Timed sequential therapy of human leukemia based upon the response of leukemic cells to humoral growth factors.
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Adolescent↗
Biomedical subjects
J E Karp
Publications and source records attributed to J E Karp.
Induction of serum stimulation and plasma cell proliferation during chemotherapy of multiple myeloma.
Sequential sera from 45 patients with multiple myeloma (MM) and from 6 patients with solid tumors but normal bone marrows who received cyclophosphamide, 15 mg/kg/day for 4 days, were assayed for their effects on tritiated thymidine (3H-TdR) incorporation by normal bone marrow cells and malignant plasma cells. Pretreatment sera from 23 of the 45 patients with MM inhibited normal marrow cell proliferation relative to the effects of normal sera. Of these 45 sera, 30 inhibited plasma cell proliferation. This humoral inhibition was overcome by the induction of humoral stimulation at a predictable time during chemotherapy. The sera obtained sequentially from patients with MM and patients with normal bone marrows increased 3H-TdR uptake by both cell types by days 12-15 of therapy. Sequential changes in malignant marrow plasma cell 3H-TdR labeling indices paralleled the changes in serum activity, with an increased tumor cell growth fraction occurring at the time of peak serum stimulatory activity. The relationship between serum stimulation and malignant plasma cell proliferation was confirmed in vitro.
Bone Marrow↗
Influence of humoral regulators on proliferation and maturation of normal and leukemic cells.
Factors that influence the proliferation of marrow elements can be detected in sera. To determine the function and to compare the effect of these factors, cells were obtained from patients with normal and leukemic bone marrows. The effects of drug-induced stimulatory and inhibitory sera and leukemic pretreatment sera over time (0 to 6 days) on proliferation and granulocytic morphology of normal and leukemic bone marrow cells in culture were evaluated. Increased proliferation was associated with stimulatory sera, while inhibitory and leukemic pretreatment sera retarded proliferation of both normal and malignant cells. Exposure of normal proliferative cells to inhibitory or leukemic pretreatment sera yielded the greatest increase in mature granulocyte forms. In contrast, although the proliferative response of leukemic cells to these sera was similar to normal, maturation was minimal. These data suggest that leukemic pretreatment sera are similar to inhibitory sera and are not leukemogenic. Both retard proliferation of normal and leukemic bone marrow cells while enhancing maturation of normal cells. Leukemic myeloblasts, however, cannot be made to mature by these humoral regulators.
Blood Specimen Collection↗
Enhancement of drug cytotoxicity by recruitment of leukemic myeloblasts with humoral stimulation.
To demonstrate that the effect of 1-beta-D-arabinofuranosylcytosine can be increased when the leukemic cell growth fraction is augmented by induced humoral factors, bone marrow cells from 14 patients with acute myeloblastic leukemia were studied in vitro. Cells were cultured in either pooled stimulatory serum, obtained from leukemic patients undergoing chemotherapy, or autologous leukemic pre-treatment serum. After 2 days in culture, serum containing 1-beta-D-arabinofuranosylcytosine was added. Cells cultured in stimulatory serum proliferated markedly when compared with cells cultured in pretreatment serum, as measured by tritiated thymidine incorporation into an acid-insoluble precipitate, tritiated thymidine labeling indices, and viable tumor cell counts. The cytotoxic effect of 1-beta-D-arabinofuranosylcytosine was enhanced in those cells initially cultured in stimulatory serum relative to cells initially cultured in pretreatment serum. These studies are consistent with the hypothesis that induced humoral stimulation of acute myeloblastic leukemic cells in vitro recruits a greater tumor growth fraction and thereby increases the cytotoxicity of cycle-dependent drugs.
Bone Marrow↗
Fibrinogen-fibrin degradation products and fibrinolysis following exercise in humans.
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Adolescent↗
Response to empiric amphotericin B during antileukemic therapy-induced granulocytopenia.
We analyzed the initial and overall responses to empiric therapy with amphotericin B as they related to the rate of occurrence and the type of fungal infection and colonization during 264 consecutive episodes of prolonged, profound, chemotherapy-induced bone marrow aplasia (greater than 30 days, less than 100 polymorphonuclear leukocytes/mm3) in 160 adults with acute leukemia. Amphotericin B was administered during 248 (94%) of these granulocytopenic episodes; in 68 cases the drug was given because of documented infection with yeasts or filamentous fungi (DFI), and in 180 cases it was given because of refractory fever without DFI. The frequency of an initial response in patients with DFI (60%) was similar to that in non-DFI-infected patients (61%). Both the initial response rate and the overall survival rate were significantly decreased when therapy with amphotericin B was not initiated empirically before documentation of filamentous DFI. Given the comparatively high rates of initial and overall response (the latter being 74% and 71% for DFI and non-DFI, respectively) and the lack of alternative fungicidal agents, our data support prompt empiric treatment with amphotericin B for refractory fever in adults with acute leukemia who are compromised by severe, therapy-induced granulocytopenia.
Adult↗
Disseminated infection with Trichosporon beigelii.
Two cases of systemic infection with Trichosporon beigelii are reported. Both patients had acute leukemia and were receiving cytotoxic and antibiotic drug therapy, which included amphotericin B, at the time of sepsis. Although clinical isolates of the organisms were found to be sensitive to amphotericin B in vitro, both patients died from severe, widespread fungal infection. The pathologic findings in these two cases suggest that the host response to trichosporon infection is a granulomatous inflammation. Trichosporon is a virulent opportunistic pathogen that may originate from the gastrointestinal tract damaged by cytotoxic therapy in the patient with aplasia. Despite aggressive antifungal therapy, survival is most closely related to recovery of the host's hematopoietic system.
Acute Disease↗
The expanding challenge of HIV-associated malignancies.
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Acquired Immunodeficiency Syndrome↗
New concepts in the treatment of acute myeloid malignancies: selected pathways for targeted therapy.
Acute myeloid leukemia (AML) and myelodysplasia (MDS) continue to present formidable treatment challenges as there is not yet a "standard approach" that reliably and safely cures the majority of adults with these disorders. Understanding the basic cellular and molecular biology of leukemia is vital to the development of better treatment approaches. All malignant cells, including leukemias, carry survival advantages compared to their normal counterparts. These survival advantages are particularly evident when the cells face both normal environmental stressors as well as extreme stressors of potentially lethal DNA damage. The impact of such stressors is ultimately determined by the signaling pathways and resultant cellular activation, including alterations in cellular growth, differentiation, survival and death. It is our improving understanding of these signaling pathways, both normal and malignant, that provide the targets for novel therapies. In this review article, we will focus on several signaling pathways, as well as the regulation of the cell cycle, that not only represent potentially accessible sites for intervention in myeloid malignancies, but those that are actively being studied.
Antibodies, Monoclonal↗
Factors affecting survival of patients with acute myelocytic leukemia presenting with high wbc counts.
Eighteen patients referred to The Johns Hopkins Oncology Center for treatment of acute myelocytic leukemia during a 2-year period had pretreatment wbc counts greater than 50,000/microliter. Despite immediate admission, aggressive supportive care, and rapid institution of chemotherapy, six patients died from complications of the high wbc count at presentation. The patients who died had significantly higher initial wbc counts, lower platelet counts, and lower arterial oxygen saturation; they were older, more likely to be female, and more likely to have abnormal serum urea nitrogen than the 12 patients who survived. Five of the six patients who died had experienced a delay of greater than 48 hours from diagnosis to referral, and only one of the 12 patients who survived was not promptly referred for treatment at the time of diagnosis (P = 0.004). A mathematical model, the logit of the fraction of the initial wbc count versus the logarithm of time after starting therapy, was used to describe the response of the wbc count to chemotherapy. This logit analysis reduced the data for individual patients to a linear function, permitting statistical description of the population as a whole. This statistical description makes possible the comparison of different approaches to lowering the wbc count in such patients and the correlation of rate of response of wbc count with the probability of achieving remission and with duration of remission.
Adolescent↗