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G Spitzer

Publications and source records attributed to G Spitzer.

At least 91 records · Page 5Linked to original sources
PubMed1987

Comparison of antitumor activity of standard and investigational drugs at equivalent granulocyte-macrophage colony-forming cell inhibitory concentrations in the adhesive tumor cell culture system: an in vitro method of screening new drugs.

We compared the in vitro growth inhibition of primary human tumor cells in the adhesive tumor cell culture system (ATCCS), exposed to the investigational agents caracemide, spirogermanium and taxol and to standard chemotherapy agents at equitoxic concentrations for granulocyte-macrophage colony-forming cells (GM-CFC) in vitro. Clinically active standard agents tested at up to GM-CFC 90% inhibitory concentrations (IC90) resulted in in vitro activity (greater than or equal to 50% tumor growth inhibition) in at least 30% of tumors tested. In vitro responses for taxol, caracemide and spirogermanium were 78%, 9% and 7%, respectively. This paper proposes a model that incorporates two hypotheses: (1) myelotoxic drugs which inhibit tumor growth at concentrations equal to or less than equitoxic GM-CFC ICs will demonstrate clinical activity; and (2) both myelotoxic and particular nonmyelotoxic drugs inactive in vitro at these doses will not be active clinically. If this drug screening concept is valid, taxol may be clinically more active than caracemide and spirogermanium.

Alkaloids↗
PubMed1987

The role of autologous bone marrow transplantation in acute leukemia.

One hundred and twenty-seven patients with acute leukemia were treated with high-dose cytoreductive programs in conjunction with autologous marrow. Transplantation in relapse resulted in a complete remission rate ranging from 33% to 72%, depending on the time of transplantation, the conditioning regimen used and the performance status of the patient. Remission duration was short, ranging from three to nine months. Transplantation in second or subsequent remission did not change the natural history of the disease. In 14% of the cases, transplantation remissions were obtained exceeding the duration of the preceding remission, results equivalent to those obtained by normal dose chemotherapy. Transplantation in first remission (CR1) resulted in a projected two-year disease-free survival of 72% (13% SE) in acute myelogenous leukemia and of 45% (17% SE) in acute lymphocytic leukemia. We conclude from these data that the results look promising in CR1 and that in second and subsequent remissions a realistic study design is possible by which the influence on the natural history of disease by changing the bone marrow transplantation program, such as purging in vitro, can be studied.

Acute Disease↗
PubMed1987

Comparison between clinical response and in vitro drug sensitivity of primary human tumors in the adhesive tumor cell culture system.

The newly described adhesive tumor cell culture system (ATCCS) offers a distinct advantage over other assays in that it has a high plating efficiency requiring low cell inoculum, it affords workable assays in approximately 70% of specimens from the heterogenous tumor types, and it has the ability to assay up to nine drugs at four different concentrations. Clinical correlations based on the ATCCS were obtained in 65 patients undergoing 71 clinical trials. Patients with melanoma, lung cancer, and sarcoma dominated the group. The most active in vitro drug was correlated per clinical trial. Thirteen of 17 (76%) sensitive in vitro predictions and 51 of 54 (94%) resistant in vitro predictions were accurate. The assay in this study had a sensitivity of 81% and specificity of 93%. These preliminary results are encouraging and warrant prospective trials to establish the true value of this assay to patients.

Adolescent↗
PubMed1987

Clonal nature of Philadelphia chromosome-positive and -negative chronic myelogenous leukemia by DNA hybridization analyses.

Evidence for the clonal nature of chronic myelogenous leukemia (CML) has been obtained primarily from studies of black females expressing polymorphic glucose-6-phosphate dehydrogenase (G6PD) isoenzymes where, instead of the heterozygous pattern normally found as a result of random X chromosome inactivation, exclusive expression of only one G6PD allele has been demonstrated in leukemic cell populations. We report here the use of two other molecular approaches to examine clonality of peripheral blood cells in patients with CML. The first of these is based on the analysis of consistent differential methylation patterns associated with active and inactive X chromosomes within the region spanned by a BamHI restriction fragment length polymorphism (RFLP) at the hypoxanthine phosphoribosyltransferase (HPRT) locus. By this method, three heterozygous females gave results consistent with monoclonal origin of the disease, including one patient lacking the Philadelphia chromosome (Ph1) normally associated with CML. In the other two patients, both of whom had Ph1-positive CML, clonality was confirmed by the demonstration of simple gene rearrangements by Southern hybridization with a breakpoint cluster region (bcr) probe from chromosome 22.

Adult↗
PubMed1987

Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia.

Treatment with recombinant human interferon alpha-A (Roferon-A) is associated with stable suppression of the population of cells that display the Philadelphia (Ph1) chromosome in some patients with chronic myelogenous leukemia (CML) as defined by cytogenetic analysis. Southern blot analyses employing a 3' breakpoint cluster region (bcr) probe (Pr-1) were performed to confirm a complete suppression of the Ph1+ chromosome-positive clone of cells at the DNA level. The complete disappearance of rearranged restriction fragments of the bcr gene, which were a characteristic of the disease prior to Roferon-A therapy, was accompanied by the restoration of normal bone marrow and achievement of durable ongoing complete remission for 9 and 6 months, respectively, in two patients with Philadelphia-positive (Ph1+) CML. Molecular analysis is a valuable probe for monitoring the clinical course of disease in patients with Ph1+ CML.

Adult↗
PubMed1987

Determination of clonality in acute nonlymphocytic leukemia by restriction fragment length polymorphism and methylation analysis.

Determination of cellular clonality in hematological malignancies provides fundamental information that is important in understanding the pathogenesis of these disorders. We present here an extension of one approach to accomplish this that is based on the interpretation of different methylation patterns on active and inactive X chromosomes within the region of the hypoxanthine-guanine phosphoribosyltransferase gene spanned by a restriction fragment length polymorphism. The successful application of the method to determine clonality is described for three female patients with acute nonlymphocytic leukemia.

Acute Disease↗
PubMed1987

Clinical application of Percoll gradient-separated bone marrow.

We have evaluated the transplantation potential of bone marrow stem cell concentrates isolated from the 40/60% interface of discontinuous Percoll gradients. This mononuclear fraction is free from platelets and depleted of granulocytes, and contains the majority of granulocyte-macrophage colony-forming cells (GM-CFC), erythroid burst-forming units (BFU-E), and granulocyte, erythroid, macrophage, megakaryocyte colony-forming cells (GEMM-CFC) in less than 10% of the cell number of the original buffy coat. This preparation allows further manipulation without the clumping and cell loss associated with buffy coat cell preparations. Cells isolated by this technique were evaluated for hematopoietic restoration potential in 14 patients who received allogeneic bone marrow transplants as supportive therapy after high dose cytoreduction to treat leukemias or lymphoma. The number of nucleated cells infused varied from 1.6-5.5 X 10(7)/kg, and the number of GM-CFC infused ranged from 0.4 to 3.7 X 10(5)/kg. There was an inverse relationship between the time to recovery of granulocytes and platelets and the number of GM-CFC infused when fewer than 10(5) GM-CFC/kg were transplanted. Above this dose, there was recovery within 10-15 days after transplantation. The stem cell-enriched fraction contained 30-40% of the original number of T lymphocytes, and acute graft-versus-host disease was observed in seven of these patients.

Adolescent↗
PubMed1987

High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma.

Seven patients with advanced multiple myeloma, refractory to therapy with alkylating agent-VAD (vincristine-adriamycin-dexamethasone), received a regimen combining high-dose melphalan with total body irradiation supported by autologous bone marrow transplantation. Very rapid, usually greater than 90% tumor mass reduction was achieved in six patients, regardless of prior chemotherapy responsiveness and marrow plasmacytosis up to 30%. Despite signs of early relapse in three patients (median remission duration of all patients, 15 months), five remain alive and well without further cytotoxic therapy from 2 to 21 months (median, 9+ months). Two patients died, one from surgical complications after transplantation and a second due to persistent neutropenia with fatal pneumonia. This treatment provides meaningful disease control for selected patients with resistant myeloma and a poor prognosis.

Blood Cells↗
PubMed1986

Activity of 2-fluoro-Ara AMP against gynecologic tumors in the soft agar assay.

To characterize in vitro activity of 2-fluoro-Ara AMP and its relation to the activities of cisplatin and doxorubicin, 28 specimens from patients wit gynecologic tumors (predominantly ovarian) were tested in a soft agar assay. Twenty-six of 28 (93%) grew when the medium was supplemented with four hormones (epidermal growth factor, hydrocortisone, estradiol-17, and insulin). Normal bone marrow cells were utilized as a biologic control to define in vitro concentrations of the three drugs. Tumors were exposed continuously to three different concentrations of each drug. 2-fluoro-Ara AMP was tested against 26 tumors, cisplatin against 24, and doxorubicin against 14. In vitro sensitivity was defined as greater than or equal to 50% colony inhibition at a drug concentration within the bone marrow inhibitory range. Seven of 26 (27%) tumor specimens were sensitive to 2-fluoro-Ara AMP. Among these, four tumors were derived from previously treated patients. However, in the 2-fluoro-Ara AMP concentration range (0.26 micrograms/ml to 0.78 micrograms/ml) tested, five of eight (62.5%) tumors from untreated patients achieved IC50 compared to only seven of 18 (39%) tumors from treated patients. Five of six (83%) specimens demonstrated cross-sensitivity between cisplatin and 2-fluoro-Ara AMP. Seventeen of 18 (94%) specimens demonstrated cross-resistance between cisplatin and 2-fluoro-Ara AMP, and 13 of 13 (100%) specimens demonstrated cross-resistance between 2-fluoro-Ara AMP and doxorubicin. A higher proportion of tumors from previously untreated patients achieved greater than or equal to 50% colony inhibition when exposed to 2-fluoro-Ara-AMP or cisplatin than did those from previously treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Agar↗
PubMed1986

Role of culture conditions and exposure duration in determining sensitivity of human bone marrow progenitor cells to methotrexate.

The effect of drug concentration, exposure duration, and culture conditions on the cytotoxic activity of methotrexate (MTX) on normal granulocyte-macrophage colony-forming units in culture (GM-CFUC) was studied using a bilayer soft agar system with nucleoside-free medium. The degree of inhibition of colony formation depended on the type of serum supplementation. A 1 h or 2 h pulse treatment with 2 X 10(-4) M (100 micrograms/ml) MTX failed to kill GM-CFUC, when the cells were subsequently plated in a system containing 15% undialyzed fetal bovine serum (FBS). For continuous exposure the observed LD50 of MTX in the agar system was higher than 10(-4) M for 15% undialyzed FBS, 10(-5) M for 15% dialyzed FBS plus 0.25% undialyzed FBS, 10(-6) M for 15% dialyzed FBS, and 10(-8) M for 15% undialyzed horse serum. The difference for dialyzed FBS versus horse serum can be explained by differences in nucleoside concentrations. The difference for dialyzed FBS versus horse serum may be secondary to an enhancer of MTX in horse serum. For studying MTX sensitivity of human tumor cells in vitro, we suggest testing conditions that lie within the dose survival curve of GM-CFUC.

Culture Media↗
PubMed1986

T-cell involvement in benign phase chronic myelogenous leukemia.

T cells from the peripheral blood of patients with chronic myeloid leukemia (CML) were cultured with phytohemagglutinin and T-cell growth factor (TCGF) in agar culture. These T-cell colonies were pooled and expanded further in liquid culture with TCGF and then simultaneously analysed for the E-rosette receptor with the monoclonal antibody OKT11 and for the presence of the Philadelphia (Ph1) chromosome. OKT11 analysis showed these populations to be composed 99.5% or more of T cells. In four of the seven patients the T-cell suspension showed 7/50 (14%), 3/36 (8%), 2/34 (6%), and 4/44 (9%) Ph1 metaphases. Furthermore, Ph1 metaphases were demonstrated in T-cell cultures in two patients when bone marrow metaphases simultaneously showed 90 and 100% Ph1 negative metaphases secondary to human leukocyte interferon therapy or combination chemotherapy. A minority of T cells in benign phase CML have the Ph1 abnormality despite reduced number of Ph1 metaphases in bone marrow from therapy.

Adult↗
PubMed1986

High-dose melphalan and total body irradiation with bone marrow transplantation for refractory malignancies.

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan (100 mg/m2-140 mg/m2) divided over 2 consecutive days followed by a rest period of 4 days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 days. Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75%. One patient is a long-term disease-free survivor (over 1 yr). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.

Adult↗
PubMed1986

High dose therapy and autologous marrow transplantation as salvage treatment for patients with diffuse large cell lymphoma.

Twenty-nine patients with diffuse large cell lymphoma who failed traditional chemotherapy were treated with high dose chemotherapy with or without total body irradiation followed by infusion of cryopreserved autologous marrow. Complete response was achieved in 11/29 patients (38%), partial response in 13/29 patients (45%) and 5/29 patients (17%) had no response. Six complete responders remain well and free of disease for 5+, 6+, 9+, 10+, 18+ and 25+ months, 3 relapsed at 2, 3 and 8 months after marrow infusion, and 2 died from infectious complications. Complete response was seen more frequently with the absence of bulky tumor (70 vs 21%, P = 0.03), a total body irradiation containing regimen (52 vs 0%, P = 0.03), a history of complete remission with initial chemotherapy (55% vs. 9%, P = 0.03), and a performance status greater than or equal to 80 (56 vs 15%, P = 0.06). High dose therapy had a high response rate (83%) in resistant diffuse large cell lymphoma and yielded durable complete responses in a minority of these patients.

Adolescent↗
PubMed1986

Clinical studies of autografting in acute lymphocytic leukaemia.

The role of autologous marrow transplantation has been reviewed in this chapter. The transplantation results in first remission are difficult to interpret due to the prognostically heterogeneous patient population transplanted and the ever-changing natural history of first complete remission due to more aggressive conventional-dose chemotherapy regimen. The biological role of marrow purging, i.e. elimination of leukaemic cells from the graft, is yet unclear. It is the opinion of the authors that studies in second and subsequent remission can resolve burning issues such as the efficacy of various high-dose conditioning regimens and of different methods of elimination of leukaemic cells such as procedures based on immunological methods, monoclonal antibodies and on differences in sensitivity of stem cells and leukaemic cells to in vitro chemotherapy. It may well be that a large number of patients is needed and, therefore, a multi-centre study is indicated.

Adult↗
PubMed1986

In vitro cytotoxicity patterns of standard and investigational agents on human bone marrow granulocyte-macrophage progenitor cells.

Inhibitory concentrations (ICs) against human bone marrow granulocyte-macrophage colony forming cells (GM-CFC) were established for 26 cancer chemotherapy agents, including seven investigational agents by ten day exposure. Each drug was tested at four or more concentrations to generate reliable survival curves. The analysis of the survival curves produced three patterns according to which drugs were classified: class A drugs had a shouldered curve with terminal exponential kill of GM-CFC, class B drugs produced initial exponential component followed by a plateau, and class C drugs produced linear curves. These categories provide the relationship between drug concentration and cytotoxicity, e.g., the cytotoxicity of class B drugs, after initial kill, did not increase in spite of serial doubling of concentrations whereas the class C drugs had proportional killing with two-fold concentration increment. A number of drugs were active at in vitro concentrations of less than or equal to 0.01 microgram ml-1 and caused log reduction of GM-CFC with an approximate concentration of 0.0001 microgram ml-1. Drugs known to require in vivo bioactivation, namely dacarbazine, procarbazine, and ifosfamide were active at high concentrations (greater than 10.0 micrograms ml-1). We propose that for myelosuppressive agents the GM-CFC provides a useful biologic reference to determine in vitro cut off concentrations to be utilized for drug screening. For nonmyelosuppressive agents, however, it may be suboptimal.

Antineoplastic Agents↗
PubMed1986

High-dose cyclophosphamide, BCNU, and etoposide followed by autologous bone marrow rescue as treatment for adult acute leukemia in relapse.

High-dose cyclophosphamide, 1,3-bis-(2 chloroethyl)-1-nitrosourea (BCNU), and VP-16-213 followed by autologous bone marrow rescue was administered to 29 adult patients with acute leukemia in relapse who had failed to respond to prior salvage treatment, with the following results: 14 patients (48%) achieved complete remission (CR), two patients died early of infection and hemorrhage during hypoplasia, and 13 patients had relapsed with leukemia after an initial hypo-plastic phase. Median remission duration was 3 1/2 months (range, 1-8 months). Maintenance treatment with cyclophosphamide and VP-16, which was given to six patients, did not prolong remission duration. Subsequent salvage treatment was well tolerated by both responders and patients who failed to reach CR. This regimen, which is active in both acute lymphocytic leukemia and acute myelogenous leukemia, had a mild toxicity.

Acute Disease↗
PubMed1986

High-dose intensification therapy with autologous bone marrow support for limited small-cell bronchogenic carcinoma.

The efficacy and toxicity of high-dose chemotherapy with autologous bone marrow transplantation (ABMT) was studied in 32 patients with untreated limited small-cell bronchogenic carcinoma (SCBC). Ten patients received three courses of induction therapy consisting of vincristine (VCR) (1.5 mg X 2), ifosfamide (5 g/m2), and Adriamycin (Ad; Adria Laboratories, Columbus, Ohio) (60 mg/m2). Patients then received two courses of intensification therapy with cyclophosphamide (CYT) (4.5 g/m2), 4' demethyl-epipodophyllotoxin-d-D-ethylidene glucoside (VP-16-213) (600 mg/m2) and VCR (2 mg) with ABMT. Another 22 patients received induction therapy with VCR, CYT (600 mg/m2), Ad (50 mg/m2), and VP-16-213 (180 mg/m2). All 22 patients also received intensification therapy of the same dose of CYT (4.5 g/m2) and VP-16-213 (600 mg/m2). Nine patients also received high-dose methotrexate (MTX), four patients received Ad (40 to 60 mg/m2), and two patients received both Ad and MTX. After intensification, patients received elective prophylactic brain irradiation (3,000 rad) and chest irradiation (5,000 rad). After induction therapy, there were 13 (41%) complete remissions (CR) and 17 (53%) partial remissions (PR). After intensification therapy, there were 22 CRs (69%) and 10 PRs (31%). Median survival for all patients was 14 months (range, 5 to 59+). Of the 13 patients who received intensification therapy in CR, five remain disease free (DF), four for 4 years or longer. Of the nine patients to achieve CR with intensification, only one is DF. No patient died during intensification. In conclusion, intensification with high-dose chemotherapy can increase the CR rate, and this approach is most likely to show long-term benefits in patients with minimal disease (CR) at the beginning of intensification therapy.

Adult↗