A phase II study of carboplatin in advanced or metastatic stomach cancer.
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Adenocarcinoma↗
Biomedical subjects
S B Kaye
Publications and source records attributed to S B Kaye.
The effect of the non-ionic surfactant Brij 30 on the cytotoxicity of adriamycin in monolayer, spheroid and clonogenic culture systems.
The effects of a non-ionic polyoxyethylated lauryl ether surfactant (Brij 30) on monolayer uptake and spheroid penetration of adriamycin have been studied. Co-incubation of adriamycin with Brij 30 increases intracellular adriamycin levels by 2-3-fold. Although, in the concentrations used, Brij 30 alone is not cytotoxic, adriamycin and Brij 30 mixtures are significantly more cytotoxic (monolayer ID90 = 0.6 microgram/ml; disaggregated spheroid ID50 = 1.9 micrograms/ml) and induce significantly longer spheroid growth delay than adriamycin alone (monolayer ID90 = 2.1 micrograms/ml; disaggregated spheroid ID50 = 3.3 micrograms/ml). Adriamycin is equally cytotoxic to mouse normal granulocytes and chronic myeloid leukaemic (M1 cell line) cells in agar clonogenic cultures. The addition of Brij 30 appears to enhance preferentially the activity of adriamycin against these tumour cells relative to the normal granulocytes.
Animals↗
Changes in testicular cancer in Scotland.
There are two purposes to this paper. Firstly to describe the temporal pattern of germ-cell testicular cancers in Scotland, both as a single entity and as the histological sub-types (pure) seminoma and teratoma. Incidence rates rose by over 50% between 1959 and 1984, with the rates of seminoma increasing only marginally and the majority of the overall increase accounted for by the substantial increase observed among the sub-type teratoma. Secondly, to investigate the impact of new therapies on the mortality rate from germ-cell testicular cancer in Scotland in the light of improvements in survival rate reported during the last 25 years from clinical trials and clinical series. Noticeable changes have occurred in the temporal pattern of mortality which cannot be explained by changes in incidence. The ever-widening gap between the increasing incidence rate and the declining mortality rate, particularly apparent in the high-risk age group 15-44, indicates an improving prognosis for patients with this malignancy in Scotland.
Adolescent↗
Combination chemotherapy prior to radical radiotherapy for stage III and IV carcinoma of the cervix.
Twenty-three patients with Stage III and seven patients with Stage IVa carcinoma of cervix were treated with two pulses of cisplatin, vincristine and bleomycin combination chemotherapy prior to radical radiotherapy. Seventeen of the 30 patients (57%) had a partial response to chemotherapy; 25 had a complete response following radiotherapy. Currently, 16 patients are tumour-free 6 to 31 months after treatment, eight are dead and six are alive, with tumour. The actuarial survival at 30 months is 66%. Acute and late effects of radiation upon normal tissue have not been increased. Pelvic tumour was eliminated in 21 of the 30 patients (70%). The high local control rate may be due to the initial tumour shrinkage after chemotherapy.
Adult↗
Circumvention of drug resistance in human non-small cell lung cancer in vitro by verapamil.
The sensitivity of 7 human non-small cell lung cancer cell lines to each of 7 cytotoxic drugs was determined. None of the cell lines used in these experiments had been previously exposed to cytotoxic drugs in vitro. A pattern of cross-resistance (P less than 0.05) between the drugs adriamycin (ADR), vincristine (VC) and etoposide (VP16) was noted similar to that seen in other models. The calcium antagonist verapamil (6.6 microM) was shown to increase sensitivity (up to 29-fold) to ADR, VC or VP16 in 5 cell lines. For 2 of the cell lines (A549 and WIL) 2.2 microM verapamil increased VP16 cytotoxicity (up to 4-fold). Drug accumulation studies in 2 cell lines (A549 and SK-MES-1) showed that 6.6 microM verapamil increased intracellular levels of VC up to 4-fold with the greatest increase seen in the cell line (SK-MES-1) for which verapamil produced the greatest increase in cytotoxicity (10-fold). For ADR and VP16 increases in drug accumulation were smaller (up to 1.6-fold). Our data support a potential clinical role for verapamil in overcoming cytotoxic drug resistance in human lung cancer.
Antineoplastic Agents↗
In vitro chemosensitivity testing using the multicellular tumor spheroid model.
Using growth delay and clonogenic cell survival as end points, we have shown that the 3-dimensional structure of human lung tumour spheroids confers a degree of resistance to the anthracyclines doxorubicin and 4'-deoxydoxorubicin, relative to cells grown as monolayer. 4'-deoxydoxorubicin induces a longer growth delay and greater clonogenic cell kill than doxorubicin in spheroids, although it is no more cytotoxic in monolayer. Using fluorescent microscopy we have demonstrated, qualitatively, that lipophilic anthracycline analogues partition into the spheroid more rapidly and to a greater degree than doxorubicin. It is apparent that penetration is an important aspect of anthracycline drug resistance in spheroids, and the spheroid model may represent a better in vitro system for testing lipophilic analogues of cytotoxic drugs.
Antibiotics, Antineoplastic↗
Multivariate analysis of prognostic variables in patients with disseminated non-seminomatous testicular cancer: results from an EORTC multi-institutional phase III study.
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Analysis of Variance↗
Candidal endophthalmitis: a manifestation of systemic candidiasis.
Two patients on total parenteral nutrition who developed endophthalmitis secondary to Candida albicans are described. Candidal endophthalmitis as a manifestation of systemic candidiasis is discussed and its early diagnosis by bedside fundal examination in patients at risk is stressed.
Aged↗
Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast.
One hundred fifteen patients with metastatic carcinoma of the breast were treated in a randomized trial of mitoxantrone (Novantrone, Lederle Laboratories, Pearl River, NY) combined with vincristine and prednisolone (VMP) or doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH) combined with vincristine and prednisolone (VAP). In 100 evaluable patients, the objective response rates were 35% for VMP and 61% for VAP, the complete response rates being 6% and 13%, respectively. In responding patients, median time to progression was 6.2 months for VMP and 7.9 months for VAP. The median survival whether measured from primary diagnosis, first metastasis, or from the start of chemotherapy was similar for both regimens. Toxicity, particularly alopecia, was appreciably lower in the VMP treated patients, but subclinical cardiotoxicity was seen within the scheduled dosage for both combinations. We conclude that VAP is clearly more active, but clinically more toxic than VMP. There is no survival advantage conferred by the more toxic combination. Cardiac toxicity is a potential hazard with either drug combination.
Antineoplastic Combined Chemotherapy Protocols↗
Comparative intracellular uptake of adriamycin and 4'-deoxydoxorubicin by non-small cell lung tumor cells in culture and its relationship to cell survival.
4'-Deoxydoxorubicin (4'-deoxy) is a new adriamycin analogue with a similar spectrum of antitumour activity but is significantly more lipophilic than the parent compound. We report the kinetics and uptake of the two drugs by human non-small cell lung tumour cells in monolayer culture and the relationship between intracellular drug levels and cytotoxicity. The rate and degree of cell uptake of 4'-deoxy (Vmax = 30 ng/10(5) cells/min) was greater than that of adriamycin (Vmax = 0.15 ng/10(5) cells/min). Although for a given intracellular drug concentration adriamycin was more lethal, on the basis of extracellular drug concentration, cell kill was virtually identical. The log cell survival vs intracellular drug concentration plot was linear for adriamycin but biphasic for 4'-deoxy. Intracellular distribution of the two drugs was followed by fluorescent microscopy and it was apparent that adriamycin was localized mainly within the nucleus whereas 4'-deoxy accumulated within the cytoplasm. Our results suggest that the relationship between intracellular distribution of the two drugs could reflect different modes of action for the drugs with respect to binding sites or could be a non-specific phenomenon, unrelated to lethal effects.
Carcinoma, Squamous Cell↗
The effect of verapamil on the pharmacokinetics of adriamycin.
The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.
Administration, Oral↗
TNO-6 has no effect in gastrointestinal cancer: N-acetyl-glucosaminidase shows renal damage.
Twenty-five patients, 16 with gastric cancer and nine with colonic cancer, received TNO-6 30 mg m-2 every four weeks. No objective tumour response was recorded. Nausea and vomiting occurred in 21 patients and was severe in 17. Severe marrow suppression developed in five patients. Renal function was unaffected in all but one patient who developed renal failure, probably as a result of septicaemia. However, the renal tubular enzyme N-acetyl-beta-D-glucosaminidase was measured in six patients and showed a rise in all. In this study TNO-6 had no anti-tumour activity in gastrointestinal malignancy, but produced significant renal tubular damage.
Acetylglucosaminidase↗
Cyclophosphamide, adriamycin, and cis-platinum for the treatment of advanced granulosa cell tumor, using serum estradiol as a tumor marker.
Two cases of advanced granulosa cell tumor are described, in both of which chemotherapy comprising cyclophosphamide, adriamycin, and cis-platinum resulted in an objective partial response with marked symptomatic improvement. In one case the response continues at 12 months, in the other the response lasted for 5 months. In both cases elevated serum estradiol levels fell during treatment. A literature review reveals two previous cases in which this combination has been reported as being effective in advanced granulosa cell tumor, but this is the first report of the use of serum estradiol as a tumor marker.
Adult↗
4'Deoxydoxorubicin in advanced renal cancer. A phase II study in previously untreated patients from the EORTC Genito-Urinary Tract Cancer Cooperative Group.
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Adult↗
A clinical and pharmacokinetic phase I study of 1,2,4-triglycidylurazol (TGU, NSC 332488).
Twenty-six patients with advanced malignancies received TGU given as an intravenous (i.v.) bolus in physiological saline at 3 weekly intervals. The starting dose was 30 mg/m2 with standard graded escalations to 900 mg/m2. Myelosuppression occurred at 800 mg/m2, with a mean nadir of 2.0 +/- 0.8 X 10(9)/l and a mean nadir platelet count of 41 +/- 31 X 10(9)/l. At 800 or 900 mg/m2 nausea and vomiting was WHO grade 0 in 5, grade I in 6, grade II in 11 and grade III in 10 courses of therapy. Alopecia did not occur. TGU was given by i.v. infusion at 800 mg/m2 in 2 patients, both of whom developed severe thrombophlebitis. Five patients given TGU by i.v. bolus developed mild phlebitis. No renal, hepatic or cardiac toxicity was noted. Two patients had partial responses; both had adenocarcinoma of unknown primary origin, one of whom had been resistant to prior therapy with FAM. An HPLC analytical method was developed with a sensitivity of 250 ng/ml. The data from 7 patients studied best fit a one compartment pharmacokinetic model with an exponential decay and a t1/2 of only 2.1 min. In conclusion, the dose limiting toxicity of TGU appears to be myelosuppression and we would recommend a dose of 800 mg/m2 given as an intravenous bolus every 4 weeks for future phase II trials.
Adult↗
Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial.
The concentration of magnesium in serum has been shown to fall to potentially dangerously low levels after several courses of treatment with cis-diamminedichloroplatinum II (cis-platin). The aims of this study were to examine the effects of magnesium supplementation on predicted outcome of treatment, rate of response to treatment and toxicity of treatment. Sixteen patients with testicular cancer were studied in detail over a 14 month period. One patient with an ovarian dysgerminoma was also included in the study. Eight patients were randomised to receive magnesium supplements both intravenous and oral; nine did not. The non-supplemented group showed significantly greater renal tubular damage as assessed by urine N-acetyl-B-D-glucosaminidase (NAG). There was a trend towards a reduction in treatment delays due to neutropenic episodes in the supplemented group, and serum magnesium concentrations remained significantly higher. Neither group showed differences in tumour growth rates or outcome. These results show that magnesium supplements are of considerable benefit and show no harmful effects in patients receiving cis-platin treatment. It is is suggested that magnesium supplements should be a routine part of the treatment regime, and that these should comprise both i.v. supplements during treatment and oral supplements between courses.
Acetylglucosaminidase↗
Resistance of human glioma to adriamycin in vitro: the role of membrane transport and its circumvention with verapamil.
We have investigated the mechanism of resistance to adriamycin (ADR) of 3 human glioma cell lines in culture. The cell lines had different inherent sensitivities to ADR. Verapamil increased the ADR sensitivities of the 2 most resistant cell lines (G-UVW and G-CCM) by up to 5-fold. This effect was not seen in a sensitive cell line (G-MCF). Although the accumulation of ADR in the 3 cell lines was not related to inherent sensitivity, energy deprivation or the addition of verapamil produced an increase (up to 46%) in net uptake for both G-UVW and G-CCM, but not for G-MCF. For G-UVW the ADR efflux data were consistent with an energy-dependent ADR efflux mechanism which could be inhibited by verapamil. A similar mechanism was not found for G-CCM. In this cell line verapamil may act by increasing intracellular ADR binding. These data indicate that, while inherent resistance to ADR may be multifactorial, one possible mechanism of resistance in human glioma may involve changes in drug accumulation and/or binding as has been seen in animals models. A potential clinical role for verapamil in overcoming drug resistance in human solid tumours is also indicated.
Biological Transport↗
The effect of adriamycin and 4'-deoxydoxorubicin on cell survival of human lung tumour cells grown in monolayer and as spheroids.
Using growth delay and clonogenic cell survival as end points, we have shown that the 3-dimensional structure of human lung tumour spheroids confers a degree of resistance to the anthracyclines adriamycin and 4'-deoxydoxorubicin, relative to cells grown as monolayer. 4'-deoxydoxorubicin induces a longer growth delay and greater clonogenic cell kill than adriamycin in spheroids, although it is no more cytotoxic in monolayer (exponential and plateau phase). There is a log linear relationship between clonogenic cell survival and duration of adriamycin exposure in monolayers, and biphasic curve with a lesser degree of cell kill for disaggregated spheroid cells. Using fluorescent microscopy we have demonstrated, qualitatively, that the more lipophilic analogue partitions into the spheroid more rapidly and to a greater degree than adriamycin. It is possible that adriamycin penetration is a relatively important aspect of spheroid drug resistance, which may be related to intraspheroidal pH gradients, and that we have partially overcome this by using a lipophilic analogue.
Cell Survival↗