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Biomedical subjects

C Hancock

Publications and source records attributed to C Hancock.

At least 19 recordsLinked to original sources
PubMed1991

HMB-45 detection in adenocarcinomas.

Several studies have suggested that HMB-45 is a specific marker for melanoma, presumably due to its ability to detect a glycoprotein that is present in premelanosomes. The present study was conducted to evaluate whether HMB-45 is an absolutely specific antigenic determinant for melanoma and the role that testing with this antibody has in the differential diagnostic workup of amelanotic melanoma vs adenocarcinoma. Formaldehyde solution-fixed, paraffin-embedded tissue samples from 52 adenocarcinomas (primary or metastatic) and five melanomas (two primary and three metastatic) were immunostained with the use of a commercially available monoclonal antibody (MoAb), ie, HMB-45 (Enzo), a polyclonal antibody to S100 protein, a wide-spectrum keratin polyclonal antibody, and a keratin MoAb, ie, AE1/AE3. Approximately 10% (ie, 9.6%) of the adenocarcinomas (five cases) expressed HMB-45 with varied intensity and distribution. Positive primary tumors (n = 3) included one each from the breast, colon, and kidney; positive metastatic tumors (n = 2) included one each from the breast and endometrium. Fifty-two percent of the adenocarcinomas were positive for S100 protein. One renal carcinoma was negative for both keratins when tested with the AE1/AE3 MoAb and polyclonal antibody (Dako). This was the only adenocarcinoma that was negative when the keratin polyclonal antibody (Dako) was used. All but one additional adenocarcinoma demonstrated keratin expression when the AE1/AE3 MoAb was used for testing. This study showed that HMB-45 is not absolutely specific for melanoma. HMB-45 may react with some adenocarcinomas, at least when tested with the commercially available MoAb (Enzo). This fact, in conjunction with aberrant keratin expression by some melanomas and S100 protein expression by adenocarcinomas and other neoplasms other than melanomas, should be considered when antibody panels are evaluated in the workup of poorly differentiated tumors. However, HMB-45 appears to be the most specific marker that is available at the present time for supporting a diagnosis of melanoma.

Adenocarcinoma↗
PubMed1989

4-demethoxydaunorubicin (idarubicin) in combination with 1-beta-D-arabinofuranosylcytosine in the treatment of relapsed or refractory acute leukemia.

We conducted a Phase I-II trial of 4-demethoxydaunorubicin (idarubicin, IDR) in combination with 1-beta-D-arabinofuranosylcytosine (ara-C) in 51 patients with relapsed or refractory acute nonlymphocytic leukemia, acute lymphocytic leukemia, or chronic myelogenous leukemia in blast crisis. Only 1 of 12 patients treated at the first dose level (idarubicin, 10 mg/m2/day for 3 days and ara-C, 25 mg/m2 i.v. bolus followed by 200 mg/m2 continuous infusion daily for 5 days) achieved aplasia and complete remission. The dose of idarubicin was subsequently increased to 10 mg/m2/day for 4 days with the ara-C dose held constant. Complete remission incidence for this dose schedule was: 7 of 31 patients with acute nonlymphocytic leukemia, 0 of 5 patients with acute lymphocytic leukemia, 0 of 1 patient with chronic myelogenous leukemia in blast crisis, and 1 of 2 patients with biphenotypic leukemia. Nonhematological toxicity included nausea, vomiting, mucositis, and abnormal liver function tests. Detailed pharmacological studies were performed to determine whether ara-C altered IDR metabolism or that of its main metabolite, 13-hydroxyidarubicinol or IDR clearance. A high degree of variability among patients was apparent and no consistent effect could be demonstrated. In summary, 9 of 37 patients (24%) with relapsed or refractory ANLL, including 1 patient with biphenotypic leukemia, achieved remission. We conclude that idarubicin in combination with ara-C is an active combination in patients with relapsed or refractory leukemia.

Adolescent↗
PubMed1988

Increased adriamycin levels in hepatic implants of rabbit Vx-2 carcinoma from regional infusion.

Regional infusion chemotherapy for the treatment of primary or secondary hepatic cancer should allow delivery of a higher drug concentration to the tumor with decreased systemic exposure when compared with systemic therapy. Fifteen rabbits, each implanted with two hepatic Vx-2 tumors, were treated with infusion of Adriamycin (3 mg/kg and 7.5 muCi of [14C]Adriamycin) through the hepatic artery (n = 5), portal vein (n = 5), and a systemic vein (n = 5) at 20 mg/min. 99Tc-labeled macroaggregated albumin flow images documented specific hepatic perfusion in selected rabbits using this technique. Thirty min after infusion the animals were sacrificed, and multiple specimens of liver, tumor, and heart were taken for liquid scintillation counting and high-performance liquid chromatography. The 14C label remained associated with Adriamycin and metabolites. After systemic infusion 11.5 nmol/g of Adriamycin were found in tumor, and 32.4 nmol/g were found in liver. Infusion of Adriamycin through the hepatic artery produced drug levels of 34.3 nmol/g of tumor and 48.4 nmol/g of liver, while infusion through the portal vein produced drug levels of 6.5 nmol/g of tumor and 54.4 nmol/g of liver. The drug concentration in tumor was significantly higher after hepatic artery infusion compared with systemic (P less than 0.05) or portal vein (P less than 0.01) infusion. The tumor/liver ratio of [14C]Adriamycin tissue levels after hepatic artery infusion was greater than that measured after systemic vein treatment (no overlap of the 90% confidence intervals). Systemic infusion of Adriamycin produced a higher level of Adriamycin in the heart (13.6 nmol/g) than did hepatic artery (10.9 nmol/g) or portal vein (8.9 nmol/g) infusion. Hepatic artery infusion achieved the highest tumor Adriamycin level compared with systemic vein and portal vein infusion. The results suggest that these tumor implants are supplied primarily by the hepatic artery, that clearance of Adriamycin is efficient after regional infusion, and that systemic toxicity may be reduced using intraarterial infusion of Adriamycin for hepatic tumors.

Animals↗
PubMed1987

Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (idarubicin) in children with advanced cancer.

We conducted a phase I and pharmacokinetic study of i.v. idarubicin, a new anthracycline analogue, in 42 evaluable children 1-19 years old. Twenty-seven had leukemia and 15 had various solid tumors. The drug was administered in escalating doses of 10 to 40 mg/m2/course in 3 equal fractions over 3 consecutive days at 14- to 21-day intervals. Myelosuppression and mucositis were the limiting toxicities for short-term administration. Nausea, vomiting, and elevation of liver enzymes and bilirubin were the other toxicities encountered. Peak toxicity occurred 2 weeks after drug administration with median recovery by day 24. All but 4 patients with solid tumors had prior anthracyclines. Mild cardiac function changes without clinical symptoms were observed in 17 of 35 patients measured by serial cardiac evaluations. In addition, there were 4 patients with congestive heart failure. On postmortem examination, 4 patients had changes consistent with anthracycline cardiomyopathy at a prior median total anthracycline dose of 175 mg/m2. The maximum tolerated dose for patients with solid tumors was 15 mg/m2 course in 3 divided doses. Patients with leukemia tolerated 30 mg/m2/course. Six of 15 evaluable patients with acute lymphoblastic leukemia who received greater than or equal to 30 mg/m2 idarubicin achieved a remission (M1 marrow status). The plasma clearance of idarubicin fits a 3-compartment model with a harmonic mean half-life of 2.4 min, 0.6 h, and 11.3 h for alpha, beta, and gamma phases, respectively. Idarubicinol was the only metabolite detected in the plasma and it accumulated during the 3 days of therapy. Idarubicin is similar to daunorubicin in pharmacology and toxicity. While the cardiotoxic dose still must be delineated, the complete remission achieved in multiple relapsed patients with acute lymphoblastic leukemia indicate promising activity in at least that disease.

Adolescent↗
PubMed1987

Toxicity, elimination, and metabolism of 10-ethyl-10-deazaaminopterin in rats and dogs.

10-Ethyl-10-deazaaminopterin (10-EdAM) is an antifolate compound with greater therapeutic activity than methotrexate against transplanted tumors in mice. When given weekly for 3 weeks, the 10% lethal dose in rats was 125 mg/kg (i.p.) and in dogs it was 2.5 mg/kg (i.v.). The major histopathological findings in intoxicated animals were damage to the mucosa of the gastrointestinal tract in rats and dogs and hypocellularity of the marrow in rats. The elimination of 50 mg/kg of 10-EdAM from the plasma of rats was triexponential with a terminal phase t1/2 of 18.5 h but a mean residence time of 0.7 h. The primary route of elimination in rats was biliary secretion of parent compound and eventual excretion of the parent compound and the deglutamate metabolite in the feces; the 7-hydroxy metabolite was also present in plasma, bile, and feces. Biliary elimination was independent of dose over a 5-fold range. The elimination of 10-EdAM from the plasma of dogs was also triexponential with a mean terminal phase t1/2 of 9.1 h and a mean residence time of 2.5 h; nonrenal clearance was the primary route of elimination. The pharmacokinetic parameters were independent of dose over the range of 0.25 to 5.0 mg/kg. High tissue concentrations of 10-EdAM were observed initially in liver, kidney, and small intestine of rats, while concentrations in bone marrow were low. Some polyglutamate formation was observed in these tissues as early as 0.5 h after drug administration but declined over 72 h.

Aminopterin↗
PubMed1987

PCNU and recurrent childhood brain tumors.

PCNU, the latest nitrosourea analogue to be subjected to clinical trials, held promise as a superior chemotherapy agent for brain tumors because of more favorable biochemical and cytotoxic characteristics in laboratory studies. Thirty-nine children with a variety of recurrent primary CNS tumors, all of whom had evaluable disease, participated in a phase II PCNU trial. Their mean age was 9.7 (3-20) years. PCNU was administered as a 2 hour intravenous infusion in one of 2 dose schedules at 6-7 week intervals; 100-125 mg/m2 for minimally treated patients and 70-90 mg/m2 for heavily treated patients. Response was assessed after 2 courses of chemotherapy after attempting to taper the steroid dose. The overall objective response rate was 18% (7/39) for a mean of 5.9 months (2+ -12). Only partial responses were observed. Disease-specific responses rates were: brainstem glioma--18% (3/17); cerebral glioma--27% (3/12); ependymoma--1/1; and primitive neuroectodermal tumors--(0/9) including 5 medulloblastomas, 2 pineoblastomas and 3 cerebral primitive neuroectodermal tumors. Toxicity was primarily hematologic and clinically significant thrombocytopenia (less than 50,000 mm3) was encountered in 30/38 (79%) patient trials. Modest activity of PCNU in recurrent childhood gliomas is confirmed. Our response rates, using objective CT criteria, are somewhat lower than those reported for BCNU and CCNU. Because of comparable hematologic toxicity and efficacy, intravenous PCNU does not appear to offer a clinical advantage to existing nitrosoureas for children with recurrent brain tumors using a 2 hour intravenous infusion schedule.

Adolescent↗
PubMed1987

Electrodermal activity as an index of motion sickness.

Sweating in the absence of thermal stimulation is one of the cardinal symptoms of motion sickness. But since sweating is closely related to electrodermal activity this may be a potentially useful index of the intensity of motion sickness. In order to evaluate this possibility, the correlations between electrodermal activity and a range of signs and symptoms of motion sickness were examined in four experiments, in which a total of 170 subjects were exposed to a cross-coupled force environment. Although increases in skin conductance did not correlate with specific single indices of motion sickness, correlations with a questionnaire based on several signs and symptoms varied from 0.89 (p less than 0.001) to 0.11 (N.S.). It is concluded that skin conductance potentially offers a valid and very precise measure of motion sickness, but that it is sensitive to extraneous factors only some of which are currently understood.

Female↗
PubMed1985

Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections.

The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.

Adult↗
PubMed1985

Phase I and clinical pharmacological evaluation of 4'-deoxydoxorubicin in patients with advanced cancer.

We have conducted a Phase I and initial clinical pharmacological evaluation of 4'-deoxydoxorubicin (4'-DXDX), administering the drug i.v. on an every 21-day schedule to 60 patients with advanced cancer. Patients were treated at six dosage levels ranging from 10 to 35 mg/sq m. Leukopenia was the dose-limiting toxic effect, and no cardiac, renal, or hepatic toxicity was observed; stomatitis was not seen; and there were no drug-related deaths. Significant alopecia was rare at doses less than 35 mg/sq m, mild nausea and vomiting occurred in one-third of patients at myelosuppressive doses; 12 patients had a transient local urticarial reaction. In the 30 patients with measurable disease, two partial remissions were seen, lasting 5 months in a patient with a nasopharyngeal adenocarcinoma, and 7 months in a patient with endometrial adenocarcinoma. The recommended dose of 4'-DXDX for Phase II studies is 30 mg/sq m in good-risk patients and 25 mg/sq m in moderate-risk or heavily pretreated patients. Pharmacokinetic studies were carried out in ten patients, four of whom received 4'-DXDX at a dose of 10 mg/sq m and six at 30 mg/sq m. Disappearance of 4'-DXDX from plasma was triphasic with a rapid initial phase clearance showing a t1/2 alpha of 1 to 2 min and a prolonged terminal phase with a median t1/2 gamma in excess of 90 h in patients receiving 30 mg/sq m.

Adult↗