dexamethasoninduzierte Erhöhung der Strahlenresistenz. Wir untersuchten deshalb weitere menschliche Tumorzellinien und Fibroblasten auf induzierbare Veränderungen der Wachstumsfähigkeit und der Strahlenempfindlichkeit. Außerdem prüften wir die Wirkung von Dexamethason auf die Sensibilität von Ovarialkarzinomproben gegenüber Carboplatin und Paclitaxel.nn Material und Methode: Wir untersuchten acht Karzinomzellinien, eine Glioblastomzellinie sowie Hautfibroblasten in Kultur. Die Wirkung auf die Wachstumsfähigkeit der Zellen und auf die Strahlenwirkung wurde unter Verwendung des üblichen Koloniebildungstests bestimmt. Die Wirkung von Dexamethason auf die Effekte der Chemotherapeutika Carboplatin und Paclitaxel wurde an Proben von 13 konsekutiven Ovarialkarzinomen im Rahmen einer klinischen Studie (SAKK 45/94) prospektiv untersucht (ATP cell viability assay).nn Ergebnisse: Dexamethason stimulierte das Wachstum einer Karzinomzellinie, ohne die Strahlenresistenz zu beeinflussen. Außerdem wurde das Wachstum einer anderen Zellinie vollständig gehemmt, so daß die Wirkung auf die Strahlenempfindlichkeit nicht untersucht werden konnte. Dexamethason bewirkte in einer der übrigen Karzinomzellinien eine erhöhte Resistenz gegenüber Bestrahlung. Wachstumsfähigkeit und Strahlenempfindlichkeit von Glioblastomzellen und Fibroblasten wurden nicht beeinflußt. Außerdem induzierte Dexamethason eine erhöhte Resistenz gegenüber Carboplatin in vier der 13 Ovarialkarzinomproben. Eine erhöhte Resistenz gegenüber Paclitaxel wurde hingegen nicht beobachtet.nn Schlußfolgerungen: Diese Ergebnisse bestätigen frühere Berichte über dexamethasoninduzierte Resistenz gegenüber Bestrahlung. Einschließlich der in der Literatur publizierten Daten findet sich eine dexamethasoninduzierte Erhöhung der Resistenz in vier von zwölf evaluierbaren Karzinomzellinien (33%), nicht jedoch in den drei Glioblastomzellinien oder in Fibroblasten. Dexamethason erzeugte ähnlich häfuig, nämlich in vier von 13 Proben (31%), eine erhöhte Resistenz gegenüber Carboplatin. Dexamethasongabe könnte sich deshalb negativ auswirken.

Strategies for the Prevention of Treatment-Induced Secondary Cancer

The risk of treatment-induced secondary cancer in patients with malignant disease is becoming more important as the treatment of primary tumors improves and more patients survive. A possible genetic or congenital predisposition, altered immunity, and the preceding or continuing exposure to certain other agents may add to the carcinogenic potential of chemotherapy and radiotherapy. It has been observed that aggressive, though successful, treatment protocols in particular enhance the risk. Some studies have reported that up to 20% of surviving patients develop a treatment-induced secondary cancer over a ten to fifteen year period following the control of the first malignancy. Effective means for the prevention of treatment-induced cancer are therefore needed. In this article, we discuss several strategies that may reduce the risk of treatment-induced cancer; namely, new multiple-drug regimens, proton beam therapy, application of tumor sensitizers, and the use of agents that inhibit malignant transformation.

Exogenous lactate modifies the repair of potentially lethal damage in three human tumor cell lines irradiated in vitro.

Lactate is one of several pathophysiological factors accumulating in the micromilieu of tumors under both hypoxic and well-oxygenized conditions, and thus may affect the recovery of irradiated tumor cells in vivo. In the present study, we investigated the effects of postirradiation incubation with exogenous lactate during confluent holding recovery on the repair of potentially lethal damage in three human tumor cell lines. Recovery was either unaffected or enhanced by low concentrations of exogenous lactate (2-5 mM), whereas it was suppressed by higher concentrations (10-50 mM). With high concentrations, survival in all three cell lines was lower at the end of the confluent holding period than at the beginning, yielding recovery ratios of less than 1.0. The effects differed quantitatively among the three tumor cell lines, and between the tumor cells and the normal diploid fibroblasts (AG 1522) studied previously.

Age-dependent modification by lactate of repair of potentially lethal damage in normal human diploid fibroblasts

We investigated age-related changes in normal human diploid fibroblasts (strain AG 1522) followed throughout their lifespan in vitro. Radiosensitivity and the capacity to repair potentially lethal radiation damage (PLD) remained constant until senescence was reached. However, the effects of incubation with lactate on PLD repair were age dependent and complex. Low millimolar concentrations of lactate increased the capacity to repair PLD, whereas higher concentrations suppressed it in a concentration-dependent manner. With increasing in vitro age, the cells became less sensitive to the modifying effects of lactate; in presenescent cells, the modifying effects of lactate on PLD repair had completely vanished.