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Biomedical subjects

G Los

Publications and source records attributed to G Los.

At least 55 records · Page 3Linked to original sources
PubMed1991

Cellular pharmacokinetics of carboplatin and cisplatin in relation to their cytotoxic action.

We have studied the cellular pharmacokinetics of carboplatin (CBDCA), as part of the evaluation of the antitumor activity of CBDCA in cancers limited to the peritoneal cavity in comparison with cisplatin (cDDP). The uptake of CBDCA into L1210 (lymphosarcoma), CC531 (colonic carcinoma), COV413.B (human ovarian carcinoma) and NB1 (human neuroblastoma) cells was 1.5 to 13 times lower than the uptake of cDDP. The uptake of CBDCA into human ovarian carcinoma cells, taken directly from patients, was also 8-20 times lower than cDDP. Platinum concentrations, expressed as a percentage of the total intracellular Pt concentration, were similar for CBDCA and cDDP in cytosol and nucleus/membrane fractions. A second major difference between the drugs was their binding to DNA. Less CBDCA-DNA than cDDP-DNA adducts were formed after incubation at equimolar amounts of drug with isolated salmon sperm DNA (5-25 times less). A 16-69 times higher concentration of CBDCA than cDDP was needed to induce similar changes in cell growth activity (50% [3H]thymidine inhibition) in CC531 and COV413.B cells, indicating that equitoxicity can only be achieved when tumor cells are exposed to higher concentrations of CBDCA than cDDP. Similar toxicity was achieved in CC531 cells after incubation with a 16-fold higher CBDCA dose than cDDP. Comparable intracellular platinum concentrations, however, were obtained with a 10-fold higher CBDCA dose, suggesting that cellular pharmacokinetics of the drugs are different. Regarding drug uptake and pharmacokinetics the mechanism of action of CBDCA differed from cDDP at a cellular level.

Animals↗
PubMed1991

Penetration of carboplatin and cisplatin into rat peritoneal tumor nodules after intraperitoneal chemotherapy.

Platinum distribution was studied in rat peritoneal tumors after i.p. treatment with equimolar doses of carboplatin and cisplatin. Low platinum concentrations (4 ppm) were detected in the periphery of the tumor after carboplatin treatment, whereas no platinum was detected 0.5 mm in from the periphery. In contrast, after cisplatin treatment, high platinum concentrations (29 ppm) were measured in the periphery of the tumor and moderate concentrations (14 ppm) were measured in the center. Only following increased carboplatin doses were low platinum concentrations detectable in the tumor. The total platinum concentration in the tumors was determined after equimolar administration of both drugs. In all, 7 times more platinum was detected after cisplatin treatment than after carboplatin treatment, and 10 times more carboplatin than cisplatin had to be injected to obtain comparable platinum concentrations in the tumors. When single cells were incubated with equimolar concentrations of carboplatin and cisplatin, 6-7 times more platinum was found in cells treated with cisplatin. However, pharmacokinetic studies favored i.p. administration of carboplatin because the clearance of this compound from the peritoneal cavity, expressed as t1/2 beta, was lower than that of cisplatin (239 vs 78 min), resulting in an AUC in the peritoneal cavity for both total and ultrafiltered drug that was almost 3 times higher for carboplatin than cisplatin. The AUC for ultrafiltered carboplatin in plasma was 2-fold that for cisplatin (2,801 +/- 210 vs 1,334 +/- 431 microM m). The present study demonstrated that in spite of the pharmacological advantages of carboplatin, its capacity to penetrate into peritoneal tumors and tumor cells is far lower than that of cisplatin.

Animals↗
PubMed1991

Optimisation of intraperitoneal cisplatin therapy with regional hyperthermia in rats.

The purpose of this study was to optimise intraperitoneal chemotherapy by combining this modality with regional hyperthermia. In vitro data demonstrated that both the uptake of cisplatin into CC531 tumour cells and cytotoxicity were increased at temperatures of 40 degrees C (factor 4) and 43 degrees C (factor 6) compared to 37 degrees C. The increase of intracellular platinum concentration correlated well with the decrease in survival of these cells. In vivo, rats were treated intraperitoneally with cisplatin (5 mg/kg) in combination with regional hyperthermia of the abdomen (41.5 degrees C, 1 h). The mean (S.D.) temperature in the peritoneal cavity was 41.5 (0.3) degrees C and outside the peritoneal cavity 40.5 (0.3) degrees C. Enhanced platinum concentrations were found in peritoneal tumours (factor 4.1) and kidney, liver, spleen and lung (all around a factor 2.0), after combined cisplatin-hyperthermia treatment. The platinum distribution in peritoneal tumours was more homogeneous after the combined treatment than after cisplatin alone, possibly due to increased penetration of cisplatin into peritoneal tumours. Pharmacokinetic data demonstrated an increased tumour exposure for unfiltered platinum in the peritoneal cavity (area under the curve [AUC] increased from 339 mumol/l/min to 486 mumol/l/min at 37 degrees C and 41.5 degrees C, respectively), and for total and ultrafiltered platinum in the blood. The AUC for total platinum increased from 97.9 to 325.8 mumol/min and for ultrafiltered platinum from 22.2 to 107 mumol/l/min at 37 degrees C and 41.5 degrees C respectively. The latter might be due to a slower elimination of platinum from the blood. The combined treatment, intraperitoneal cisplatin and regional hyperthermia, also increased toxicity. The thermal enhancement ratio (TER) using lethality as endpoint was 1.8.

Animals↗
PubMed1990

Selective reduction of cis-diamminedichloroplatinum(II) nephrotoxicity by ebselen.

2-Phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) is classified as a relatively nontoxic selenium compound, probably because of its bound selenium moiety. In thiol-rich tissues, such as the kidneys, ebselen is converted into selenol intermediates. Selenols are nucleophilic agents which might be able to react with platinum compounds. The influence of ebselen on cis-diamminedichloroplatinum(II) (cisplatin)-induced nephrotoxicity in mice was assessed, using single doses of both compounds. Ebselen prevented cisplatin-induced elevations of blood urea nitrogen and serum creatinine levels and morphological kidney damage in BALB/c mice. This protective effect of ebselen was dose dependent: at a cisplatin dose of 14.5 mg/kg, maximal protection was achieved when a single dose of 10 mg of ebselen/kg was administered 1 h before cisplatin. Administration of ebselen, 10 mg/kg, 1 h after cisplatin also protected against severe nephrotoxicity. Treatment with ebselen did not reduce the antitumor activity of cisplatin against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. However, this reduction of cisplatin-induced nephrotoxicity would be of little clinical value if it was achieved at toxic doses of ebselen. Ebselen, 10 mg/kg, did not induce blood urea nitrogen, serum creatinine, serum glutamic pyruvate transaminase, or serum glutamic oxalate elevations in the mice. These results are in agreement with the reported low toxicity of ebselen, which is now in Phase I clinical trials as an antiinflammatory drug. The present results indicate that ebselen may provide protection against cisplatin-induced nephrotoxicity, when it is given before or after cisplatin. This might open new perspectives in cancer chemotherapy.

Animals↗
PubMed1990

The use of oxaliplatin versus cisplatin in intraperitoneal chemotherapy in cancers restricted to the peritoneal cavity in the rat.

Pharmacokinetic studies demonstrated the advantage of intraperitoneal oxaliplatin (1-OHP) for cancers restricted to the peritoneal cavity. The area under the concentration X time curve (AUC) in the peritoneal cavity for both total and ultrafiltered drug was almost 2 times higher for 1-OHP than cisplatin (cDDP). The AUC for ultrafiltered 1-OHP in plasma was also a factor 4 higher than cDDP, indicating that peritoneal tumors received a higher exposure from 1-OHP than cDDP directly in the peritoneal cavity and indirectly via the systemic circulation. Total platinum concentrations in peritoneal tumors of rats were determined after i.p. administration of equimolar doses of 1-OHP and cDDP. In spite of the pharmacological advantages, no significant difference in platinum concentration was demonstrated. In addition, no difference in the distribution of platinum within peritoneal tumors was detected after i.p. treatment with equimolar doses, i.e., platinum concentrations were comparable both in the periphery, 29 +/- 4 ppm for cDDP and 22 +/- 8 for 1-OHP and in the center of the tumor, 18 +/- 3 for both drugs. When CC531 tumor cells were incubated in vitro with equimolar concentrations of 1-DHP and cDDP in vitro, 2 to 4 times less platinum was found in cells treated with 1-OHP, indicating that the uptake of 1-OHP differed from that of cDDP. Oxaliplatin was not cross resistant for cDDP in CC531.RL4 tumor cells, a cDDP resistant cell line, which may indicate its value in ovarian cancer patients who did not respond to earlier cDDP treatment.

Animals↗
PubMed1990

Platinum distribution in intraperitoneal tumors after intraperitoneal cisplatin treatment.

The spatial distribution of platinum (Pt) in the kidney was studied by an autoradiographic technique, in which cisplatin (CDDP) was replaced by 195mPt-labeled CDDP, and by proton-induced X-ray emission (PIXE). Although both studies demonstrated comparable spatial distribution patterns, PIXE had the advantage that Pt concentrations could be determined quantitatively, in contrast to the relative information obtained by the autoradiographic technique. Using PIXE, the distribution of Pt in i.p. tumors was studied after i.p. administration of CDDP. The highest Pt concentrations were always found on the periphery of tumors, indicating that the periphery was exposed to a higher drug concentration than the center. Dose was correlated to the concentration of CDDP at both the center and the periphery (r = 0.99). The Pt concentration in the periphery was usually higher by a factor of 2-3 after i.p. administration than after i.v. treatment, whereas in the center of the tumor no concentration difference could be detected. The penetration depth of CDDP lay between 1 and 2 mm and was calculated from the differences in Pt concentration after i.p. and i.v. treatment. This indicates that the effective advantage of i.p. chemotherapy with CDDP in cases of cancers limited to the peritoneal cavity is accentuated at the periphery of the tumor.

Animals↗
PubMed1990

A new intraperitoneal tumor model in the rat.

A new tumour model that is particularly suitable for testing intraperitoneal chemotherapy is described. Single tumours were induced to grow in the mesentery of rats by the implantation of small pieces taken from subcutaneous tumours. Tumour growth was monitored by repeated laparotomies at which the tumour size was measured with calipers. In this way, growth curves of treated and untreated tumours could be defined. The diameter of untreated intraperitoneal tumours increased linearly with time [diameter (mm) = 0.39 t (days) +2.4]. Tests using different numbers of laparotomies showed that the procedure itself had little influence on growth. Cell kinetic studies of 6-mm tumours showed a mean labelling index of 31% and a volume-doubling time of 3.9 days, resulting in cell-loss factors probably in excess of 70%. The model was tested by assessing the effect of the chemotherapeutic agent cisplatin. Regression and regrowth could be satisfactorily followed, leading to estimates of growth delay. This model therefore provides a quantitative way to assess the response of intraperitoneal tumours to chemotherapy.

Adenocarcinoma↗
PubMed1990

Anti-tumor effect of cisplatin, carboplatin, mitoxantrone, and doxorubicin on peritoneal tumor growth after intraperitoneal and intravenous chemotherapy: a comparative study.

Tumor growth was studied in a peritoneal tumor model in the rat after intravenous and intraperitoneal administration of doxorubicin (4 mg/kg), mitoxantrone (2.5 mg/kg) and cisplatin (4 mg/kg) and after intraperitoneal administration of carboplatin (20 mg/kg). All treatments delayed tumor growth and intraperitoneal treatment was more effective initially than intravenous treatment for all drugs tested. Regrowth occurred between 2 and 7 weeks after treatment and was less pronounced after intravenous treatment. Tumor sizes in cisplatin treated rats 7 weeks after treatment were comparable after intraperitoneal and intravenous treatments. Intraperitoneal carboplatin even with a dose 5 times higher than cisplatin resulted in a less tumor growth delay in all stages of the treatment, compared to cisplatin. All cytostatic drugs, except carboplatin, induced loss of body weight. Weight loss was similar for intraperitoneal and intravenous treatment with both cisplatin and mitoxantrone while for doxorubicin the weight loss was significantly higher after intravenous treatment than after intraperitoneal therapy. Considering the "therapeutic index", defined as the ratio of tumor growth delay to weight loss, cisplatin had the highest "therapeutic index", 1.5 (intraperitoneal) and 1.7 (intravenous) compared to 0.3 (intraperitoneal) and 0.6 (intravenous) for Mitoxantrone and 0.4 (intraperitoneal) and 0.5 (intravenous) for doxorubicin. This indicated that cisplatin was the most favorable drug to use in this peritoneal tumor model for both intraperitoneal and intravenous treatment. The tumor growth delay was initially more pronounced after intraperitoneal cisplatin compared with intravenous.

Animals↗
PubMed1989

Two specific T cell factors that initiate immune responses in murine allograft systems. A comparison of biologic functions.

It has been suggested that Ag-specific T cell factors play a role in the early phase of cellular immune responses. Two of these factors are studied in this paper. The first factor is specific macrophage arming factor (SMAF), that binds to (arms) macrophages and renders them specifically cytotoxic against tumor cells. The second factor is involved in the induction of an early (2 h) mast cell-dependent hypersensitivity reaction, that precedes the delayed-type hypersensitivity response (mast cell arming T cell factor; MTCF). In this study we compare both factors in an allogeneic murine tumor system (C57BL (H-2b) mice sensitized against SL2 (H-2d) lymphoma cells), both factors were: 1) dependent on T lymphocytes for their production, 2) detectable in serum 2 to 3 days after immunization, and 3) MHC (H-2)-Ag specific. Immunochemical studies showed that both factors have a molecular mass between 45 and 90 kDa and bind to the mAb 14-30 (directed against specific T cell factors), but not to anti-kappa/lambda L chain antibodies. Furthermore, it was shown that SMAF produced in vitro could induce a mast cell-dependent early 2-h hypersensitivity reaction against SL2 tumor cells, and resembled in this way MTCF. We concluded that the biologic activities and immunochemical characteristics of SMAF and MTCF are similar. Both factors are produced during the early stages of the immune response and seem to play a role in the initiation of the cell-mediated immune response.

Animals↗
PubMed1989

Direct diffusion of cis-diamminedichloroplatinum(II) in intraperitoneal rat tumors after intraperitoneal chemotherapy: a comparison with systemic chemotherapy.

Chemotherapy i.p. is increasingly being tested as a treatment modality for cancer limited to the peritoneal cavity. We have developed a rat tumor model in which penetration and distribution of cis-diamminedichloroplatinum(II) into intraperitoneal tumors have been studied. The platinum concentration in intraperitoneal tumor nodules, measured by two techniques, flameless atomic absorption spectroscopy and proton-induced X-ray emission, was always higher after i.p. treatment than i.v. Further, platinum concentrations were higher at the periphery of the tumor after i.p. administration than after i.v., while platinum concentrations in the center of the tumor nodules were identical. No difference was detected in platinum concentrations in s.c. tumors nor in the total area under the curve (plasma) after i.p. and i.v. administration of cis-diamminedichloroplatinum(II), suggesting that the higher drug concentration measured in peritoneal tumors after i.p. administration is due to direct diffusion of the drug from the peritoneal cavity.

Adenocarcinoma↗
PubMed1989

Selenium-induced protection against cis-diamminedichloroplatinum(II) nephrotoxicity in mice and rats.

The influence of selenium on cis-diamminedichloroplatinum(II) (c-DDP) nephrotoxicity in mice and rats was assessed, using single doses of both compounds. Sodium selenite, 2 mg of selenium per kg, given 1 h before c-DDP, greatly reduced blood urea nitrogen and creatinine levels and morphological kidney damage in both BALB/c mice and Wistar rats, while administration 1 h after c-DDP did not. Liver toxicity of selenium was evaluated by measuring serum glutamic pyruvate transaminase and serum glutamic oxalate transaminase and by routine histology. No liver damage was observed in animals treated with sodium selenite, 2 mg of selenium per kg, and physiological saline or c-DDP. Pretreatment with sodium selenite did not reduce the antitumor activity of c-DDP against MPC 11 plasmacytoma or Prima breast tumor in BALB/c mice. The present results indicate that sodium selenite may provide protection against c-DDP nephrotoxicity, when it is given before c-DDP. Moreover, selenium has an antineoplastic activity against several tumors. The combination of these qualities may open new perspectives in cancer chemotherapy.

Animals↗
PubMed1989

Intraperitoneal tumor growth and chemotherapy in a rat model.

Animal models are important to evaluate new treatment modalities. In the present paper a new animal model is described, in which the effects of intraperitoneal (i.p.) administration of cytostatic drugs on cancers restricted to the peritoneal cavity can be studied. The tumor cell line used is a chemically induced carcinoma (CC531), sensitive in vitro to cisplatin (cDDP), carboplatin (CBDCA), 5-fluorouracil (5-FU), doxorubicin and mitoxantrone. Three to 5 weeks after i.p. inoculation of 2 x 10(6) CC531 cells, 80% of Wag/Rij rats develop small tumor nodules on peritoneal surfaces. Both tumor size and localization at this time are comparable to the human situation, especially to cases of minimal residual disease ovarian carcinoma. The model has been used to determine the usefulness of i.p. treatment in comparison to i.v. Changing the route of administration of cDDP from i.v. to i.p. increases tumor platinum concentrations and prolongs survival. The model offers the possibility to study drug pharmacokinetics and tumor drug penetration related to i.p. drug administration.

Animals↗
PubMed1989

Impairment of allograft tumor immunity by isotype-like suppression of antigen-specific T cell factors.

PCl-F is an antigen-binding factor that is derived from T cells of picryl chloride (PCl) contact-sensitized mice. Intravenous transfer of PCl-F into naive recipients, followed immediately by PCl challenge, results in the ability to elicit an immediate hypersensitivity-like cutaneous response. This PCl-F-dependent early response is an obligatory step in the mediation of a PCl-specific delayed-type hypersensitivity reaction by late-acting, antigen/MHC-restricted effector T cells. These latter cells recruit a local infiltrate of inflammatory cells by producing chemoattractant lymphokines. Injection of PCl-F also induces a T cell-dependent feedback circuit that ultimately suppresses production of PCl-F, and thus suppresses DTH to PCl. This form of regulation is not antigen-specific, since PCl-F induces suppression of DTH to PCl and to other antigens via suppression of the production of antigen-binding T cell factors necessary for initiation of DTH. This form of regulation does not affect classic, late-acting, lymphokine-producing effector T cells of DTH, or helper T cells for antibody responses. We now report that injection of PCl-F is also capable of inducing suppression of cutaneous hypersensitivity responses to allogeneic and syngeneic tumor cells, and of immune resistance to an allogeneic tumor graft. Our results suggest, therefore, that antigen (tumor)-specific T cell factors play a role in initiation of hypersensitivity responses to tumor cells. Injection of PCl-F suppressed, besides tumor-specific cutaneous hypersensitivity, production of the tumor-specific T cell factor that renders macrophages cytotoxic to tumor cells (i.e., specific macrophage-arming factor or SMAF). Thus, PCl-F injection may impair immune resistance to tumor cells by suppressing initiation of hypersensitivity responses that recruit macrophages, and also by inhibiting production of SMAF that renders macrophages cytotoxic. It is therefore tempting to conclude that the antigen-specific T cell factors that initiate DTH, such as PCl-F and SMAF, belong to the same isotype or group of antigen-specific T cell products that can be regulated by a form of feedback suppression that is isotype-like and inhibits production of these related, antigen-specific T cell factors.

Animals↗
PubMed1988

Macrophage infiltration in tumors and tumor-surrounding tissue: influence of serotonin and sensitized lymphocytes.

In a delayed-type hypersensitivity reaction serotonin released from mast cells plays an important role in the induction of a cellular infiltrate at the site of antigen challenge. In analogy, we have studied whether it is possible to enhance the number of intratumoral macrophages by injecting serotonin into a s.c. SL2 lymphosarcoma. The vessels in the tissue surrounding the tumor responded well to serotonin, as there was an influx of i.v. injected 51Cr-labeled sensitized spleen cells in this tissue during the first 4 h after intratumoral injection of serotonin. At 24 h after serotonin injection there was an influx of macrophages into this tumor-surrounding tissue. No influx of cells was detected in the tumor itself during the first hours after injection of serotonin. In the tumor, similar phenomena occurred as in the surrounding tissue, but with a delay of about 24 h. This suggests that lymphocytes leave the blood circulation in the tumor-surrounding tissue and migrate to the tumor. The influx of macrophages into the tumor after intratumoral injection of serotonin is probably due to an immunological reaction as the lymphocyte influx preceeds the macrophage influx into tumors. In addition, transfer of sensitized lymphocytes, as well as lymphocytes from a tumor-bearing host caused an enhanced influx of macrophages into the tumor. To test the specificity and serotonin dependency of the phenomenon of infiltrating cells in tumors we have used a footpad swelling assay in which the serotonin dependency and the antigen specificity of the response against syngeneic tumor cells was shown. The following picture emerged: an intratumoral serotonin injection enables lymphocytes to leave blood vessels in the tumor-surrounding tissue. These lymphocytes with specificity for tumor antigens migrate to the tumor. After contact with the antigenic tumor cells, these lymphocytes secrete chemoattractive factors for monocytes/macrophages. Also these monocytes/macrophages leave the circulation in the tumor-surrounding tissue. Subsequently the macrophages invade the tumor. We conclude that the number of intratumoral macrophages can be enhanced by serotonin.

Animals↗
PubMed1987

Murine mammary tumor response to hyperthermia and radiotherapy evaluated by in vivo 31P-nuclear magnetic resonance spectroscopy.

The response of the s.c.-implanted murine mammary carcinoma NU-82 to hyperthermia was followed as a function of time by 31P-nuclear magnetic resonance spectroscopy. Treatment consisted of elevation of the temperature of the tumors to 41-45 degrees C during 15 min. At 18 h after temperatures of up to 42, 43, 44, and 45 degrees C the ratio of ATP/Pi was unchanged, decreased, largely decreased, and approaching zero, respectively. After the higher doses the relative concentrations (in percentage of total phosphate as visible in the nuclear magnetic resonance spectrum) of phosphomonoesters (mainly phosphoethanolamine) and phosphocreatine also decreased in favor of Pi. The changes in phosphodiesters (mainly glycerophosphocholine) correlated linearly with the changes in ATP (r = 0.84, P less than 0.025). Whereas the limited spectral changes after a dose of 43 degrees C were nullified within 24 h, the more drastic changes after a dose of 45 degrees C lasted at least 8 days. The heavier dose not only induced temporary decreases in tumor perfusion like the lower dose (phase 1) but subsequently, unlike the lower dose, resulted in formation of necrosis (phase 2). In the same tumor we found increases in Pi and decreases in ATP and phosphodiesters after radiotherapy with a dose of 20 Gy. Radiotherapy (20 Gy) combined with hyperthermia (44 degrees C) appeared to strengthen these effects and resulted in an improved tumor response (regression).

Adenosine Triphosphate↗