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Biomedical subjects

J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 37 records · Page 2Linked to original sources
PubMed1995

Recombinant human retinoblastoma protein inhibits cancer cell growth.

Aberrant expression of the tumor suppressor gene RB1 is associated with a variety of solid tumors and hematopoietic neoplasms. Certain cancer cell lines in which the protein encoded by RB1 (p110RB) is absent have been reported to show decreased growth rate, clonogenicity, or tumorigenicity following insertion of a transcriptionally active RB1 gene. We asked whether these RB-deficient cells could be growth inhibited by direct exposure to purified p110RB. We report a decrease in uptake of tritiated thymidine by 5637 bladder carcinoma cells (RB-negative) when purified recombinant p110RB is added to culture media. Internalization of the protein by cells and translocation to the nucleus are demonstrated by immunohistochemistry, FACS, and detection of radiolabeled protein in subcellular fractions. Next, we chose a well-described leukemia cell culture model to investigate the potential effect of recombinant p110RB in clinical disease. We observed dose-related decreases in cell number of colony formation in vitro in 8 of 20 acute myelogenous leukemia samples, 7 of which did show endogenous p110RB detectable by immunohistochemistry. Histological appearance following exposure to p110RB shows cytoplasmic vacuolization and nuclear lobulation of degenerating cells. We conclude that purified p110RB added to culture media is internalized by cells, translocated to the nucleus, and exerts a growth-inhibitory effect on certain cancer cell types.

Acute Disease↗
PubMed1994

Cytokine therapeutics: lessons from interferon alpha.

Cytokines are soluble proteins that allow for communication between cells and the external environment. Interferon (IFN) alpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of growth and differentiation, affecting cellular communication and signal transduction pathways as well as immunological control. This review focuses on the biological and clinical activities of the cytokine. Originally discovered as an antiviral substance, the efficacy of IFN-alpha in malignant, viral, immunological, angiogenic, inflammatory, and fibrotic diseases suggests a spectrum of interrelated pathophysiologies. The principles learned from in vivo studies will be discussed, particularly hairy cell leukemia, chronic myelogenous leukemia, certain angiogenic diseases, and hepatitis. After the surprising discovery of activity in a rare B-cell neoplasm, IFN-alpha emerged as a prototypic tumor suppressor protein that represses the clinical tumorigenic phenotype in some malignancies capable of differentiation. Regulatory agencies throughout the world have approved IFN-alpha for treatment of 13 malignant and viral disorders. The principles established with this cytokine serve as a paradigm for future development of natural proteins for human disease.

Fibrosis↗
PubMed1993

CHOP-Bleo plus interferon for stage IV low-grade lymphoma.

BACKGROUND: Alpha interferon (IFN) is an effective single agent for patients with low-grade lymphoma, but until 1982 had not been integrated with standard chemotherapy for these patients. Since relapse from complete remission (CR) is the rule for patients with advanced stage low-grade lymphoma, a maintenance IFN schedule was explored for patients in CR. PATIENTS AND METHODS: From 1982-1987, 127 patients with stage IV low-grade lymphoma were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) for 9-18 mo. (median 13 mo.), followed by interferon alfa-n-1 (Wellferon) maintenance therapy for 24 mo. for CRs. RESULTS: The overall response rate for the entire treatment program was 73% CR and 23% partial remission. The median follow up was 59 months. At 5 years, survival was 74%, failure-free survival (FFS) 47%, and FFS of CRs 60%. Compared to a group of 96 patients with similar pretreatment clinical features treated with CHOP-Bleo from 1972-1982, this represents a significant improvement for both overall FFS (p = 0.01) and FFS of CRs (P < 0.01). Toxicity from the IFN maintenance was generally acceptable, but even at the modest dose employed in this trial (3 x 10(6) U/m2 three times weekly), dose modification was required in more than 30% of patients, usually because of fatigue. CONCLUSIONS: The integration of IFN and conventional chemotherapy is feasible and effective. Maintenance IFN prolongs remission duration for patients with stage IV low-grade lymphoma.

Adult↗
PubMed1993

The myeloprotective effect of recombinant human granulocyte-macrophage colony-stimulating factor given sequentially with continuous infusion vinblastine in metastatic breast cancer patients.

Colony-stimulating factors have been shown to have a myeloprotective effect when administered following chemotherapy. Chemotherapy of short duration with predominantly cell-cycle nonspecific agents has been most used. The myeloprotective effects of colony-stimulating factors given after cell-cycle specific or continuous infusion chemotherapy have not previously been assessed. Twenty-one evaluable patients with metastatic breast cancer progressing after one prior chemotherapy regimen were treated with continuous infusion vinblastine 2.0 mg/m2/day for 5 days. After the second chemotherapy cycle, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for 10 days. Serial complete blood counts, differential, and platelet counts were obtained to document myelotoxicity. GM-CSF administration resulted in a significantly shorter duration of granulocytopenia, < 500/microliters, at the maximum GM-CSF dose. Significantly more rapid recovery of granulocytes to > 500/microliters, > 1000/microliters, and > 1500/microliters was seen with all doses and schedules of GM-CSF administered. The nadir absolute granulocyte counts were unaffected. GM-CSF given after continuous infusion cell-cycle specific chemotherapy is therefore myeloprotective.

Adult↗
PubMed1993

Granulocyte-macrophage colony-stimulating factor as a cause of paraneoplastic leukaemoid reaction in advanced transitional cell carcinoma.

Increasing evidence suggests that paraneoplastic syndromes may be mediated by tumour-related cytokine release, although the specific factor(s) involved remain poorly defined. Colony-stimulating factors (CSF) and interleukins (IL) promote colony growth in semi-solid media and, when administered in recombinant form, increase blood counts in patients. However, normal serum CSF levels in individuals with physiologic blood counts and the relationship between specific serum CSF levels and paraneoplastic leukaemoid reaction are not well established. In this study, we found that normal serum levels of granulocyte-macrophage CSF (GM-CSF), as measured by ELISA, were generally < 55 pg ml-1; IL-3, < 30 pg ml-1; and granulocyte CSF (G-CSF), < 50 pg ml-1. In contrast, high levels of GM-CSF (132 pg ml-1), but not G-CSF or IL-3, were found in a patient with a transitional cell carcinoma of the renal pelvis and increased leukocytosis correlating with the tumour burden. The GM-CSF was biologically active, as demonstrated by its ability to stimulate colony growth in vitro. Based on these results it appears that autonomous production of GM-CSF is one possible pathophysiologic mechanism underlying leukaemoid reaction in cancer patients.

Aged↗
PubMed1993

Intensive preoperative chemotherapy with colony-stimulating factor for resectable adenocarcinoma of the esophagus or gastroesophageal junction.

PURPOSE: The curative resection rate in patients with potentially resectable carcinoma of the esophagus is approximately 55% and their median survival time is 11 months. Preoperative chemotherapy with high doses of chemotherapeutic agents was used to evaluate clinical and pathologic responses, curative resection rate, toxicity, and survival. Colony-stimulating factor (CSF) was added to reduce the severity of myelosuppression. PATIENTS AND METHODS: Twenty-six consecutive assessable patients with potentially resectable adenocarcinoma of the esophagus or gastroesophageal junction were treated with two preoperative courses of intensive chemotherapy (etoposide, doxorubicin, and cisplatin [EAP]) with granulocyte-macrophage CSF (GM-CSF). Additional three conventional-dose postoperative chemotherapy courses without GM-CSF were given to patients who responded to preoperative chemotherapy. RESULTS: A median of three courses (range, one to six), were administered. Of 27 patients, 26 were assessable for response to preoperative EAP; 13 (50%) achieved a major response. Among 23 patients who underwent surgery, 15 (65%) had a curative resection (58% of 26 assessable patients); none of the patients had a pathologic complete response, but two patients had only microscopic carcinoma in the resected specimen. Six patients had carcinoma present at the resection margins and received postoperative radiotherapy. Two patients were found to have liver metastases at exploration. At a median follow-up of 22 months, the median survival of 26 patients was 12.5 months (range, 2 to 32 +). Fourteen patients died of their carcinoma; two patients died of treatment-related causes; one died of an unrelated CNS arterial malformation; and the causes of death in two patients remain unknown. Seven patients are alive with no evidence of relapse. Major toxicities of this regimen included severe myelosuppression, nausea and vomiting, infections, and severe constitutional symptoms related to GM-CSF. However, subcutaneous injection of GM-CSF was well tolerated. CONCLUSION: High-dose EAP is active against locoregional adenocarcinoma of the esophagus and gastroesophageal junction but can be associated with significant toxicity. Although this strategy remains attractive and needs to be developed further, less toxic and more effective regimens need to be identified.

Adenocarcinoma↗
PubMed1993

Phase I and plasma pharmacokinetic study of infusional fluorouracil combined with recombinant interferon alfa-2b in patients with advanced cancer.

PURPOSE: Enhanced fluorouracil (FUra) cytotoxicity caused by recombinant interferon alfa-2b (rIFN-a) has been reported, but the mechanism, optimal dose, and schedule remain unknown. Therefore, a phase I and pharmacokinetic study of FUra with escalating doses of rIFN-a was initiated. PATIENTS AND METHODS: FUra (750 mg/m2/d) was given by continuous intravenous (IV) infusion for 5 days. rIFN-a (0.1 to 15 x 10(6) U/m2/d) was given subcutaneously (SC) daily for 5 days concurrent with FUra. Courses were repeated every 14 to 21 days. Forty-four patients were enrolled; 39 received at least two courses. During the first course of therapy, FUra levels before and after administration of rIFN-a were quantitated in 26 patients by high-pressure liquid chromatography. RESULTS: The maximum-tolerated dose of rIFN-a was 10 x 10(6) U/m2/d. Stomatitis was dose-limiting. Three partial and five minor responses occurred. Interpatient pharmacokinetics showed that rIFN-a did not alter steady-state plasma concentration (Css; range, 0.77 +/- 0.35 mumol/L to 1.85 +/- 0.48 mumol/L), elimination half-life (t1/2; mean, 9.7 +/- 4.3 minutes), area under the concentration-versus-time curve (AUC; range, 93 to 224 mumol/L x hours), total-body clearance (CI; range, 1,172 to 3,236 mL/min), or volume of distribution (range, 11.9 to 49.2 L) of FUra. Intrapatient data evaluation revealed a dose-independent effect of rIFN-a. The mean FUra Css after rIFN-a administration (1.31 mumol/L) was greater than that before rIFN-a administration (1.02 mumol/L, P < .0001). FUra Cl after rIFN-a administration was reduced by 20% to 35% compared with use of FUra alone (P < .0001). Patients with a greater than 20% decrease in FUra Cl had a fourfold greater incidence of diarrhea. CONCLUSION: rIFN-a reduces FUra Cl and, consequently, increases FUra-associated toxicity. Phase II studies of FUra and rIFN-a seem to be warranted.

Adult↗
PubMed1993

A phase-I clinical study of low-dose oral interferon-alpha.

Twenty-five patients with systemic malignancies or cutaneous disorders were treated with low dosages (1-16 IU/kg/day) of oral interferon-alpha in a phase-I study. There were no grade-3 or -4 toxicities. No patients achieved a partial or complete response. One patient with renal cell carcinoma had prolonged disease stabilization lasting for 22 months. No significant changes in lymphocyte subsets including T4/T8 ratio, or serum immunoglobulins were observed. Subjective improvement in general well-being was reported by three patients. Low dosages of interferon-alpha administered orally do not appear to have any significant immunomodulatory or antitumor activity.

Administration, Oral↗
PubMed1993

Ubiquitous expression of cytokines in diverse leukemias of lymphoid and myeloid lineage.

It has recently been suggested that autocrine production of hematopoietic regulatory molecules can modulate the cardinal features of many leukemic states: excessive proliferation of the neoplastic cells and suppression of the normal elements. We therefore analyzed samples obtained from 57 patients with a variety of hematologic malignancies (21, acute myelogenous leukemia; 14, acute lymphoblastic leukemia; 12, Philadelphia chromosome-positive chronic myelogenous leukemia [blast phase] or acute leukemia; 5, chronic lymphocytic leukemia; and 5, chronic myelomonocytic leukemia) for expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) transcripts on Northern blots. TNF-alpha mRNA was discerned in almost half of the samples (47%), and was expressed in some patients with every type of leukemia, except T-cell acute lymphoblastic leukemia (ALL). Expression occurred with great frequency in samples (12 of 15 [80%]) from monocytic (acute or chronic) leukemias, and from advanced chronic lymphocytic leukemia (4 of 5 samples [80%]). IL-1 beta transcripts were detected in 20 of 57 samples (35%). Its presence, like that of TNF-alpha, was ubiquitous, and only chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia cells consistently failed to produce IL-1 beta message. Therefore it appears that TNF-alpha and/or IL-1 beta mRNA can be found in the leukemic cells from a substantial subset of patients with B cell-derived acute lymphoblastic leukemia as well as with chronic and acute myeloid, monocytic or lymphocytic leukemias. Because these cytokines have potent direct and indirect effects on normal and malignant hematopoiesis, their widespread constitutive expression by neoplastic blood cells may play a fundamental role in driving the leukemic process.

Blotting, Northern↗
PubMed1993

Suppression of chronic myelogenous leukemia colony growth by interleukin-4.

Interleukin-4 (IL-4) is a cytokine with pleiotropic activities. In normal bone marrow cultures grown in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), IL-4 suppresses granulocyte-macrophage colony-forming unit (CFU-GM) proliferation but it enhances the colony-stimulatory effect of granulocyte colony-stimulating factor (G-CSF). We studied the effect of IL-4 on chronic myelogenous leukemia (CML) bone marrow or peripheral blood cells from 30 patients using the CFU-granulocyte-erythrocyte-monocyte-megakaryocyte colony culture assay. In several repetitive experiments, IL-4 inhibited CFU-GM colony replication by 24 to 65% in a dose-dependent fashion at concentrations ranging from 0.01 to 10 micrograms/ml when patients' cells were cultured in the presence of erythropoietin alone or with phytohemagglutinin-conditioned medium, GM-CSF, or IL-3. The addition of 100 U/ml of IL-1 beta to the CML cultures partially reversed the inhibitory effect of IL-4. Incubation of CML low-density peripheral blood cells with IL-4 resulted in down-regulation of IL-1 beta and IL-6 production in three of four samples, suggesting that the suppressive effect of IL-4 is mediated by inhibition of IL-1 and by other mechanisms including inhibition of IL-6 production. In contrast to the stimulatory effect exerted by IL-4 on G-CSF-dependent CFU-GM progenitor proliferation in normal marrow, the addition of IL-4 to CML cultures grown in the presence of G-CSF resulted in a divergent effect: suppression of CML CFU-GM in two, stimulation in three, and no significant effect in two CML patients' samples. It is therefore possible that IL-4 may have an in vivo antiproliferative effect in a subpopulation of CML patients.

Adult↗
PubMed1992

Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors.

Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1-inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Adult↗
PubMed1992

Interferon-stimulated genes in interferon-sensitive and -resistant chronic myelogenous leukemia patients.

alpha-Interferon induces hematological and cytogenetic remissions in some individuals with newly diagnosed Philadelphia-positive chronic myelogenous leukemia. However, interferon-resistant disease occurs in a consistent patient subset (primary resistance) and develops during therapy in additional patients (secondary resistance). Several alpha-interferon-inducible genes have been characterized. In interferon-resistant cell line variants, defects in these genes have been implicated in the mechanisms mediating resistance. We have, therefore, evaluated mRNA expression of four interferon-stimulated genes (ISGs) following alpha-interferon therapy. Twenty-seven chronic myelogenous leukemia patients (ten interferon-sensitive patients, 17 interferon-resistant patients) were studied. Peripheral blood samples were collected prior to and 1 to 7 days after starting interferon therapy and analyzed for the expression of 2'-5' oligoadenylate synthetase, ISG-15, ISG-54, and 6-16 transcripts. Following therapy with alpha-interferon, 2'-5' oligoadenylate synthetase, ISG-54, and 6-16 transcripts were discerned in all patients regardless of their response to interferon. The ISG-15 message was detected in eight of nine interferon-sensitive and in 15 of 16 interferon-resistant patients, as well. Overall, no consistent defect in the ISG system could be identified. Therefore, lack of induction of these genes cannot explain resistance to alpha-interferon in chronic myelogenous leukemia patients. Other mechanisms such as posttranslational modification, leading to defects in the ISG corresponding proteins, may play a role in the development of resistance.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

13-cis-retinoic acid and interferon alpha-2a: effective combination therapy for advanced squamous cell carcinoma of the skin.

BACKGROUND: Retinoids (vitamin A derivatives) and interferon-alpha (IFN-alpha) are potent regulators of malignant cell differentiation and proliferation, and both have immunomodulatory and antiangiogenesis activity. A large body of preclinical and clinical data supports the use of combination therapy with 13-cis-retinoic acid (13-cRA) and IFN-alpha in patients with squamous cell carcinoma of the skin. This carcinoma is an extremely common and frequently severely disfiguring cancer, for which about 10% of patients remain uncured following standard local therapy. PURPOSE: Our purpose was to test whether a 20% or greater complete response rate could be achieved using a combination of these two agents in patients with advanced squamous cell carcinoma of the skin in whom local therapy had failed or was unfeasible or who had regional and/or distant metastases. METHODS: Thirty-two patients with heavily pretreated, advanced inoperable cutaneous squamous cell carcinoma of the skin were given a combination of oral 13-cRA (1 mg/kg per day) and subcutaneous recombinant human IFN alpha-2a (3 million units per day) for at least 2 months, unless disease progressed earlier, in a phase II trial. RESULTS: Nineteen (68%) of the 28 assessable patients responded, seven (25%) of whom had complete responses. Response rates were 93% (13 of 14) in patients with advanced local disease (six complete responses), 67% (four of six) in patients with regional disease (no complete responses), and 25% (two of eight) in patients with distant metastases (one complete response). The relationship between decreased response rate and increased extent of disease was highly statistically significant (P less than .005, chi-square test). The median response duration was greater than 5 months. No life-threatening toxic effects occurred in assessable patients treated with this combination, although dose reductions were required in 18 patients. The major limiting side effect in this elderly patient population (median age, 67 years) was cumulative fatigue. CONCLUSION: These results indicate that combined systemic therapy with 13-cRA and IFN alpha-2a is highly effective in patients with advanced squamous cell carcinoma of the skin.

Aged↗
PubMed1992

Bone marrow hypoplasia and aplasia complicating interferon therapy for chronic myelogenous leukemia.

In four patients with Philadelphia chromosome-positive (Ph1) chronic myelogenous leukemia (CML), bone marrow hypoplasia (three patients) and aplasia (one patient) developed during or after therapy with either alpha-interferon (IFN) or gamma-IFN. The predominant clinical characteristic of this complication was protracted pancytopenia, which required 2 to 5 months recovery time after treatment and did not resolve in one patient. Bone marrow cytogenetic analysis in two of the patients demonstrated 100% Ph1 metaphases despite the profound bone marrow suppression. Overall, this complication was uncommon, occurring in less than 2% of the patients with CML treated with various IFN. The possible underlying causes include previous therapy with alkylating agents, lack of "reservoir" or normal stem cells, or pronounced sensitivity of the malignant cell clone to the suppressive effect of IFN.

Adult↗
PubMed1992

Regional biologic therapy. Hepatic arterial infusion of recombinant human tumor necrosis factor in patients with liver metastases.

Twenty-two chemotherapy-resistant patients with liver metastases received 46 courses of recombinant human tumor necrosis factor (rhTNF) administered by 5-day continuous infusion through percutaneously inserted hepatic arterial catheters. The maximum tolerated daily dose of rhTNF was 150 micrograms/m2. This is six times the maximum tolerated daily dose of rhTNF that could be given systemically (intravenous) on the same schedule. The dose-limiting toxicity resulted in severe, although transient, hypophosphatemia (less than 1.0 mg/dl) associated with myocardial dysfunction. Objective tumor response (partial tumor response or greater) was observed in 2 of 14 patients (14%) with colorectal cancer and lasted as long as 3 months. Three additional minor responses occurred among these patients with colorectal cancer. Plasma carcinoembryonic antigen levels also decreased significantly (greater than 25%) in 7 of the 14 (50%) patients with colorectal cancer. Regional biologic therapy with rhTNF as a sole modality has definite antitumor activity in colorectal cancer metastatic to the liver and warrants additional study in previously untreated patients.

Adult↗
PubMed1992

Very low doses of GM-CSF administered alone or with erythropoietin in aplastic anemia.

UNLABELLED: PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy. PATIENTS AND METHODS: We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously). RESULTS: In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin. CONCLUSIONS: Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.

Adolescent↗
PubMed1992

Adjuvant therapy with escalating doses of doxorubicin and cyclophosphamide with or without leukocyte alpha-interferon for stage II or III breast cancer.

PURPOSE: A prospective study in breast cancer patients was undertaken to determine whether escalating doses of doxorubicin and cyclophosphamide would result in a higher fraction of patients free of disease, and to evaluate the role of leukocyte alpha-interferon. PATIENTS AND METHODS: Between 1982 and 1986, 319 consecutive patients with stage II or III breast cancer with one or more positive nodes were assigned randomly to receive adjuvant chemotherapy that consisted of escalating doses of doxorubicin and cyclophosphamide in combination with vincristine and prednisone or the same chemotherapy regimen followed by 1 year of leukocyte alpha-interferon. Doxorubicin was administered by 72-hour continuous infusion through a central venous catheter (maximum total cumulative dose, 430 mg/m2). All patients with positive or unknown estrogen receptor status were also given tamoxifen for 1 year. RESULTS: The median follow-up was 71 months (range, 35 to 99 months). Correlation of disease-free survival (DFS) with dose-intensity of cyclophosphamide and doxorubicin showed no improvement in DFS for patients who were able to receive escalated drug doses compared with those who were not. Doxorubicin administered by continuous infusion was associated with a negligible risk of cardiotoxicity in this study despite the administration of higher accumulative doses than in our previous adjuvant therapy studies. The DFS rates of patients who did and those who did not receive leukocyte alpha-interferon were similar. CONCLUSIONS: In this study, there was no real evidence that higher drug dose intensity was associated with longer DFS. Leukocyte alpha-interferon as it was used in this study had no therapeutic value. Doxorubicin administered by infusion was associated with a reduced risk of cardiotoxicity.

Adult↗