As part of the treatment protocol in 40 leukaemia patients using cytosine arabinoside for remission induction therapy, the sensitivity of each patient's blast cell progenitors to the drug was determined by the liquid suspension assay. To summarize the dose-response curves obtained in this assay, we considered a model that assumes the existence of a resistant subpopulation of progenitor cells. We also considered the median effect model popular in pharmacokinetics. Both models were similar in their ability to describe the data. Parameter values that characterize a low baseline number of progenitor cells exhibiting high sensitivity both at low and high dosages were found to indicate good prognosis. We also identified a simple, economical, robust and efficient design for conducting future assays.

Antimetabolites, Antineoplastic↗

PubMedDate not supplied

Natural cytotoxicity of peripheral blood leukocytes from normal subjects and patients with Hashimoto's thyroiditis against human adult and fetal thyroid cells.

Natural cytotoxicity of human peripheral blood leukocytes against fetal and adult human thyroid cells was investigated in vitro. Natural killer (NK) cell activity was determined at various effector: target cell ratios in a standard 51Cr release assay with human thyroid cells as targets. The effector cells were unfractionated peripheral blood mononuclear cells obtained by Hypaque-Ficoll gradient centrifugation. We have demonstrated that peripheral blood leukocytes from normal subjects and patients with Hashimoto's thyroiditis exhibit natural cytotoxicity against both human fetal and adult thyroid cells. This was effector: target cell ratio and incubation time dependent. Although there was a tendency for increased killing of fetal thyroid cells by peripheral blood leukocytes from patients with Hashimoto's thyroiditis compared to age/sex matched normal subjects this was not significant and there were no significant differences between the two groups for killing of adult thyroid cells. A possible role for natural cytotoxicity in progressive thyroid tissue destruction in Hashimoto's thyroiditis is discussed.

Adolescent↗

PubMedDate not supplied

Metabolism of bradykinin analogs by angiotensin I converting enzyme and carboxypeptidase N.

Bradykinin (BK) analogs such as Lys-Lys-BK, des-Arg9-BK and [Leu8]des-Arg9-BK were poor substrates for angiotensin I converting enzyme (ACE), and analogs containing D-Phe7 residues, or a pseudopeptide C-terminal bond, were completely resistant. However, many of these analogs were metabolized by carboxypeptidase N (CPN) including Lys-Lys-BK, [Tyr8(OMe)]BK and D-Phe7-containing analogs, with Km and Vmax values comparable to those for BK. The only analogs completely resistant to both ACE and CPN were the B2 agonist [Phe8 psi(CH2NH)Arg9]BK, the B2 agonist D-Arg[Hyp3,D-Phe7,Phe8 psi(CH2NH)Arg9]BK, and the B1 agonist [D-Phe8]des-Arg9-BK. These data indicate an important role for plasma CPN and vascular CPN-like activity in the metabolism of the widely used ACE-resistant/D-Phe7-containing antagonists of B2 kinin receptors.

Amino Acid Sequence↗

PubMedDate not supplied

Differential processing of substance P and neurokinin A by plasma dipeptidyl(amino)peptidase IV, aminopeptidase M and angiotensin converting enzyme.

In addition to plasma metabolism of substance P (SP) by angiotensin converting enzyme (ACE; EC 3.4.15.1) (less than 1.0 nmol/min/ml), the majority of SP hydrolysis by rat and human plasma was due to dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) (3.15-5.91 nmol/min/ml), which sequentially converted SP to SP(3-11) and SP(5-11). In turn, the SP(5-11) metabolite was rapidly hydrolyzed by rat and human plasma aminopeptidase M (AmM; EC 3.4.11.2) (24.2-25.5 nmol/min/ml). The Km values of SP for DAP IV and of SP(5-11) for AmM ranged from 32.7 to 123 microM. In contrast, neurokinin A (NKA) was resistant to both ACE and DAP IV but was subject to N-terminal hydrolysis by AmM (3.76-10.8 nmol/min/ml; Km = 90.7 microM). These data demonstrate differential processing of SP and NKA by specific peptidases in rat and human plasma.

Aminopeptidases↗

PubMedDate not supplied

Isolation of human lymphocytes by a Ficoll barrier method.

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Centrifugation, Density Gradient↗