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Biomedical subjects

J E Karp

Publications and source records attributed to J E Karp.

At least 109 records · Page 6Linked to original sources
PubMed1984

Two-cycle timed-sequential chemotherapy for adult acute nonlymphocytic leukemia.

Based on a series of clinical and laboratory studies of leukemia cell kinetics and responses to chemotherapy, we have developed an intensive timed-sequential regimen of daunorubicin and high-dose infusion 1-beta-D-arabinofuranosyl cytosine for the treatment of adult acute nonlymphocytic leukemia. Of the first 34 patients achieving complete remission (CR) with a single cycle of this therapy, four (12%) remain in complete remission without further therapy after a minimum of five years of follow-up. Treatment of relapsed patients with a second course of the same regimen at relapse and no chemotherapy in second remission increased to seven (21%) the number of patients expected to remain in remission for four years or more from their last chemotherapy. Beginning in 1980, however, we gave all consenting adults a second cycle of this chemotherapy in early first remission. Of the first 25 patients treated with a second cycle of this chemotherapy in early first remission, there was one toxic death, but 11 patients (44%) remain in CR with a median follow-up of almost three years.

Acute Disease↗
PubMed1984

Direct relationship of marrow cell growth and 1-beta-D-arabinofuranosylcytosine metabolism.

To define the relationship between perturbed cell growth and intracellular metabolism of 1-beta-D-arabinofuranosylcytosine (ara-C) in sensitive human cells, growth kinetic, and biochemical pharmacological determinants were examined in normal human bone marrow populations in vitro in normal serum and in the presence of drug-induced humoral stimulatory activity (HSA). Cells cultured in HSA demonstrated both increased proliferation and greater ara-C-related inhibition of DNA synthesis than did cells maintained in normal serum, as measured by [3H]thymidine incorporation into DNA and [3H]thymidine granulocyte precursor labeling index. Parallel measurements of [3H]ara-C incorporation into DNA demonstrated similar behavior in HSA-perturbed cells. When these cultured cells were exposed to 1 and 10 microM ara-C, intracellular formation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate over 3 hr and retention of this active form during 1 subsequent hr in drug-free medium were both increased in HSA-stimulated cells relative to cells cultured in normal serum. These studies demonstrate coupling of induced cell growth kinetics with enhanced intracellular metabolism of the S-phase-specific antimetabolite ara-C in normal human marrow cells. The close direct relationship between growth kinetic perturbation and augmentation of intracellular ara-C activation in this normal hematopoietic model provides a basis for comparison with leukemic cell populations, in which uncoupling of growth kinetics and pharmacokinetics may signify divergence from normal drug-sensitive cell behavior and, thus, resistance to ara-C cytotoxicity.

Bone Marrow↗
PubMed1984

Correlation of proliferative and clonogenic tumor cells in multiple myeloma.

To expand on the findings from previous clinical trials that the growth of residual tumor is increased at a predictable time following initial drug administration, malignant plasma cells from bone marrows of patients with multiple myeloma (MM) were examined for changes in proliferation and clonogenicity induced in vivo by cyclophosphamide and in vitro by drug-induced humoral stimulatory activity. Peak plasma cell [3H]thymidine labeling index (LI) occurred predictably following drug and paralleled changes in agar colony formation by marrow cells obtained during therapy. Colony-forming capacity of pretreatment MM marrow populations was enhanced when those cells were cultured with humoral stimulatory activity, similar to the increased colony formation detected in Day 9 postcyclophosphamide marrows at the time of peak plasma cell LI. To further define a relationship between proliferative plasma cells and colony-forming tumor cells, MM marrows were fractionated by sedimentation on an isokinetic gradient. Enrichment of a proliferative tumor cell cohort was achieved, evidenced by [3H]thymidine LI. Colony-forming cells were also enriched by isokinetic gradient sedimentation, and agar colony formation by MM marrow cell fractions correlated with the kinetic characteristics of the isolated subpopulations. These studies of whole and fractionated human MM marrow cell populations suggest that the kinetically active cells which are induced to proliferate in vivo and in vitro are closely related to the clonogenic tumor cells which produce colonies in agar and which, like those cells measured by [3H]thymidine LI, respond to growth stimulation by drug-induced humoral stimulatory activity.

Bone Marrow↗
PubMed1983

Postleukemic dysmyelopoiesis.

The morphologic and clinical features of four patients who developed significant bone marrow and blood dyspoiesis after successful chemotherapy for acute nonlymphocytic leukemia (ANLL) are described. This postleukemic dyspoiesis developed 1-6 months after leukemia induction therapy and persisted for 5-20 months in a relatively stable state. This period of prolonged dyspoiesis was not associated with rising myeloblast counts or clinical evidence of relapse. Dyspoietic abnormalities developed while two patients were receiving maintenance chemotherapy; the other two patients received no maintenance therapy. The dyspoietic changes in these four patients greatly exceeded those noted in a control group of ANLL patients on maintenance chemotherapy. The morphologic features of postleukemic dysmyelopoiesis were similar to those described in preleukemic dysmyelopoietic disorders. Erythroid abnormalities included hyperplasia with ring sideroblasts, megaloblastic changes, and cytoplasmic PAS reactivity. Myeloid abnormalities consisted of left-shifted granulopoiesis with hyper- and hyposegmentation; megakaryocytic abnormalities included hyperplasia with a predominance of hypolobulated forms. Three of the four patients eventually suffered relapse and have died. The fourth patient died of sepsis after 20 months of pancytopenia and dysmyelopoiesis. Theories to explain the development of postleukemic dysmyelopoiesis are presented which emphasize the possibility of drug-induced leukemia cell differentiation. Cytogenetic studies will be necessary to establish any relationship between ANLL and the subsequent postleukemic dysmyelopoiesis.

Acute Disease↗
PubMed1983

Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy for prior malignancy.

Eleven consecutive patients with acute myelocytic leukemia occurring as a second malignancy were treated with high-dose, timed, sequential chemotherapy. Eight of the patients were felt to have "secondary" acute leukemia because they had received an alkylating agent or radiation therapy. The other three patients were considered controls. Despite a median age of 65, four of the eight secondary leukemia patients achieved complete remission with this regimen. One of the three control patients also achieved complete remission. This remission rate and duration are comparable to what was achieved with this treatment of "primary" acute myelocytic leukemia during the same period of time. These results suggest that patients with leukemia occurring after an alkylating agent or radiation therapy are not at especially high risk if treated aggressively.

Adult↗
PubMed1983

The relationship between humoral stimulating activity and colony stimulating factor.

Humoral stimulatory activity (HSA) is detected in the sera of neutropenic rodents and humans by its effects on in vitro marrow cell [3H] TdR incorporation. Increased levels of CSA are also found in such sera; however, the relationship between these two activities has not been established. To examine this question, sera were obtained from mice, rats and humans at the peak occurrence of HSA following cyclophosphamide administration and were incubated with rabbit antiserum directed against mouse L-cell CSF. Anti-CSF neutralized the HSA effect on species-specific marrow cell [3H] TdR incorporation relative to the effects of normal sera with an efficiency of anti-CSF produced graded neutralization of the human HSA effect on human marrow cell proliferation. This neutralizing effect of anti-CSF on human HSA was obrogated by prior incubation of anti-CSF with sheep-anti-rabbit-IgG (S-anti-R-IgG) serum. The human serum activities on marrow cell proliferation, as determined by the [3H] TdR incorporation assay, correlated closely with their effects on human granulocyte colony formation in agar culture. These data indicate that human and rodent drug-induced HSA are cross-reactive with CSF as measured by a simple proliferation assay.

Animals↗
PubMed1982

Recruitment of quiescent tumor by humoral stimulatory activity: requirements for successful chemotherapy.

Acute leukemia is a heterogeneous tumor with respect to cellular proliferation and is sensitive to positive and negative growth control factors. Tumor associated inhibitory activity (TAIA) and simultaneously present humoral stimulatory activity (HSA) in this disease may be modulated by timed sequential chemotherapy to increase tumor growth at a predictable time and make it more sensitive to accurately administered drug. Our in vivo studies of timed sequential chemotherapy in human leukemia demonstrate than an increase in tumor labeling index (LI) temporally coincides with the detection of HSA following drug administration. Maximal HSA occurs at a predictable time following initial administration of the aplasia-producing drug and is coincident with an increased LI of recovering normal marrow granulocytic elements and marrow tumor cells. These studies demonstrate the salutary effect of drugs given in high dose to reduce tumor mass and recruit tumor cells to further high-dose drug sensitivity.

Acute Disease↗
PubMed1981

Chemotherapy of leukemia in mice, rats, and humans relating time of humoral stimulation, tumor growth, and clinical response.

Studies were conducted in the leukemic mouse and rat to test the hypothesis that enhanced effects of drugs given in sequence relate to a predictable increase in tumor growth and sensitivity to cycle-active agents. The rationale is based on a) evidence that, following drug-induced aplasia, resultant bone marrow proliferation in vivo corresponds temporally with induced humoral stimulatory activity, and on b) models that demonstrate increased cytotoxicity of beta-cytosine arabinoside (Ara-C) to myeloblasts cultured in humoral stimulatory activity (HSA). CD2F1 mice bearing L-1210 leukemia received a course of 60 mg Ara-C/kg every 8th hour (q.8 h) three times on day 0 and on another day in sequence (0,1 through 0,7). The longest survival (250% of controls) was in animals whose second course began on day 3, the time of peak HSA as measured by DNA synthesis induced in L-1210 cells in culture. LBN rats bearing acute myelocytic leukemia (AML) were treated with 100 mg Ara-C/kg q.8 h six times beginning on day 0 and on other days in sequence (0,1 through 0,12). The longest survival was in those treated on day 0,6 (760% of controls), the time of peak serum stimulation, and tumor labeling index (LI). Thirty-seven patients with AML received a single course of therapy with 45 mg Ara-C/kg by a 72-hour infusion and 1.0 mg daunorubicin/kg every day three times. On day 8, the time of peak HSA and tumor LI, Ara-C was again infused. Complete remission was achieved in 56% (65% of all patients less than 60 yr old) with a single cycle of therapy. Median duration of chemotherapy-free remission was 10 months. Of 11 relapsing patients, 8 achieved a second remission with the same regimen. These studies demonstrated that the amount of proliferation of residual tumor and thereby sensitivity to cycle-active drugs given in sequence relates to the initial drug effect on tumor proliferation and the induction of humoral stimulation.

Animals↗
PubMed1981

Timed sequential chemotherapy of cytoxan-refractory multiple myeloma with cytoxan and adriamycin based on induced tumor proliferation.

Malignant plasma cell proliferation and induced humoral stimulatory activity (HSA) occur in vivo at a predictable time following drug administration. Sequential sera from 11 patients with poor-risk multiple myeloma (MM) undergoing treatment with Cytoxan (CY) 2400 mq/sq m were assayed for their in vitro effects on malignant bone marrow plasma cell tritiated thymidine (3HTdR) incorporation. Peak HSA was detected day 9 following CY. Sequential changes in marrow malignant plasma cell 3HTdR-labeling indices (LI) paralleled changes in serum activity, with peak LI occurring at the time of peak HS. An in vitro model of chemotherapy demonstrated that malignant plasma cell proliferation was enhanced by HSA, as determined by 3HTdR incorporation assay, 3HTdR LI, and tumor cells counts, and that stimulated plasma cells were more sensitive to cytotoxic effects of adriamycin (ADR) than were cells cultured in autologous pretreatment serum. Based on these studies, we designed a clinical trial to treat 12 CY-refractory poor-risk patients with MM in which ADR (60 mg/sq m) was administered at the time of peak HSA and residual tumor cell LI (day 9) following initial CY, 2400 mg/m (CY1ADR9). Eight of 12 (67%) responded to timed sequential chemotherapy with a greater than 50% decrement in monoclonal protein marker and a median survival projected to be greater than 8 mo duration (range 4-21+ mo). These clinical results using timed sequential CY1ADR9 compare favorably with results obtained using ADR in nonsequential chemotherapeutic regimens.

Cell Division↗
PubMed1980

Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia.

Thirty-seven patients with acute myelocytic leukemia were treated with a timed-sequential regimen of arabinosyl cytosine and daunorubicin followed by no further therapy until relapse. The cycle-specific agent arabinosyl cytosine was given by three-day infusion at the time when the malignant cell population was predicted to have a maximal regrowth rate following an initial three-day infusion of arabinosyl cytosine and daunorubicin together. Malignant myeloblasts demonstrated an increased in vivo tritiated thymidine uptake prior to the second infusion. Complete remission was achieved in 56% of previously untreated evaluable patients (65% of all patients less than 60 years of age) with a single cycle of this therapy. Median duration of chemotherapy-free remission for these patients was 10 months, 47% were still in remission at one year and 31% are projected to be in remission at two years. Eight of 11 relapsing patients achieved a second remission with the same regimen and the median survival cannot yet be predicted. These results compare favorably with results from other centers using regimens involving multiple courses of remission induction, consolidation, and continuous maintenance chemotherapy.

Adolescent↗
PubMed1980

Isokinetic gradient sedimentation of normal human bone marrow cells: a simple method for isolation of proliferative granulocytic and erythroid elements.

Proliferative granulocytes and erythroid precursors were isolated from cell suspensions of human normal bone marrow by sedimentation on an isokinetic gradient of continuous low-density Ficoll. A fivefold enrichment with a 70% recovery of the proliferative granulocyte cohort and of early erythroid elements was achieved, as determined by differential morphology and tritiated thymidine incorporation. Viability and in vitro proliferative capacity following gradient centrifugation remained intact. This method of cell separation, based on differences in cell diameter, affords a simple and rapid means for the purification of specific cell populations from heterologous human normal bone marrow.

Bone Marrow Cells↗
PubMed1978

Intermittent high-dose cyclophosphamide chemotherapy for small cell carcinoma of the lung.

Twenty-three patients with small cell carcinoma of the lung (15 with limited disease and eight with extensive disease) were randomized into one of two induction schedules of high-dose cyclophosphamide (CY), 60 mg/kg iv, given either on Days 1 and 2 or on Days 1 and 8. Following the high-dose CY, patients were treated with a sequence of three monthly courses of COMB (CY, 800 mg/m2; vincristine [Oncovin], 1.4 mg/m2; methotrexate, 20 mg/m2; and BCNU, 60 mg/m2) alternating with high-dose CY. The overall response rate to the high-dose CY was 70% with 17% being complete responses (CRs). COMB produced no additional responses. There was no significant difference in response rate with either high-dose CY schedule. There was no unexpected morbidity associated with the intensive regiment despite marked myelosuppression. The high-dose CY administered on Days 1 and 8 appeared less toxic than that given on Days 1 and 2. Laboratory studies demonstrated that small cell carcinoma cells respond to drug-induced humoral stimulation in vitro; and that tumor proliferation in vivo temporally coincides with increased serum stimulatory activity. This study demonstrates that high-dose CY is a safe and effective induction therapy for small cell carcinoma of the lung although the low CR rate obtained is disappointing.

Aged↗