PubMed Health⌕ Search

Biomedical subjects

C A Koller

Publications and source records attributed to C A Koller.

50 records · Page 3Linked to original sources
PubMed1983

Alterations in erythrocyte adenine nucleotide pools resulting from 2'-deoxycoformycin therapy.

2'-Deoxycoformycin, a tight-binding adenosine deaminase inhibitor, was administered to 11 adult patients with refractory lymphoproliferative diseases. Total doses ranged from 1.0 to 13.5 mg/kg. Inhibition of lymphoblast adenosine deaminase was obtained in all cases and tumor cytoreduction was noted in eight of ten cases, but no clinically meaningful remissions were obtained. Major toxicities occurred in five patients and included pulmonary edema, renal failure, central nervous system toxicity, hypotension, and death. Toxicity prevented retreatment in several cases in which marked cytoreduction occurred. Deoxyadenosine triphosphate accumulated to a variable extent in the red blood cells of all patients, and a reciprocal decrease in erythrocyte adenosine triphosphate was noted in all cases but one. All patients who suffered major organ toxicity had red blood cell deoxyadenosine triphosphate/adenosine triphosphate ratios greater than 1.3. These data suggest that the degree of replacement of adenosine triphosphate by deoxyadenosine triphosphate in erythrocytes reflects the biochemical milieu which may result in systemic toxicity following treatment with 2'-deoxycoformycin.

Adenine Nucleotides↗
PubMed1983

S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine.

A patient with refractory T-cell acute lymphoblastic leukemia was treated with eight courses of the adenosine deaminase inhibitor, 2'-deoxycoformycin (dCF), over a 5-month period. After developing resistance to dCF, he responded to treatment with the combination of dCF and 9-beta-D-arabinofuranosyladenine (ara-A). We monitored the levels in plasma and urine of adenosine, 2'-deoxyadenosine, and ara-A as well as the accumulation of their nucleotide derivatives in erythrocytes and circulating lymphoblasts. We also monitored the activities of adenosine deaminase and S-adenosylhomocysteine (AdoHcy) hydrolase and the concentrations of AdoHcy and S-adenosylmethionine in lymphoblasts. Production of 2'-deoxyadenosine was related to both the duration of dCF infusion and the magnitude of cytolysis that occurred during treatment: much more 2'-deoxyadenosine was produced by dCF infusion when disease was active than by the same infusion given during remission. Resistance to dCF was associated with a decrease of greater than 90% in the amount of deoxyadenosine 5'-triphosphate accumulated by circulating lymphoblasts. Infusion of dCF resulted in increases of up to 20-fold in the concentration of AdoHcy in circulating lymphoblasts, causing a decrease in the S-adenosylmethionine:AdoHcy ratio (the "methylation index") from a pretreatment value of greater than 40:1 to less than 4:1. This ratio decreased to 2.5:1 during combined treatment with dCF and ara-A, which caused nearly complete inactivation of lymphoblast AdoHcy hydrolase. Decline in the methylation index was accompanied by inhibition of the methylation of newly synthesized lymphoblast RNA. Impaired ability to catabolize AdoHcy may have contributed to the cytolytic responses to dCF and ara-A, as well as to hepatic and central nervous system toxicity associated with their combined use.

Acute Disease↗
PubMed1983

Deoxyribonucleoside triphosphate accumulation by leukemic cells.

The toxicity of the deoxyribonucleosides, 2'-deoxyadenosine, 2'-deoxyguanosine, and thymidine, for human T lymphoblasts is mediated by the accumulation of the corresponding deoxyribonucleoside triphosphate (dATP, dGTP, or dTTP, respectively). We have examined whether leukemic cells of non-T-cell origin are capable of accumulating deoxyribonucleotides in culture and whether this capability correlates with the activities of purine metabolizing enzymes in these cells. We have found that non-T, non-B acute lymphoblastic leukemia cells with low ecto-5'-nucleotidase and high adenosine deaminase activities increase their dATP pools by greater than tenfold when exposed to deoxyadenosine and an inhibitor of adenosine deaminase in culture. Cells from 2 of 9 patients with chronic lymphocytic leukemia and 4 of 11 patients with acute nonlymphoblastic leukemia achieved similar elevations in dATP, but there was no relationship between dATP accumulation and adenosine deaminase, purine nucleoside phosphorylase, or ecto-5'-nucleotidase activities. Treatment of four individuals with acute lymphoblastic leukemia with the adenosine deaminase inhibitor, 2'-deoxycoformycin, resulted in elevations in plasma deoxyadenosine concentrations and in increments in lymphoblast dATP levels that were similar to those measured in lymphoblasts cultured with deoxyadenosine and deoxycoformycin prior to treatment. In vitro incubations of leukemic cells with deoxyribonucleosides may provide a rational basis for the use of these compounds as chemotherapeutic agents.

Adenosine Deaminase↗
PubMed1983

Phase I evaluation of semustine in a weekly schedule.

A phase I study of weekly semustine was conducted in 32 patients with advanced cancer. Doses were escalated from 18 to 36 mg/m2/week. At a dose of 36 mg/m2/week, 43% of the patients developed platelet counts less than 100,000/mm3 after a median of 20 weeks on study, and 25% developed wbc counts less than 3000/mm3 after a median of 16 weeks on study. Drug-related nausea was reported by only one patient and was the only subjective toxic effect reported. Tumor regressions were noted in patients with adenocarcinoma of the colon, melanoma, and mixed adenocarcinoma and squamous cell lung cancer. A reasonable starting dose for phase II studies is 36 mg/m2/week, with dose adjustments based on platelet and wbc counts.

Dose-Response Relationship, Drug↗
PubMed1981

Monocyte-mediated antibody-dependent cell-mediated cytotoxicity: the role of the metabolic burst.

Human monocytes respond to opsonized microorganisms with a "metabolic burst" composed of an increase in oxygen consumption, an increase in hexose monophosphate shunt (HMPS) activity, and the generation of reactive oxygen species (ROS). We investigated the role of the metabolic burst in antibody-dependent cell-mediated cytotoxicity (ADCC) by human monocytes toward anti-D coated erythrocyte target cells because recent studies suggested a role for oxygen-dependent bactericidal mechanisms in ADCC. In normal monocytes, we found that ADCC was nearly halved under hypoxic conditions. Several agents known to impair activation of the burst, such as vincristine, cation chelators, and a sulfhydryl reagent, all decreased cytotoxicity if added before initiation of contact between target and effector cells. Cytotoxicity was inhibited by 2-deoxyglucose but not fluoride, suggesting a nonglycolytic role for glucose in ADCC, perhaps in the HMPS pathway. Although these data suggested a role for the metabolic burst in ADCC, scavengers of ROS did not impair cytotoxicity, and monocytes from chronic granulomatous disease (CGD) patients who had a defective metabolic burst had normal levels of ADCC. We conclude that ADCC toward anti-D coated erythrocyte target cells was the result of at least two independent but closely related cytotoxic pathways. Although one of these pathways appeared to involve the metabolic burst, the potentially cytotoxic reactive oxygen species did not appear to play a role in this system.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1980

ATP depletion as a consequence of adenosine deaminase inhibition in man.

Hereditary deficiency of the enzyme adenosie deaminase (adenosine aminohydrolase, EC 3.5.4.4) results in an immunodeficiency syndrome characterized by a marked reduction in circulating lymphocytes. We have administered 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase, to a patient with a lymphoproliferative malignancy. The clinical consequences of pharmacologic inhibition of adenosine deaminase activity included an abrupt decrease in the lymphocyte count, abnormalities of renal and hepatic function, and hemolytic anemia. The plasma concentrations of adenosine and deoxyadenosine rose to peak values of 13 microM and 5 microM, respectively, and erythrocyte dATP levels increased to 110 pmol/10(6) cells over 9 days. There was a corresponding decrease in erythrocyte ATP levels from 128 to < 6 pmol/10(6) cells. A similar profound reductin in ATP occurred in the erythrocytes of a second patient. The rapid and unexpected depletion of ATP associated with dATP accumulation may account, at least in part, for the toxicity associated with 2'-deoxycoformycin administration. The inverse relationship of ATP and dATP raises major questions about the control of energy metabolism in erythrocytes.

Adenosine↗
PubMed1980

Inhibition of adenosine deaminase activity results in cytotoxicity to T lymphoblasts in vivo.

We have treated a patient with refractory T-cell acute lymphoblastic leukemia with 2'-deoxycoformycin, a potent inhibitor of the enzyme adenosine deaminase. Inhibition of adenosine deaminase activity resulted in (1) an abrupt rise in plasma deoxyadenosine, but not adenosine, concentrations; (2) accumulation of deoxyadenosine triphosphate by lymphoblasts; (3) inhibition of the enzyme S-adenoylhomocysteine hydrolase; and (4) rapid lysis of the leukemic cells. The patient died suddenly 3 days after therapy was discontinued, and postmortem examination revealed a complete absence of leukemic cells in all organs. Pharmacologic inhibition of adenosine deaminase activity can result in the lysis of T lymphoblasts in vivo, and this effect appears to be mediated by deoxyadenosine.

Adenosine↗
PubMed1980

Immune thrombocytopenic purpura.

ITP is a hemorrhagic disorder in which thrombocytopenia is associated with increased peripheral destruction of platelets. It is a syndrome of different diseases, all of which have in common shortened platelet survival owing to the presence of an antiplatelet antibody. Most cases are secondary to an identifiable etiologic agent.

Acute Disease↗
PubMed1979

Quinine protects pyruvate-kinase deficient red cells from dehydration.

Pyruvate kinase deficient red blood cells have an abnormal tendency to lose ATP when exposed to low pO2 or cyanide, whereas normal red cells do not. Once energy is depleted, all red cells take up calcium and subsequently lose intracellular potassium and water. It has been shown previously that quinine will inhibit the potassium and water flux seen in energy depleted normal cells. The present study indicates that quinine protects cyanide treated pyruvate kinase deficient erythrocytes from water and potassium loss. Quinine does not prevent ATP depletion or calcium uptake. By six hours, cyanide treated pyruvate kinase deficient cells have lost an average of 486 gm of water per kilogram cell solids and 140 mmoles of potassium per kilogram of cell solids, while cells treated with both quinine and cyanide have lost only 106 gm of water per kilogram of cell solids and 77 mmoles of potassium per kilogram of cell solids. These data support the concept that the membrane lesion in pyruvate kinase deficiency is secondary to ATP depletion and is a manifestation of the Gardos effect. Quinine may have therapeutic potential in the treatment of pyruvate kinase deficiency hemolytic anemia.

Adenosine Triphosphate↗
PubMedDate not supplied

"T-cell-rich B-cell lymphoproliferative disorder" of the bone marrow.

We report four cases of a "T-cell-rich B-cell chronic lymphoproliferative disorder" involving the bone marrow and not extramedullary sites. The neoplastic B-cell proliferation in these cases was composed predominantly of small lymphoid cells with features of both hairy cell leukemia and lymphoplasmacytoid lymphoma. All cases presented with neutropenia and with difficulty in diagnosis. We present the clinical, morphologic, cytochemical, and immunophenotypic findings in these cases and discuss this entity.

Adult↗