Biomedical subjects

R Reynolds

Publications and source records attributed to R Reynolds.

169 records · Page 10Linked to original sources

PubMedDate not supplied

Synergism between alkylating agent and cis-platin with moderate local hyperthermia: the effect of multidrug chemotherapy in an animal system.

The combined effect of multidrug chemotherapy given in combination with hyperthermia was investigated using early-generation isotransplants of a spontaneous fibrosarcoma, FSa-II in C3Hf/Sed mice. Combinations of various types of chemotherapeutic agents, including alkylating agents, cyclophosphamide (CY) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU); antibiotics, bleomycin (BLM) and mitomycin C (MMC); an antimetabolite, 5-fluorouracil (5FU); and a platinum complex, cis-diamminedichloroplatinum(II) (cDDP), were examined using the tumour growth (TG) time assay. Simultaneously, the effect of glucose on the response to thermochemotherapy was investigated. Graded doses of the multidrugs were given i.p. immediately before hyperthermia with or without a glucose dose of 5 g/kg given i.p. 60 min before hyperthermia. Hyperthermia was given by immersing the tumour-bearing murine feet into a water bath set at 41.5 +/- 0.05 degrees C for 60 min. Dose-response curves were obtained between the TG time and drug dose. The thermal enhancement ratio (TER) was expressed as a ratio of the slope of the dose-response curve obtained at 41.5 degrees C to that obtained at room temperature. To evaluate normal tissue damage, the number of white blood cells (WBC) was counted from a day before treatment to the 21st day after treatment. A substantial thermal enhancement of the anti-tumour effect was observed in all five multidrug regimens tested. Glucose administered prior to thermochemotherapy further enhanced the antitumour effect. The TER was largest for the combination of CY+cDDP (TER was 5 without glucose). The second largest TER was obtained for a combination of CY+cDDP+MMC (TER was 4.1 without glucose and 6.5 with glucose). The antitumour effects of these two combinations were synergistic at a test elevated temperature only. No synergistic effect was found at room temperature for any of the drug combinations tested. The smaller TERs were observed in the treatment regimens that included 5FU. In general, a decrease in the number of WBC following multidrug chemotherapy was slightly less than that following the individual drugs.

Alkylating Agents↗

PubMedDate not supplied

Interaction between adriamycin cytotoxicity and hyperthermia: growth-phase-dependent thermal sensitization.

Thermal sensitization of adriamycin cytotoxicity was studied in vitro and in vivo using tumour cells originated from a spontaneous mouse fibrosarcoma, FSa-II. The adriamycin dose-cell survival curve for exponentially growing cells was biphasic with the initial sensitive portion followed by a resistant tail. The survival curves determined in vitro as a function of treatment time at various temperatures were also biphasic. With increasing temperatures the initial portion became steeper and the resistant fraction decreased. At a temperature of 43 degrees C, which gives lethal damage to cells by itself, the cell survival decreased rapidly during the initial 30 min of treatment and became relatively constant for subsequent treatment times up to 180 min. The tumour response determined by the median tumour growth time for one-half of treated tumours to reach 1000 mm3 from the treatment day (35 mm3) indicated that the tumour response to adriamycin was independent of temperature. Hyperthermia at 43.5 degrees C for 60 min prolonged the tumour growth time without showing chemosensitization. The maximum drug dose used was 12 mg/kg that is < LD10 or the drug dose that kills animals with < 10% probability. The dose-response curves (tumour growth versus drug dose) showed identical slopes at room temperature, 41.5 and 43.5 degrees C. Further studies were conducted in vitro. Plateau phase cells were treated with graded adriamycin doses for 60 min at 37 degrees C, or with a constant adriamycin dose of 0.25 microgram/ml for various times at 37 or 43 degrees C. The dose-cell survival curves for both exponential and plateau phase cells were biphasic, but the plateau phase cells were more resistant to adriamycin at 37 degrees C than the exponential phase cells. The survival curve for plateau phase cells, determined as a function of treatment time, showed an initial shoulder followed by an exponential portion. Compared with the heat survival curve at 43 degrees C, the survival curve for the drug treatment at 43 degrees C was identical to that for the heat alone treatment for the first 60 min and then became steeper than the heat alone survival curve. These results suggest that adriamycin cytotoxicity may be enhanced at elevated temperatures only when tumours are treated for a prolonged time or possibly with a large drug dose.

Animals↗

PubMedDate not supplied

The advantageous use of hypoxic tumour cells in cancer therapy: identical chemosensitization by metronidazole and misonidazole at moderately elevated temperatures.

Chemosensitization by two nitroimidazoles (NIs), metronidazole (METRO) and misonidazole (MISO), of the anti-tumour effect of alkylating agents was studied at three different temperatures: room temperature (RT), 37 and 41.5 degrees C. Three alkylating agents, cyclophosphamide (CY), 1,3 bis(2-chloroethyl)-N-nitrosourea (BCNU) and melphalan (L-PAM) were tested when the tumours reached an average diameter of 4 mm. Tumours were 4th generation isotransplants of a spontaneous fibrosarcoma, FSa-II. Treatment at 37 or 41.5 degrees C was given by immersing the tumour-bearing foot for 60 min in a water bath set at these temperatures. The test agents were injected ip immediately before immersing the foot in the water bath, whereas METRO or MISO (2.5 mmol/kg) was given ip 30 min before the injection of a test agent. Following treatment the tumour growth (TG) time, i.e. the time required for one-half of treated tumours to reach 1000 mm3 after the treatment day, was studied. For CY, MISO was a better sensitizer than METRO at RT and 37 degrees C, but the magnitude of the chemosensitization by MISO and METRO became identical at 41.5 degrees C. Notably, the chemosensitization was substantially enhanced at 41.5 degrees C, whereas neither 41.5 degrees C-heat, NIs or combined NI and heat prolonged the TG time. Although no chemosensitization was observed for BCNU at RT, both METRO and MISO equally enhanced the effect of BCNU at 41.5 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Thermal enhancement of the effect of ifosfamide against a spontaneous murine fibrosarcoma, FSa-II.

The effect of hyperthermia on the cytotoxicity of 3-(2-chloroethyl)-2-[(2-chloroethyl)amino]-tetrahydro-2H-,1,3, 2-oxazaphosphorine-2-oxide, ifosfamide (IFO) was investigated in vivo. Tumours were early generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. The tumour cell suspensions containing approximately 2 x 10(5) cells were transplanted into the dorsal site of the C3Hf/Sed mouse foot. Hyperthermia was given by immersing the tumour-bearing foot into a constant temperature water bath set at 41.5 degrees C for 0-90 min when tumours reached 34 mm3. IFO was administered i.p. immediately before hyperthermia. Tumour response was studied by the tumour growth (TG) time assay; namely, the TG time or the time for one-half of the treated tumours to reach 700 mm3 from the initial treatment day was determined and the dose-response curves was fitted between the TG time and IFO dose. The anti-tumour effect of IFO was enhanced at this elevated temperature. The thermal enhancement ratio (TER) or the ratio of the slope of dose-response curve at 41.5 degrees C to that of dose-response curve without hyperthermia was relatively small for a short treatment time of 30 min. This TER was smaller for IFO than the TERs for cyclophosphamide (CY) and BCNU which had been studied in our laboratory. However, the TER for IFO increased greatly with a prolongation of treatment time from 30 to 90 min, and exceeded the TER for CY. The TERs were 1.5, 2.6 and 3.6 for heating time of 30, 60, and 90 min, respectively, indicating that a long treatment time such as 90 min at moderately elevated temperatures could result in a substantial enhancement of the antitumour effect of IFO.

Animals↗

PubMedDate not supplied

Phase II study of sequential methotrexate and 5-FU plus mitomycin and leucovorin in patients with disseminated large bowel cancer: a Northern California Oncology Group study.

Sequential methotrexate (MTX) and 5-FU plus leucovorin and mitomycin (MMC) was given to 52 patients with disseminated, measurable colorectal cancer. Complete and partial responses were seen in 19 of 49 (39%) evaluable patients. Nine additional patients achieved a minimal response. Median overall survival was 8.8 months, while that for patients objectively responding was 13.6 months. This study utilized a MTX exposure period of 12 hours prior to 5-FU. In comparison to other trials utilizing sequential MTX and 5-FU, the addition of MMC to the regimen may improve the response rate but increases the incidence of adverse effects, particularly myelosuppression and renal toxicity. This phase II trial suggests that sequential MTX and 5-FU plus leucovorin and MMC is an active combination therapy and warrants further comparative trial in patients with large bowel cancer.

Adult↗

PubMedDate not supplied

Randomized comparison of two combination chemotherapy regimens containing doxorubicin in patients with metastatic breast cancer: a Western Cancer Study Group trial.

Ninety-six patients with metastatic breast cancer were entered in a prospectively randomized trial comparing a five-drug doxorubicin (Adriamycin)-containing regimen given in two different schedules. Both regimens included cyclophosphamide, methotrexate, 5-FU, prednisone, and doxorubicin. On one schedule, referred to as "combination" treatment, doxorubicin was given every 21 days and cyclophosphamide was given daily. On the less intensive "fixed-rotation" schedule, doxorubicin was given on alternative cycles every 42 days and cyclophosphamide was given for 21 days of the 42-day cycle. Response frequency and survival were comparable among patients receiving either regimen. Significantly less (P < 0.05) nausea and leukopenia occurred on the fixed-rotation schedule. Therefore, similar therapeutic benefit along with decreased toxicity was obtained by use of combination chemotherapy involving doxorubicin and cyclophosphamide given in the less intensive schedule.

Antineoplastic Agents↗

PubMedDate not supplied

Excessive thyroid hormone replacement therapy.

BACKGROUND: Excessive thyroid hormone replacement carries the potential for serious long-term metabolic complications (e.g., accelerated osteoporosis). The increased bioavailability of commercially available products, along with improved laboratory assays for measuring thyrotropin (TSH), has led to an increased chance of actual or detected iatrogenic hyperthyroxinemia. The purpose of this study was to determine the frequency of excessive prescribing and to examine the impact of changes in potency of replacement thyroid hormone formulations and sensitivity of thyroid function tests on its incidence. METHODS: A retrospective chart review was done of patients requiring thyroid hormone replacement therapy treated at a university-based, family medicine residency training program. The following information was extracted from each chart: specific thyroid medication (including dose and date of onset of therapy) and thyroid laboratory tests results (including serum thyroxine [T4] and TSH). This information from two different time periods (1975 to 1981 and 1982 to 1989) was compared using one-way analysis of variance. RESULTS: Serum T4 levels were not significantly different between the two time periods, 1975 to 1981 and 1982 to 1989 (8.06 +/- 2.93 micrograms/dl versus 9.0 +/- 03.69 micrograms/dl; NS), despite significant changes in TS serum levels (23.6 +/- 38.9 mIU/mL versus 7.44 +/- 18.7 mIU/ml; P = 0.009) and levothyroxine dosage (184 +/- 59.6 micrograms/d versus 145 +/- 64.1 micrograms/d; P = 0.002). Significantly more patients had low (supersuppressed) TSH levels between 1982 and 1990 than between 1975 and 1981 (33 percent versus 10 percent; P = 0.02.) CONCLUSIONS: Excessive thyroid hormone replacement with iatrogenic hyperthyroxinemia is a common occurrence. Clinicians need to be aware of this problem and implement measures (e.g., periodic monitoring of TSH) to minimize the occurrence of overdosing and the potential for long-term complications.

Adult↗