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Biomedical subjects

H B Niell

Publications and source records attributed to H B Niell.

13 recordsLinked to original sources
PubMed1992

Pharmacodynamics of three daily infusions of etoposide in patients with extensive-stage small-cell lung cancer.

The objectives of this study were to define the pharmacodynamics of etoposide and to develop potentially useful models (1) to estimate the plasma clearance using a limited number of samples and (2) to describe the relationship between clearance and the dose-limiting toxicity. A total of 17 patients with extensive-stage small-cell lung cancer were treated with 150 mg/m2 etoposide daily for 3 consecutive days and with 100 mg/m2 cisplatin on day 3 only. Both drugs were given intravenously over 1 h. Treatment was repeated every 21 days for up to six courses. All patients were newly diagnosed (no previous chemotherapy or irradiation) and had a performance status of 0-2. Six patients achieved a complete response as confirmed by repeat bronchoscopy and five patients showed a partial response, for an overall objective response rate of 65% (95% confidence interval, 38%-87%). The median survival was 8 months (range, 1-24+ months). The dose-limiting toxicity was neutropenia. Etoposide pharmacokinetics were measured during the first course and determinations were repeated during courses 3 or 4 and 6. Complete blood counts were obtained weekly. Correlations for etoposide clearance and hematologic toxicities were evaluated for 17 initial courses and for an overall number of 33 courses. Pharmacodynamic correlations were significant for graded hematologic toxicities, as well as nadirs of leukocytes, neutrophils, and platelets for the initial courses and for all courses. To reduce the requirement for numerous blood samples, a limited sampling model was developed to estimate the area under the concentration versus time curve (AUC) with the following equation: AUC = 15.45 + 3.86 x C2 + 7.10 x C4, where C2 and C4 represent the etoposide concentrations at 2 and 4 h, respectively. The total plasma clearance was calculated as the dose divided by the AUC; correlations with toxicity were better for clearance expressed in milliliters per minute than for that expressed in milliliters per minute per square meter of body surface area. The absolute neutrophil count at the nadir (ANCn) can be estimated by the following pharmacodynamic model, which is based on 33 courses: ANCn = -0.399 + 0.024 x Ecl, where Ecl represents the etoposide clearance expressed in milliliters per minute. Further studies are necessary to validate both models prospectively.

Adult↗
PubMed1990

Clonal growth requirements of human bladder tumor cell lines.

We have serially investigated the role of nutrients and growth factors for their ability to support the clonal growth of human bladder tumor cell lines. Five established human bladder tumor cell lines were selected for study of their requirements for clonogenic growth in semisolid cultures. We identified an "optimal medium" to be Alpha MEM medium, 15% horse serum, five micrograms/ml. of transferrin, five micrograms/ml. of insulin and 30 ng./ml. of epidermal growth factor. The "optimal assay" enhanced the growth of human bladder tumor cell lines 2.5 times compared to the standard clonogenic assay. The resulting medium is less complicated to maintain, less expensive and supports the growth of human bladder tumor cell lines better than the standard clonogenic assay.

Cell Line↗
PubMed1989

Combination versus sequential single-agent chemotherapy in the treatment of patients with advanced non-small cell lung cancer.

We have carried out a randomized phase III study in 105 patients with advanced non-small cell lung cancer, comparing a four-drug cisplatin-mitomycin-based combination chemotherapy regimen to sequential single-agent therapy. The combination chemotherapy regimen consisted of mitomycin C (10 mg/m2), vinblastine (5 mg/m2), methotrexate (40 mg/m2), and cisplatin (40 mg/m2) given every 28 days. Sequential single-agent chemotherapy consisted of mitomycin C (10 mg/m2) monthly until progression followed by vinblastine (5 mg/m2) every 2 weeks until progression followed by methotrexate (40 mg/m2) weekly until relapse. Patients failing either regimen were followed with supportive care. The objective response rate for the sequential single-agent therapy was 19% versus 25% for the combination chemotherapy group (P greater than .5). The median survival for the single-agent group was 166 days and 191 days for the combination chemotherapy group. Overall survival was not statistically different between the two groups (P greater than .5). Leucopenia, anemia, and prolonged anorexia with nausea and vomiting were more common in the combination chemotherapy group compared to the single-agent group. This study failed to demonstrate a sufficient therapeutic benefit in the face of the added toxicity for the combination chemotherapy regimen compared to sequential single-agent therapy.

Antineoplastic Agents↗
PubMed1989

5-Fluorouracil infusion and mitomycin combination chemotherapy in the management of patients with advanced non-small-cell lung cancer.

We have carried out a phase II study evaluating the activity of a 5-fluorouracil drug combination in patients with advanced non-small-cell lung cancer. Patients were given 60 mg/m2 of methotrexate i.v. on day 1. On day 2, 750 mg/m2 of 5-fluorouracil was administered as a 24-h infusion daily for 3 days. Also on day 3, 10 mg/m2 of mitomycin was given i.v. along with folinic acid. Folinic acid was started on day 3 initially at a dose of 25 mg/m2 intravenously every 6 h for three doses, followed by a 2-h infusion of 200 mg/m2 daily on days 3 and 4. Therapy was repeated every 28 days. Fourteen of 35 patients (40%) experienced a partial response to chemotherapy. The median survival of the entire group was 19 weeks. Mucositis was a common side effect but severe leukopenia, anemia, renal insufficiency, and skin ulceration were rare. This study demonstrated that 5-fluorouracil infusion therapy has activity in advanced non-small-cell lung cancer but the responses are not durable. Further studies evaluating differing dose schedules and alternate 5-fluorouracil infusion-based drug combinations seems warranted.

Adult↗
PubMed1987

Detection of small cell lung cancer bone marrow involvement by discontinuous gradient sedimentation.

Marrow involvement by small cell lung cancer (SCLC) is detected in 10-23% of patients at initial diagnosis by marrow aspirate and biopsy techniques. To improve the detection and potentially monitor marrow involvement by SCLC we have attempted to concentrate malignant cells with clonogenic potential on a discontinuous density gradient (DDG). The bone marrow from 43 patients with SCLC (36 with histologically negative marrow aspirates and biopsies) were separated on a Ficoll-based DDG. Samples were also separated by conventional Ficoll-diatrizoate (FD) (density, 1.077) gradient sedimentation. The cellular interphase from three fractions (F X) corresponding to specific densities 1.050 (F X 1), 1.055 (F X 2), and 1.060 (F X 3) as well as cells separated by Ficoll-diatrizoate (F X FD) centrifugation were isolated and 2.5 X 10(5) cells from each fraction were cultured in 2 ml of 0.3% agar in McCoy's media with 10% fetal calf serum, 2.5 micrograms transferrin, 1 microgram insulin, and 1% penicillin-streptomycin. Colony growth was assessed after 14 days of culture at 37 degrees C and 6% CO2. Tumor colony growth was seen in eight of 36 (22%) patients with histologically negative marrows as well as in four of seven (57%) patients with known involvement. Mean colony growth per 2.5 X 10(5) cells for all 12 patients was 4.3 colonies for F X 1; 8.8 for F X 2; and 2.7 for F X 3. In contrast mean growth from the F X FD was 1.0 colonies. Cells with clonogenic potential could be demonstrated from F X 2 and F X 3 in seven of 12 and eight of 12 patients, respectively; in F X FD four of 12 patients had tumor growth. We conclude that separation of marrow samples by DDG concentrates malignant cells with clonogenic potential at least 8-fold compared to FD separation and that the sensitivity of the clonogenic assay in detecting marrow involvement by SCLC is enhanced by DDG sedimentation.

Biopsy↗
PubMed1987

Effects of N-trifluoroacetyladriamycin-14-valerate (AD-32) on human bladder tumor cell lines.

We have compared the in vitro activity of N-trifluoroacetyladriamycin-14-valerate (AD-32) and doxorubicin hydrochloride (ADR) on the clonal growth of human bladder tumor cell lines (HBTCL). In order to determine the relatively toxicity of ADR and AD-32 on hematopoietic stem cells, CFU-GM assays were set up using 10 normal human bone marrow samples. The mean lethal dose for 50% of the colonies (LD-50) for ADR was 1.6 +/- 1.4 microM and that for AD-32, 3.9 +/- 4.9 microM (P less than 0.55), suggesting that these agents have similar bone marrow toxicity. Both drugs produced enhanced inhibition of clonal growth of HBTCL with increasing C X Ts. The spectrum of activity of the two drugs was similar against a panel of seven HBTCL. The activity of ADR was inhibited at 4 degrees C while the activity of AD-32 was unaffected by temperature. ADR was more effective against HBTCL in the log growth phase than the plateau phase while the reverse was found using AD-32. Verapamil was found to enhance the activity of both ADR and AD-32 against a HBTCL (T24), found to be resistant to both agents. The lipophilic properties of AD-32, along with its enhanced activity when used over prolonged periods of time and its activity against tumor cells in the plateau phase, suggest that AD-32 could be useful in the management of patients with superficial bladder cancer.

Biological Transport↗
PubMed1987

Evidence for depressed humoral immunity to Pneumocystis carinii in homosexual males, commercial plasma donors, and patients with acquired immunodeficiency syndrome.

Heterosexual controls were found to have significantly higher titers of immunoglobulin G antibody to Pneumocystis carinii than did patients with the acquired immunodeficiency syndrome (AIDS) and P. carinii pneumonitis, human immunodeficiency virus (HIV) antibody-positive or -negative homosexual male "gay bar" patrons, and HIV antibody-positive or -negative commercial plasma donors. The T-helper/T-suppressor lymphocyte ratios of HIV antibody-negative homosexual male gay bar patrons were slightly depressed (mean = 1.31 +/- 0.54) compared with those of heterosexual controls (mean = 1.79 +/- 0.32). In addition to other recognized factors, preexisting humoral as well as cell-mediated immune deficits before infection with HIV may help to explain the prevalence of and morbidity and mortality associated with P. carinii pneumonitis in AIDS patients.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Skeletal surveys in multiple myeloma. Radiologic-clinical correlation.

Thirty-three patients with multiple myeloma were studied with serial skeletal surveys, serum immunoglobulin levels, and postabsorptive urinary hydroxyproline (Spot-HYPRO) determinations. Twenty receiving chemotherapy were also followed with skeletal surveys in order to evaluate bone response to treatment. A close association was found between skeletal findings and changes in immunoglobulin levels with positive correlation in 71% of the patients. A similar association was found between skeletal disease and Spot-HYPRO level changes in 65%. Five of 12 patients (42%) with partial or complete clinical response to chemotherapy, demonstrated improvement in the appearance of skeletal lesions. Positive correlation between the roentgenographic changes and clinical markers of myeloma as well as therapeutic response, indicates that skeletal surveys are useful and effective in monitoring patients with multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Combination chemotherapy with mitomycin-C, cisplatin, and vinblastine in the treatment of non-small-cell lung cancer.

The drug combination of mitomycin-C, cisplatin, and vinblastine was administered to 30 patients with stage III non-small-cell lung cancer. All patients had a performance status of 50% or greater, had evaluable disease, and had not received previous chemotherapy. The overall response rate was 37% with responses seen in 7 of 18 (39%) squamous cell and 3 of 11 (27%) patients with adenocarcinoma of the lung. Mean survival was greater by 2 months in those patients with an objective response to chemotherapy (8.1 vs 5.5). Drug-associated gastrointestinal toxicity was the most common side effect observed. This three-drug combination appears to be an active regimen in the treatment of non-small-cell bronchogenic carcinoma; however, altered dosage schedules should be examined in order to decrease drug-related toxicity.

Adenocarcinoma↗
PubMed1985

Effect of concentration and time of drug exposure on clonal growth of murine bladder cancer.

The use of a tumor colony assay was evaluated for its ability to predict anticancer drug response in an N[4-(5-nitro-2-furyl)-2-thiazolyl] formamide mouse bladder tumor model. One-hour and continuous drug exposure were compared to determine what effect altering drug concentration and time of exposure would have on the predictability of the tumor colony assay in the murine model. Ten anticancer drugs were tested in the murine model, and tumor cells removed from control mice were used for in vitro drug testing. One-hour and continuous drug exposure (using the one-hour drug level) were performed simultaneously and the in vitro and in vivo data compared. Using one-hour drug incubation in the tumor colony assay resulted in a true positive predictive rate of 54 per cent and a true negative predictive rate of 70 per cent. Continuous drug incubation overestimated drug sensitivity resulting in a drop in the predictability of the tumor colony assay. We conclude that using one-hour drug exposure the tumor colony assay is predictive of chemotherapeutic drug response in this murine bladder tumor model.

Animals↗
PubMed1985

In vitro and in vivo activity of two second generation platinum analogs in murine bladder cancer.

The activity of cis-diamminedichloroplatinum(II) was compared to two second generation platinum analogs, cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) and cis-dichlorotransdihydroxybisisopropylamine platinum(IV) in the N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced murine bladder tumor model and a tumor colony assay. Murine drug testing revealed that all three drugs were active against the MBT-2 tumor line, although cis-diamminedichloroplatinum(II) was more active than its analogs. All drugs produced enhanced inhibition of clonal growth with increasing drug exposure times. Cis-diamminedichloroplatinum(II) was more active against MBT-2 cells in the plateau growth phase versus the log growth phase after a one hour drug exposure. Similar differential activity depending upon the proliferative state of MBT-2 was not seen with the two platinum analogs. These two platinum analogs have somewhat less activity in vivo and in vitro than cis-diamminedichloroplatinum(II) and would be predicted to be less effective clinically in human bladder cancer than the parent compound.

Animals↗
PubMed1979

Zinc metabolism in sickle cell anemia.

Zinc metabolism was studied in 34 patients with sickle cell anemia in a steady state and in six patients during sickle cell crisis. The patients in steady state were found to have significantly lower plasma levels and higher urinary levels of zinc than the 50 healthy adults in the control group. During sickle cell crisis the plasma zinc levels dropped to a mean value of 0.54 microgram/microL. These results support the concept that zinc deficiency occurs in sickle cell anemia and that further drops occur in the serum zinc levels during sickle cell crisis.

Anemia, Sickle Cell↗