[Show abstract][Hide abstract] ABSTRACT: Platinum(IV) compounds like oxoplatin (cis, cis, trans-diammine-dichlorido-dihydroxido-platinum(IV)) show increased stability and therefore can be applied orally. In a panel of 38 human cancer cell lines this drug induced S-phase arrest and cell death with IC(50) values 2.5-fold higher than cisplatin. Oxoplatin may be converted to cisplatin by intracellular reducing agents, however, exposure to 0.1 M HCl mimicking gastric acid yielded cis-diammine-tetrachlorido-platinum(IV) exhibiting twofold increased activity. Similar results were obtained for another platinum(IV) compound, JM 149 (ammine-dichlorido-(cyclohexylamine)-dihydroxido-platinum(IV)), but not for its parent drug JM 216/satraplatin. Genome-wide expression profiling of H526 small cell lung cancer cells treated with these platinum species revealed clear differences in the expression pattern of affected genes between oxoplatin and cisplatin. In conclusion, oxoplatin constitutes a potent oral agent that is either reduced or converted to distinct active compounds, for example, by gastric acid or acidic areas prevailing in solid tumors, in dependence of the respective pharmaceutical formulation.
[Show abstract][Hide abstract] ABSTRACT: Specific tumors express high amounts of receptors for somatostatin (SST), providing the basis for imaging and treatment using radiolabeled SST analogs. However, little is known about the potential influence of cytotoxic drugs on SST receptor (SSTR) expression in malignant cells.
To study the interaction between cytotoxic drugs and SSTR expression, the pancreatic cancer-derived tumor cell lines BxPC-3, Panc-1, Capan-1, and ASPC-1 were exposed to a range of cytotoxic drugs in vitro: Gemcitabine, 5-fluorouracil, cisplatin (cis-diaminedichloroplatinum [II]), camptothecin, mitomycin C, and doxorubicin were checked for changes in binding characteristics of the SSTR ligand (111)In-1,4,7,10-tetraazacyclododecane- N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN). Chemosensitivity was quantitated by measurements of reduction in cell numbers, changes in cell cycle distribution, and appearance of apoptotic subG1 (subG1/0 cell DNA content) cells.
Cells were treated with gemcitabine (1.0 or 2.0 microg/mL), 5-fluorouracil (65-520 microg/mL), camptothecin (1.5 or 3 microg/mL), mitomycin C (0.1 or 0.2 microg/mL), and doxorubicin (1.0 or 2.0 microg/mL). Each of the chemotherapeutic agents induced a loss of high-affinity receptors. In addition, gemcitabine caused a reduction of low-affinity receptors in BxPC-3, Panc-1, and ASPC-1 cells. Mitomycin C, camptothecin, and 5-fluorouracil also induced an overexpression of low-affinity receptors. In cells pretreated with cisplatin (2-10 microg/mL), binding of DOTA-LAN was increased. Excluding gemcitabine, the increase in low-affinity binding sites exhibits a weak correlation with apoptosis (r(2) = 0.62). For gemcitabine, these effects were reversed after 4 d of recovery of the cell lines, eventually revealing overexpression of low- and high-affinity sites for BxPC-3 and Panc-1 cells and low-affinity sites for ASPC-1 cells.
Our results clearly show that the pancreatic tumor lines reduce the expression of high-affinity DOTA-LAN binding sites during application of chemotherapeutic drugs, which is accompanied by variable overexpression of low-affinity binding sites. In the case of gemcitabine, SSTRs are overexpressed during recovery from drug exposure within 4 d. These findings may have implications on the interpretation of scintigraphic results obtained by receptor ligands.
Journal of Nuclear Medicine 01/2002; 42(12):1856-62. · 5.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aromatic fatty acids such as phenylbutyrate (PB) and its metabolite phenylacetate (PA) induce growth arrest, differentiation and apoptosis in solid tumor cells. Despite their antiproliferative action they were reported to exhibit a synergistic effect in combination with cytotoxic drugs like topotecan, and others. Since the activity of the camptothecines (CPTs) depends on local pH conditions, we investigated, whether PB/PA modulate CPT effects indirectly by affecting intracellular pH in SW620 and SW480 colon cancer cells. The results for the colon carcinoma cells show an antagonistic interaction for the combination of CPT and 0.25-5 mM PA in viability assays, resulting in an approximately 3-fold increase in IC50 (control: 20+/-7 nM). A synergistic effect with significantly increased numbers of late apoptotic/necrotic cancer cells (difference +21+/-4%) and 1.4-fold sensitization were detected upon inclusion of 2.5 mM PA during a 4-h CPT (10 micro;M) loading phase. In response to 0.25-1 mM PA/PB the cells exhibit a reversible decrease of pHi (0.1-0.31 pH units) in HEPES- or bicarbonate-buffered media. Dose-dependent acidification and pHi-recovery occurred following addition of PA and PB after an acid load and inhibition of the Na+/H+-antiporter and bicarbonate exchangers, pointing to a possible intracellular mechanism of cytoplasmic acidification. It is concluded that the synergistic modulation of CPT toxicity by short-term PA/PB treatment in colon carcinoma cells is caused by changes in intracellular pH, possibly affecting quantity and localization of the active closed lactone form of this drug.
International Journal of Oncology 12/2001; 19(5):1069-74. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Prostate cancer metastases induce a predominantly osteoblastic response in bone tissue, resulting in new bone formation and associated morbidity; however, the mechanisms of these tumor-host responses are not fully understood.
Supernatants of prostate (PC3, DU145, LNCaP), breast (BT20, ZR-75-1), colon (SW620, Colo 320DM), pancreatic (ASPC1, Capan-1), renal cell (ACHN) and hepatoma (HepG2) cell lines were tested for their capacity to modulate proliferation, activity of alkaline phosphatase (ALP) and CD99/MIC2 expression in AHTO-7 (large T antigen transfected human trabecular osteoblasts) cells in vitro.
Osteoblastic stimulation is not restricted to prostate cancer derived conditioned media CM and high activity is found in CM from Capan-1, HepG2 and ACHN lines. Furthermore these CM down-regulate the expression of the CD99/MIC2 antigen in comparison to medium by AHTO-7 cells as detected by HBA-71 immunofluorescence, with the exception of prostate cancer-derived CM. Induction of the differentiation marker ALP was detected in response to CM derived from Capan-1, BT-20 and Colo320DM. Stimulation of the proliferation of AHTO-7 cells (105-138% of control), induction of ALP (1.17-5.29-fold) and down-regulation of CD99 (13.6-57.5%) exhibited no correlation. CM derived from PC3 and LNCaP metastatic prostate cancer cell lines specifically resulted in the retention/stimulation of the expression of CD99/MIC2 in AHTO-7 cells in contrast to all other cell lines tested.
The CD99/MIC2 antigen, which is expressed on human osteoblasts and osteosarcoma cells, seems to constitute a new and independent response marker of osteoblasts in the triggering of osteoblastic reaction by prostate cancer cells.
Anticancer research 01/2001; 21(6A):3909-13. · 1.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In an intermittent androgen suppression therapy (IAS) trial we observed regular cycles of tumor suppression and regrowth in the majority of patients (17 +/- 2.6 month), with a subpopulation of patients (14 of 72) exhibiting a prolonged response of 28 +/- 7 month (range 18-64+ month) to the first eight-month androgen suppression cycle.
To compare clinical data and laboratory tests (testosterone, prostate-specific antigen, and tissue polypeptide-specific antigen) of matched IAS patients showing either regular treatment cycles (n = 16) or prolonged response (n = 14).
Periods of androgen suppression resulted in reversible reduction of serum testosterone (< 1 nmol/l), PSA (< 1 ng/ml) indicating partial growth arrest and apoptotic regression of the tumors. The long-term response subgroup showed significantly lower mean values of tumor gradings, of pretreatment PSA values (11.36 +/- 4.54 vs. 47.5 +/- 12.4 ng/ml PSA), of PSA nadirs during androgen suppression (0.5 vs. 1 ng/ml PSA), and of overall testosterone values (3.9 +/- 1.14 vs. 6.6 +/- 1.18 mmol/l pretreatment) associated with low TPS values.
Patients exhibiting prolonged response to a single cycle of androgen suppression during IAS are characterized by a lower tumor burden, slow growing and less aggressive tumors, lower testosterone serum concentrations and lower absolute PSA nadirs during androgen suppression compared to a matched control group of short-term responders.
Annals of Oncology 07/2000; 11(7):877-81. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Resveratrol, a natural phytoestrogen, has been reported to promote differentiation of murine MC3T3-E1 osteoblasts and to inhibit proliferation of prostate cancer cell lines. In the present study we tested the effects of resveratrol on the increased proliferation of human AHTO-7 osteoblastic cell line induced by conditioned media (CM) from a panel of carcinoma cell lines. This compound was found to modulate AHTO-7 proliferation in a tamoxifen-sensitive mechanism at lower concentrations, but failed to induce the osteoblast differentiation marker alkaline phosphatase (ALP) in contrast to vitamin D3. The proliferative response of AHTO-7 cells to conditioned media from carcinoma cell lines was diminished (30-71.4% inhibition) upon pretreatment with 0.5 microM resveratrol. Highest inhibition was demonstrated for pancreas (BxPC3, Panc-1), breast (ZR75-1) and renal (ACHN) carcinoma cell line supernatants whereas the effect on colon carcinoma (SW620, Colo320DM) cell CM and prostate cancer (PC3, DU145 and LNCaP) CM was less pronounced. Direct addition of resveratrol affected only supernatants of cell lines (<25% inhibition) exhibiting growth stimulatory activity for normal WI-38 lung fibroblasts. Resveratrol inhibited proliferation of DU145 and LNCaP cells in concentrations exceeding 5 microM, altered cell cycle distribution of all prostate cancer cell lines in concentrations as low as 0.5 microM, but did not inhibit the production of osteoblastic factors by these lines. In conclusion, resveratrol failed to induce ALP activity as marker of osteoblast differentiation in human osteoblastic AHTO-7 cells, however, inhibited their response to osteoblastic carcinoma-derived growth factors in concentrations significantly lower than those to reduce growth of cancer cells, thus effectively modulating tumor - osteoblast interaction.
International Journal of Oncology 12/1999; 15(5):955-9. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study evaluated monthly measurements of free and total prostate-specific antigen (PSA), and the tumor proliferation markers tissue polypeptide-specific antigen (TPS) and cytokeratin fragment 21-1 (CYFRA 21-1) in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS).
Thirty-four men received alternating cycles of 8 month androgen suppression and treatment cessation (mean duration, 10.3 months) until PSA increased to >20 microg/l. Measurements of testosterone, percentage of free PSA, TPS, and CYFRA 21-1 were performed using ELISA and RIA assays.
Periods of androgen suppression resulted in reversible reductions of testosterone (from 6 +/- 0.8 to <0.58 ng/ml), PSA (from 31.2 +/- 4.5 to <1.7 microg/l), and prostatic volume (mean reduction, 22.2 +/- 4.6%), indicating apoptotic regression of the tumors. Upon treatment cessation, testosterone increased to 6.1 +/- 0.56 ng/ml within 2 months, followed by an increase of PSA to 5.8 +/- 0.8 microg/l. The mean percentage of free PSA (15.1 +/- 2.6%) exhibited no significant change during the whole IAS cycle. TPS showed a decrease of 50% after 3 months, and CYFRA 21-1 a 25% decrease after 7 months of androgen suppression treatment. During treatment cessation, TPS exceeded the normal cutoff value of 90 U/l late in tumor regrowth (9-11 months), whereas CYFRA 21-1 remained below the normal cutoff value of 3.3 ng/ml.
PSA is the best and most sensitive marker of prostate cancer regression and regrowth during IAS cycles of the markers tested in this study. Free PSA constitutes approximately 15% of total PSA (range, 5-32%), and its percentage showed no significant change during IAS cycles. The TPS and CYFRA 21-1 proliferation marker changes in IAS seem to be related mainly to effects on normal androgen-dependent tissues.
The Prostate 10/1999; 41(2):71-7. · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemoresistance is of outstanding importance for the limited results of chemotherapy in solid tumors. Chemoresistance of multicellular tumor tissues is more pronounced than that of single cells in vivo and in vitro. The enzyme hyaluronidase is able to loosen the cell-cell contact and the interstitial connective tissue and as such, in a number of preclinical and clinical trials, was shown to enhance the efficacy of cytostatic agents. Although proven to be very effective as additive to local chemotherapy, the systemic efficacy is not documented as well. We present a randomized trial done in high-grade astrocytomas with combined chemotherapy and radiation therapy with and without hyaluronidase. After very promising pilot results with systemic hyaluronidase in various tumor entities and also astrocytomas, this randomized study failed to show synergy to chemotherapy and radiation therapy in high-grade astrocytomas concerning survival. The promising preclinical data and the rather well documented activity in therapeutic use as additive to local chemotherapy seem to be an adequate motive to further elucidate the complex manner in which hyaluronidase is active in the interstitial tumor matrix and to obtain more information concerning the optimal route of application, the optimal dosage and the spectrum of tumor entities where it is synergistic with cytostatic chemotherapy and perhaps even radiation therapy.
Cancer Letters 10/1998; 131(1):85-99. · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gemcitabine has shown activity in different solid tumors. In the present study we have evaluated its efficacy in 32 patients with advanced non-small-cell lung cancer in a phase II trial. Gemcitabine (1250 mg/m2) was given intravenously as a 30-minute infusion on days 1, 8 and 15. Cycles were repeated every 4 weeks. Twenty-nine patients were evaluable for response and all patients for toxicity. Partial remissions and stable disease were seen in 4 (14%) and 13 (45%) patients, respectively. Improvement of symptoms occurred in 54% of the patients. Side effects were mild and included predominantly leukopenia and thrombocytopenia. In conclusion, gemcitabine is active and well tolerated in patients with advanced non-small-cell lung cancer.
Wiener klinische Wochenschrift 10/1997; 109(17):688-91. · 0.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pseudoautosomal encoded MIC2 glycoprotein is a tumor-associated antigen of Ewing's sarcoma (ES) and closely related tumors of unknown function. To investigate the use of this protein as selective drug carrier recombinant MIC2 was coupled to doxorubicin by a two step glutaraldehyde method (molar ratio DOX/MIC2 of 32 and 16). The conjugates showed dose-dependent cytostatic activity against the ES cell line SK-ES1, the peripheral neuroectodermal line KAL and the prostate cancer cell line PC-3 concurrent with reduced toxicity against normal lymphoblasts. In comparison to free doxorubicin the MIC2-doxorubicin conjugates exhibited highest activity against the PC-3 cell line. Confocal microscopy showed intracellular accumulation of MIC2 conjugates.
International Journal of Oncology 09/1996; 9(3):527-31. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The treatment of advanced metastatic prostate cancer by hormone manipulation or orchiectomy is frequently followed by the appearance of hormone-insensitive and highly chemoresistant tumor cells. In this study we have investigated the contribution of the P-glycoprotein-mediated drug efflux (multidrug-resistance; MDR) to the cellular resistance of prostate carcinoma-derived cell lines to diverse cytotoxic drugs by detection of P-glycoprotein (P-gp) measurement of P-gp-mediated drug transport and reversal of MDR by chemosensitizers. The in vitro chemosensitivity of three prostate cancer cell lines (PC-3, DU-145 and LNCaP) to doxorubicin was measured in a thymidine incorporation proliferation assay. Growth of the partially hormone-sensitive cell line LNCaP is inhibited by low doses of doxorubicin (IC50:27 ng./ml.), but PC-3 and DU-145 are highly resistant to the drug, with IC50 values of 10 micrograms./ml. and 7.5 micrograms./ml., respectively. The chemosensitivity of the PC-3 and DU-145 cells is increased in response to 1 microM. verapamil, 1 micrograms./ml. cyclosporine A and 2 microM. tamoxifen, which are known to partially reverse the MDR phenotype in other resistant tumors. A verapamil-sensitive drug efflux has been demonstrated for the PC-3 and Du-145, but not for the LNCaP, cell lines, using flow cytometric measurements of the P-gp substrate rhodamine 123 efflux from preloaded cells. In agreement with the functional measurements, the expression of the P-glycoprotein was detected in the PC-3 and Du-145 cell lines in Western blots using the monoclonal C 219 antibody. In conclusion, the chemoresistant and hormone-insensitive PC-3 and Du-145 cell lines express P-gp and exhibit verapamil-sensitive drug efflux, indicative of MDR. However, the low MDR-reversal rates observed in these cell lines in response to chemosensitizers in clinically achievable concentrations (approximately 2- to 3-fold reversal), point to non-MDR-associated cellular mechanisms as dominant factors of chemoresistance in prostate cancer.
The Journal of Urology 12/1993; 150(5 Pt 1):1544-7. · 3.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multidrug-resistance (MDR) is a cellular mechanism, which in certain tumors reduces the chemosensitivity of cells to a characteristic group of structural different cytostatic drugs, as anthracyclines, Vinca alkaloids and others, and correlates with a unfavourable clinical prognosis. In MDR-cells the intracellular concentration of cytostatic drugs is reduced due to the action of the mdr-1-gene-encoded P-glycoprotein (P-gp/gp 170), which functions as drug efflux pump with broad substrate specificity. Many calcium channel blockers of all subclasses (phenylalkylamine, dihydropyridine and benzothiazepine type) and other calcium antagonists inhibit the P-gp-mediated drug efflux and represent modulators of MDR (resistance modifiers, chemosensitizers). Since the sensitized tumor cells express no voltage-gated calcium channels, the induction of changes in intracellular free calcium showed no effect on MDR and the MDR-activity of antagonists is not correlated with their cardiovascular effects, the chemosensitization by these drugs is independent from their action on calcium channels and Ca(++)-regulation. Photoaffinity labelling with reactive derivatives proved the direct competitive interaction of calcium antagonists with the binding site of P-gp for cytostatic drugs as mechanism of action. The MDR-modulation of the doxorubicin or Vinca alkaloid resistance of tumor cells in vitro by verapamil and other calcium channel blockers was confirmed in vivo as increased survival length in mice with tumor transplants in combination with cytostatic therapy. The clinical application of calcium antagonists is limited by their severe cardiovascular side effects associated with the high concentrations required for successful reversal of MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
Wiener Medizinische Wochenschrift 02/1993; 143(19-20):526-32.
[Show abstract][Hide abstract] ABSTRACT: Coumarin as well as its derivatives 7-OH coumarin and 4-OH coumarin were found to stimulate interleukin-1 beta (IL-1 beta) release from freshly isolated human mononuclear cells (MNC) if the culture medium contained fetal calf serum. Under serum-free conditions, almost no induction of IL-1 beta release was observed and the former effect could be completely eliminated by polymyxin B. Therefore, the combined action of endotoxin and coumarin was tested on MNC IL-1 beta production. The coumarins were able to potentiate human MNC IL-1 beta production by lipopolysaccharide (LPS) in a dose-dependent manner. That the effect was due to the presence of coumarins and not endotoxin contamination was shown by negative Limulus amebocyte lysate tests and pre-incubation of the coumarins with polymyxin B-agarose. The latter procedure was able to block endotoxin induced IL-1 beta production but the synergism between coumarin and endotoxin was not influenced by pre-incubating the coumarins with polymyxin B-agarose. Cycloheximide as well as actinomycin D eliminated the induction of IL-1 release by coumarin and LPS demonstrating that the cytokine was newly synthesized after MNC stimulation. In addition, both the total amount of MNC IL-1 beta (cell-associated + extracellular) and the extracellular portion of the cytokine were synergistically decreased if coumarin or its derivatives were added to endotoxin-stimulated cultures. Synergism of coumarin and endotoxin in the induction of interleukin-6 or tumour necrosis factor-alpha could be observed in a smaller percentage of donors. These findings demonstrate an immunomodulatory effect of coumarin on cytokine production by monocytes in vitro which might help to explain some of the biological activities attributed to the drug upon its application in tumour patients.
[Show abstract][Hide abstract] ABSTRACT: Prostate carcinoma-derived factors induce a proliferative response in osteoblasts. The present study investigated the involvement of MAP kinase in the osteoblastic reaction of osteocytes and the response of 1alpha,25-hydroxy-vitamin D3 (1,25-vitD3)-pretreated osteoblasts. Conditioned media (CM) from prostate, colon, pancreatic, renal cell and breast cancer cell lines were tested on their proliferative activity using murine osteoblast-like MC3T3-E1 cells, MG63 human osteosarcoma cells and immortalized human osteoblasts (AHTO-7). Changes in osteoblastic activities of the supernantants were measured in the presence of MAP kinase inhibitors and following 1,25-vitD3-induced differentiation of the target osteoblasts. Supernatants of prostate cancer cells stimulated proliferation of osteoblasts in all three indicator cell lines, with AHTO-7 exhibiting the most significant correlation to human primary osteoblast cultures. 1,25-vitD3 induced the differentiation marker alkaline phosphatase (ALP) in MC3T3-E1 and AHTO-7, but only to a minor degree in MG63 cells. 1,25-vitD3-induced differentiation reduced the proliferative response to CM from several cell lines in MC3T3-E1 and MG63 to a minor degree, whereas in AHTO-7 cells the osteoblastic reaction was reduced for 2/4 pancreatic, 3/3 colon and 1/1 renal cancer CMs, however not for 3/3 prostate cancer CMs. Stimulation of AHTO-7 cells by CM from prostate cancer lines is inhibited significantly by MEK1 kinase inhibitor PD 98059 in contrast to CMs derived from other carcinomas, except ACHN renal cancer cells. The findings in the present study demonstrate that human AHTO-7 cells seem to represent a valid human system to monitor osteoblastic activity, especially in respect to 1,25-vitD3-induced differentiation. Vitamin D3-induced differentiation has no direct effect on prostate cancer-derived osteoblastic activity in the same cell line in vitro, which however, could be reversed by disruption of the signal transduction at the MAP kinase level, revealing a new target for the inhibition of prostate cancer-associated bone formation.