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Biomedical subjects

D Blakey

Publications and source records attributed to D Blakey.

18 recordsLinked to original sources
PubMed1999

Repetitive high-dose therapy with ifosfamide, thiotepa and paclitaxel with peripheral blood progenitor cell and filgrastim support for metastatic and locally advanced breast cancer: results of a phase I study.

BACKGROUND: This phase I study was designed to determine the optimal dosages of a novel repetitive high-dose therapy regimen for patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: The planned treatment was three cycles of high-dose ifosfamide, thiotepa and conventional-dose paclitaxel delivered every 28 days with progressive dose-escalation in successive cohorts. Each cycle was supported by peripheral blood progenitor cells (PBPC) and filgrastim. RESULTS: Twenty-three patients were entered into this trial. Of the planned 69 treatment cycles, 59 were delivered and fifteen patients completed all three cycles. The dose-limiting toxicities were renal tubular acidosis, encephalopathy, mucositis and enterocolitis. There was one treatment-related hemorrhagic death. CONCLUSIONS: The recommended doses for phase II or III studies are ifosfamide (10 g/m2), thiotepa (350 mg/m2) and paclitaxel (175 mg/m2).

Adult↗
PubMed1998

Engineered human carboxypeptidase B enzymes that hydrolyse hippuryl-L-glutamic acid: reversed-polarity mutants.

Variants of human pancreatic carboxypeptidase B (HCPB), with specificity for hydrolysis of C-terminal glutamic acid and aspartic acid, were prepared by site-directed mutagenesis of the human gene and expressed in the periplasm of Escherichia coli. By changing residues in the lining of the S1' pocket of the enzyme, it was possible to reverse the substrate specificity to give variants able to hydrolyse prior to C-terminal acidic amino acid residues instead of the normal C-terminal basic residues. This was achieved by mutating Asp253 at the base of the S1' specificity pocket, which normally interacts with the basic side-chain of the substrate, to either Lys or Arg. The resulting enzymes had the desired reversed polarity and enzyme activity was improved significantly with further mutations at residue 251. The [G251T,D253K]HCPB double mutant was 100 times more active against hippuryl-L-glutamic acid (hipp-Glu) as substrate than was the single mutant, [D253K]HCPB. Triple mutants, containing additional changes at Ala248, had improved activity against hipp-Glu substrate when position 251 was Asn. These reversed-polarity mutants of a human enzyme have the potential to be used in antibody-directed enzyme prodrug therapy of cancer.

Alanine↗
PubMed1997

Radiotherapy treatment for isolated loco-regional recurrence of rectosigmoid cancer following definitive surgery: Peter MacCallum Cancer Institute experience, 1981-1990.

PURPOSE: To assess the success of external beam radiation treatment in the management of loco-regional recurrence of rectosigmoid cancer. METHODS AND MATERIALS: A retrospective analysis of 135 patients with locally recurrent rectosigmoid cancer presenting to Peter MacCallum Cancer Institute between January 1981 and December 1990 was undertaken. Patients were treated with three different dose ranges of radiotherapy: 50-60 Gy ("Radical" group), 45 Gy ("High-dose palliative" group), and <45 Gy ("Low-dose palliative" group). Symptomatic response rates and overall survival for each group were determined. RESULTS: Symptomatic response rates of 85, 81, and 56% were achieved in the radical, high-dose palliative, and low-dose palliative groups, respectively. Estimated median survival times were 17.9, 14.8, and 9.1 months for the radical, high-dose palliative, and low-dose palliative groups, respectively.

Adult↗
PubMed1996

Toward antibody-directed "abzyme" prodrug therapy, ADAPT: carbamate prodrug activation by a catalytic antibody and its in vitro application to human tumor cell killing.

Antibody-directed enzyme prodrug therapy, ADEPT, is a recent approach to targeted cancer chemotherapy intended to diminish the nonspecific toxicity associated with many commonly used chemotherapeutic agents. Most ADEPT systems incorporate a bacterial enzyme, and thus their potential is reduced because of the immunogenicity of that component of the conjugate. This limitation can be circumvented by the use of a catalytic antibody, which can be "humanized," in place of the bacterial enzyme catalyst. We have explored the scope of such antibody-directed "abzyme" prodrug therapy, ADAPT, to evaluate the potential for a repeatable targeted cancer chemotherapy. We report the production of a catalytic antibody that can hydrolyze the carbamate prodrug 4-[N,N-bis(2-chloroethyl)]aminophenyl-N-[(1S)-(1,3- dicarboxy)propyl]carbamate (1) to generate the corresponding cytotoxic nitrogen mustard (Km = 201 microM, kcat = 1.88 min-1). In vitro studies with this abzyme, EA11-D7, and prodrug 1 lead to a marked reduction in viability of cultured human colonic carcinoma (LoVo) cells relative to appropriate controls. In addition, we have found a good correlation between antibody catalysis as determined by this cytotoxicity assay in vitro and competitive binding studies of candidate abzymes to the truncated transition-state analogue ethyl 4-nitrophenylmethylphosphonate. This cell-kill assay heralds a general approach to direct and rapid screening of antibody libraries for catalysts.

Aniline Mustard↗
PubMed1996

Postoperative radiotherapy for Dukes' B and C rectal cancer: Peter MacCallum Cancer Institute experience.

This retrospective study reviews the outcome of patients with Dukes' B and C rectal cancer treated with adjuvant post-operative pelvic radiotherapy at the Peter MacCallum Cancer Institute from 1981 to 1990. Sixty-one patients (22 Dukes' B, 36 Dukes' C and 3 unknown stage) received a median dose of 50 Gy of pelvic irradiation. Locoregional relapse occurred in 33% of patients. Estimated median progression-free survival was 1.7 years with 46% surviving without progression at 2 years and 30% at 5 years. There was no difference according to Dukes' stage. The estimated median survival was 2.6 years, with no difference according to disease stage. These results with postoperative radiotherapy alone are inferior to results achievable by combination chemotherapy and radiotherapy as adjuvant therapy which should now be considered standard therapy following surgical resection for Dukes' B and C rectal cancer.

Adenocarcinoma↗
PubMed1995

Low-dose caudal morphine for postoperative analgesia in infants and children: a report of 500 cases.

STUDY OBJECTIVE: To determine the effectiveness of morphine 0.03 mg/kg or 0.04 mg/kg administered caudally to children for postoperative pain relief. DESIGN: Retrospective chart review. SETTING: University-affiliated hospital. PATIENTS: The charts of 500 children who had undergone various surgical procedures and who were given caudal morphine 0.03 mg/kg or 0.04 mg/kg either prior to the surgical procedure or immediately at the conclusion of the surgical procedure. MEASUREMENTS AND MAIN RESULTS: Parameters of respiratory rate, oxygen saturation, nausea and vomiting, voiding problems, and pruritus were recorded for each patient. There was no respiratory depression noted in the review of the 500 patients; 23% had nausea and vomiting, 3% had voiding problems needing bladder catheterization, and 7% reported pruritus, which was treated with either diphenhydramine or naloxone. CONCLUSION: Statistically there were no differences between morphine 0.03 mg/kg and morphine 0.04 mg/kg in all the study parameters. There was no respiratory depression in the 500 cases reviewed. The postoperative pain relief ranged from 6 hours to over 24 hours. This method of immediate postoperative pain management proved to be effective and safe.

Adolescent↗
PubMed1995

Three-probe fluorescence in situ hybridization to assess chromosome X, Y, and 8 aneuploidy in sperm of 14 men from two healthy groups: evidence for a paternal age effect on sperm aneuploidy.

The method of simultaneous three-chromosome fluorescence in situ hybridization (FISH) was developed using repetitive DNA sequence probes for chromosomes 8, X and Y and applied to semen of 14 men from two healthy groups who differed in their average ages (46.8 +/- 3.1 years, n = 4 v. 28.9 +/- 5.0 years, n = 10). The frequencies of disomic sperm determined by FISH compared well with frequencies obtained using the hamster-egg technique for human-sperm cytogenetics and with the frequencies of disomic and diploid sperm reported in previous FISH studies in this laboratory. The two groups of men did not differ in their baseline frequencies of sperm disomic for chromosome 8 (approximately 6.5 per 10(4) sperm), sperm with XY8 aneuploidy (approximately 9.5 per 10(4) sperm), or sperm with autodiploidy XX88 or YY88 (approximately 2 per 10(4) sperm). However, the older group had statistically higher frequencies of sperm carrying sex chromosomal disomy than the younger group (5.1 v. 2.2 per 10(4) sperm for XX8; 5.9 v. 2.0 per 10(4) sperm for YY8; P < 0.005). A recent report from this laboratory of sex-chromosomal aneuploidy in sperm of aged mice provides inter-species corroborating evidence for this preliminary finding of a paternal age effect on sperm aneuploidy in human males.

Adult↗
PubMed1995

A proposed system for scoring structural aberrations detected by chromosome painting.

The advent of chromosome painting has brought the realization that structural aberrations can be far more complicated than previously imagined. Various investigators have devised their own nomenclature systems to deal with this difficulty, with the result that the terminology has become inconsistent and confusing. Recently, an international group of cytogeneticists experienced in chromosome painting gathered to address this issue. Results of the meeting are presented in this report, which provides a nomenclature system capable of describing chromosome aberrations that occur between painted and unpainted chromosomes, as well as aberrations involving only painted chromosomes. The nomenclature is flexible enough to describe accurately even the extensively rearranged chromosomes. As a consequence of this flexibility, the scheme upon which the nomenclature is based differs substantially from other systems of aberration classification. We call this system the Protocol for Aberration Identification and Nomenclature Terminology (PAINT).

Chromosome Aberrations↗
PubMed1994

Suppression of tumorigenicity in human teratocarcinoma cell line PA-1 by introduction of chromosome 4.

Teratocarcinomas are tumors that develop spontaneously in the gonads and usually contain a rapidly dividing, undifferentiated stem cell population. Immature ovarian teratocarcinomas are highly malignant with only 30-60% of patients surviving for 2 years after diagnosis. We have used microcell fusion to introduce individually tagged normal human chromosomes into the PA-1 human teratocarcinoma cell line. Introduction of human chromosome 4 caused a cell morphology in culture and suppressed PA-1 tumorigenicity in nude mice, whereas addition of portions of either chromosome 7 or 12 had no effect on the cell phenotype. The PA-1 cell line regained its tumorigenicity when the tagged chromosome 4 was lost under negative selection. We conclude that there is a putative tumor suppressor gene on human chromosome 4 whose expression interferes with the tumorigenicity of PA-1 cells.

Animals↗
PubMed1981

Transmission of multiple drug-resistant tuberculosis: report of a school and community outbreak.

An outbreak of tuberculosis in 1976 was caused by mycobacteria resistant to isoniazid (INH), streptomycin (SM), and para-aminosalicylic acid (PAS). High rates of infection associated with exposure to the index case suggested that transmission of resistant organisms had occurred, and the subsequent appearance of bacteriologically proven INH-SM-PAS-resistant tuberculosis in four school contacts of the index case confirmed this fact. Retrospective investigation revealed that the school outbreak was part of an ongoing community outbreak dating back at least to 1964. Through the use of case histories, drug-susceptibility patterns, and phage typing, 15 documented and seven presumed INH-SM-PAS-resistant, epidemiologically linked cases were found; two of these persons died of tuberculosis. Six additional cases with INH-SM-PAS resistance that could not be epidemiologically linked to the outbreak were also identified. The potential of drug-resistant strains for causing disease in humans should not underestimated.

Adolescent↗
PubMedDate not supplied

Site-specific conjugation of an enzyme and an antibody fragment.

A site-specific immunoconjugate was prepared between an F(ab')2-like fragment of the monoclonal anti-CEA murine IgG1 A5B7 and a mutant of the dimeric enzyme carboxypeptidase G2 possessing an N-terminal Thr in place of Ala. First an aldehyde was introduced at the N-terminus of the enzyme by mild periodate oxidation and a residue of carbohydrazide was specifically introduced at the C-terminus of the truncated heavy chain of the F(ab')2-like fragment by reverse proteolysis. Then the two modified proteins were conjugated by the formation of a hydrazone bond between the hydrazide and the aldehyde groups. The conjugate obtained retained both enzymic activity and antigen-binding capacity. The antigen-binding capacity was better than that of a similar conjugate made conventionally by random reaction with side chains.

Antibodies, Monoclonal↗