A phase I clinical trial of flavone-8-acetic acid in combination with interleukin 2.
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Antineoplastic Agents↗
Biomedical subjects
J E Janik
Publications and source records attributed to J E Janik.
Erythropoietin production. A potential marker for interleukin-2/interferon-responsive tumors.
BACKGROUND: Interleukin-2 (IL-2) recently was approved by the Food and Drug Administration for the treatment of renal cell cancer. It is effective in a small minority of patients, but no markers identify individuals likely to respond to treatment. METHODS: Two polycythemic patients with erythropoietin-producing renal cell cancer and three other polycythemic patients with renal cell cancer were treated with the combination of IL-2 and alpha-interferon (alpha-IFN). RESULTS: All five patients achieved a partial or complete remission. In both patients in which it was measured, the erythropoietin level decreased significantly with treatment, and the polycythemia resolved in all patients. Hypothyroidism developed in two patients, and transient hyperthyroidism developed in another. CONCLUSION: These results contrast with those achieved with IL-2 alone or in combination with lymphokine-activated killer cells, for which a 15% response rate was seen in patients with renal cell cancer and polycythemia. Although less than 5% of renal cell tumors produce erythropoietin, its production may identify a subset of individuals with renal cell cancer responsive to IL-2 and alpha-IFN.
Adult↗
Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment.
Interstitial pressure (IP) is a physiological variable that may have its greatest influence on the transport of high-molecular-weight therapeutic agents. IP in tumor nodules was measured in patients with metastatic melanoma or non-Hodgkin's lymphoma to determine the influence of this physiological variable on treatment outcome. The wick-in-needle technique was used to measure IP at time points before and after treatment with a variety of immunotherapy and chemotherapy regimens. Selected patients had IP measurements during chemotherapy or immunotherapy infusions. Ultrasound or computed tomography was used to evaluate the size of the studied lesions and their relationship to normal structures. The mean baseline IP in melanoma nodules (n = 22) and lymphoma nodules (n = 7) was 29.8 and 4.7 mm Hg, respectively (P = 0.013 for the difference between tumor types). In a subset of melanoma nodules for which IP had been measured before and after treatment, the IP increased significantly over time for nonresponding melanoma lesions from a baseline of 24.4 to 53.9 mm Hg after treatment (P = 0.005) and decreased in melanoma lesions that responded to treatment where the mean baseline and post-treatment IPs were 12.2 and 0 mm Hg, respectively (P = 0.001 for the difference in IP profiles between responding and nonresponding lesions). Six of seven lymphoma nodules responded completely to chemotherapy or radiation. The single nodule that did not respond had a baseline IP of 1 mm Hg that increased to 30 mm Hg after treatment. Tumor IP differs significantly between melanoma and non-Hodgkin's lymphoma. The changes in IP over time differ significantly between responding and nonresponding melanoma lesions. IP that increases during treatment appears to be associated with tumor progression in these tumor types.
Adult↗
The effects of treatment with interleukin-1 alpha on platelet recovery after high-dose carboplatin.
BACKGROUND: Thrombocytopenia is a frequent side effect of cancer chemotherapy and commonly limits attempts to escalate drug doses. To determine whether interleukin-1 alpha could ameliorate carboplatin-induced thrombocytopenia, we combined it with high-dose carboplatin in 43 patients with advanced neoplasms. METHODS: High-dose carboplatin (800 mg per square meter of body-surface area) was administered alone to a control group. Subsequent patients were randomly assigned to receive the same dose of carboplatin with interleukin-1 alpha, administered either before or after carboplatin. Interleukin-1 alpha was given intravenously at a dose of 0.03, 0.1, or 0.3 microgram per kilogram of body weight per day for five days. RESULTS: Carboplatin alone consistently produced thrombocytopenia with a median nadir of 19,000 platelets per cubic millimeter and a median of 10 days with less than 100,000 platelets per cubic millimeter. All 15 patients receiving interleukin-1 alpha before carboplatin had similar findings. In contrast, 5 of the 15 patients given one of the two higher doses of interleukin-1 alpha after carboplatin had minimal thrombocytopenia (nadir, 91,000 to 332,000 platelets per cubic millimeter). In the 10 patients given 0.3 microgram of interleukin-1 alpha per kilogram after carboplatin treatment, the platelet count recovered to 100,000 per cubic millimeter significantly earlier than in either the control group (P = 0.002) or the patients who received interleukin-1 alpha before carboplatin (P = 0.003), with the median times to recovery in the three groups being 16, 21, and 23 days, respectively. At the highest dose of interleukin-1 alpha, toxicity was substantial (but reversible), requiring inpatient support for hypotension, supraventricular arrhythmias, and pulmonary-capillary leak. CONCLUSIONS: Interleukin-1 alpha can accelerate the recovery of platelets after high-dose carboplatin therapy and may be clinically useful in preventing or treating thrombocytopenia induced by chemotherapy.
Adult↗
Intensive therapy with cisplatin, interleukin-2 and interferon-alpha-2a in patients with metastatic melanoma. A phase II Study.
OBJECTIVE: Based upon their individual clinical activity and combined effects in animal models or in vitro, we wished to evaluate a regimen of cisplatin, interferon-alpha, and IL-2 in patients with metastatic melanoma. DESIGN: Phase II pilot study. SETTING: Referral-based US Government clinical research unit. PATIENTS: Nine patients with metastatic malignant melanoma. INTERVENTION: Cisplatin 75-100 mg/m2 was administered intravenously over 30 minutes on days 1 and 8. Interferon-alpha 2a 5 Mu/m2 body surface area (BSA) was given subcutaneously for 4 days beginning 1 day before each dose of cisplatin. Beginning on day 15 and day 22, IL-2 was administered by intravenous continuous infusion at 3 Mu/m2 BSA/d for 96 hours and by daily intravenous bolus concurrent with daily subcutaneous doses of interferon-alpha 2a. MAIN OUTCOME MEASURES: Antitumor response and toxicities. RESULTS: The study was stopped due to renal and hematopoietic toxicity and severe, delayed nausea and vomiting associated with the cisplatin-interferon treatment. Three of 9 patients achieved a partial response (duration 2.5, 4, 14+ months), and an additional patient had a 50% reduction in measurable tumor volume before undergoing resection of residual disease. Overall response rate was 45%. CONCLUSION: This regimen was associated with excessive toxicity, and the lack of complete responses in a patient cohort with favorable characteristics for response (good performance status, predominance of skin and lymph node metastatic sites) suggests that it had no advantage over less toxic treatment regimens. REGISTRATION: National Cancer Institute/Cancer Therapy Evaluation Program T89-0137.
Adult↗
The toxic and hematologic effects of interleukin-1 alpha administered in a phase I trial to patients with advanced malignancies.
PURPOSE: A phase I trial was undertaken because interleukin-1 alpha (IL-1 alpha) possesses antiproliferative, immunostimulatory, antiinfection, myeloprotective, and myelorestorative properties that could be beneficial in cancer treatment. PATIENTS AND METHODS: In this phase I trial, IL-1 alpha was administered intravenously (IV) during a 15-minute period daily for 7 days to patients with advanced solid malignancies. RESULTS: The maximum-tolerated dose (MTD) of IL-1 alpha alone was 0.3 microgram/kg. A second group of patients received indomethacin plus IL-1 alpha based on preclinical studies, which indicated that indomethacin could abrogate IL-1 alpha-induced hypotension; however, the MTD of IL-1 alpha plus indomethacin was 0.1 microgram/kg lower than IL-1 alpha alone. Fever, chills, headache, nausea, vomiting, and myalgia were common but were not dose-limiting. Hypotension resulted from a marked decrease in systemic vascular resistance and required pressors at 0.3 and 1.0 micrograms/kg IL-1 alpha. Dose-limiting toxicities included hypotension, myocardial infarction, confusion, severe abdominal pain, and renal insufficiency. IL-1 alpha treatment caused a significant, dose-related increase in the total WBC count (mainly segmented neutrophils and neutrophilic bands). Bone marrow cellularity increased because of enhanced numbers of relatively mature myeloid cells and megakaryocytes. Platelet counts decreased during therapy but were significantly elevated above baseline values 1 to 2 weeks posttreatment; this may have been an effect of IL-6 that was shown to be induced by IL-1 alpha treatment. Significant increases in triglycerides, cortisol, C-reactive protein, thyroid-stimulating hormone and decreases in cholesterol, testosterone, and protein-C were observed with treatment. CONCLUSION: We conclude that at doses of IL-1 alpha that can be given safely to cancer patients, significant, potentially beneficial hematopoietic effects occur.
Adult↗
Biological response modifiers in breast cancer.
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Breast Neoplasms↗
Efficient synthesis of adeno-associated virus structural proteins requires both adenovirus DNA binding protein and VA I RNA.
We have shown previously that replication of defective parvoviruses [adeno-associated viruses (AAV)] requires several early adenovirus (Ad) gene products [J. E. Janik, M. M. Huston, and J. A. Rose (1981) Proc. Natl. Acad. Sci. USA 78, 1925-1929]. To examine their possible roles in the transcription and translation of AAV mRNA, 293-31 cells, a human embryonic kidney cell line that constitutively expresses the Ad early region IA and IB gene products, were transfected with a pBR325 plasmid (pLH1) that contains a duplex AAV2 DNA segment (0.03-0.97 map units) which encompasses the promoters and coding sequences necessary for expression of all AAV polypeptides. When cells were transfected with pLH1 alone, both spliced and unspliced AAV-specific cytoplasmic RNAs accumulated. These transcripts were capable of directing synthesis of the three AAV capsid polypeptides in vitro, whereas in vivo synthesis of AAV protein was not detected by immunofluorescence or immunoprecipitation. When cells were cotransfected with pLH1 and intact Ad DNA, the level of cytoplasmic AAV RNA was enhanced and AAV protein was synthesized in vivo. Additional experiments demonstrated that in vivo AAV protein synthesis also could be induced when pLH1 was cotransfected with plasmids that contain the Ad DNA-binding protein (pDBP) and VA I RNA (p2BalM) genes; however, a low level of in vivo AAV capsid protein was occasionally detected in cotransfections with pLH1 and a plasmid that contains both VA I and VA II RNA coding sequences (p2SalC). Cotransfection of pLH1 and pDBP or pLH1 and p2SalC showed complex alterations in the steady-state patterns of AAV cytoplasmic transcripts. In both cases, increased levels of transcripts, particularly the 2.3-kb spliced species, were detected in comparison to levels seen in cells transfected with pLH1 alone. Despite these increases, however, there was little, if any, induction of AAV protein synthesis unless both the DNA-binding protein (DBP) and VA I RNA coding sequences were present in cotransfection with pLH1. We conclude that, in 293-31 cells, the Ad VA I RNA and DBP gene products regulate AAV capsid protein synthesis at least at two levels: (i) by increasing the steady-state levels of structural protein transcripts in the cytoplasm, especially the spliced species, and (ii) by enhancing the translation of these messages.
Capsid↗
Adeno-associated virus proteins: origin of the capsid components.
The three primary capsid proteins (A, B, and C) of adeno-associated viruses have been shown previously to contain overlapping amino acid sequences (R. McPherson and J. Rose, J. Virol. 46:523-529, 1983). In the present study we demonstrate definitively that these proteins are encoded in the right half of the adeno-associated virus 2 genome, and one or both of the smallest adeno-associated RNA species (2.3- or 2.6-kilobase RNA) account for their synthesis. Protein A (90 kilodaltons) apparently initiates from a site within the intervening sequence, which is intact in the larger (unspliced) 2.6-kilobase mRNA, and may read through one or more termination codons, including a strong stop signal (UAA) that lies 31 bases downstream from the end of the intervening sequence. Proteins B (72 kilodaltons) and C (60 kilodaltons) are not derived from protein A but apparently originate from independent, in-frame initiations that lie downstream from the splice junction. It thus seems likely that production of the three adeno-associated virus capsid proteins involves at least two mRNA species. The B and C proteins presumably arise from the spliced 2.3-kilobase RNA, whereas protein A should be generated by the 2.6-kilobase RNA or a hitherto unidentified spliced RNA species.
Base Sequence↗
Locations of adenovirus genes required for the replication of adenovirus-associated virus.
We have used DNA transfection to identify several regions of the adenovirus genome needed to induce replication of the defective parvovirus, adenovirus-associated virus (AAV). Previous studies have indicated that only early adenovirus functions are needed to aid the replication of AAV. In this report, we demonstrate that three restriction endonuclease fragments of adenovirus DNA are necessary for production of infectious AAV in 293-31 cells (an adenovirus type 5-transformed human embryonic kidney cell line). These fragments map from 28.5 to 29.4, 59.5 to 75.9, and 89.7 to 100 map units on the adenovirus type 2 genome and correspond to the locations of the VAI RNA gene, early region 2, and early region 4, respectively. The 293-31 cell line, which has been found to express early region 1A and 1B proteins, alone is incapable of supporting AAV replication or even AAV DNA synthesis. Additional experiments with adenovirus type 5 host range mutants (group I, hr1 and group II, hr7) indicate, however, that early region 1A provides an essential function(s) for AAV replication, whereas early region 1B probably does not.
Adenoviruses, Human↗
Herpes simplex virus types 1 and 2 completely help adenovirus-associated virus replication.
In addition to adenoviruses, which are capable of completely helping adenovirus-associated virus (AAV) multiplication, only herpesviruses are known to provide any AAV helper activity, but this activity has been thought to be partial (i.e., AAV DNA, RNA, and protein syntheses are induced, but infectious particles are not assembled). In this study, however, we show that herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are in fact complete AAV helpers and that AAV type 2 (AAV2) infectivity yields can approach those obtained when coinfections are carried out with a helper adenovirus. AAV helper activity was demonstrated in KB cells with two HSV-1 strains (11124 and 17MP) and an HSV-2 strain (HG52). Each herpesvirus supported AAV2 multiplication with comparable efficiency. AAV2 multiplication was similarly efficient in HSV-1 coinfections of HeLa cells, whereas lower yields were obtained in HEp-2 and primary human embryonic kidney cells. HSV-1 also supported AAV1 multiplication in HeLa cells but, at corresponding multiplicities of infection, AAV1 grew less efficiently than AAV2. Comparisons of the time courses of AAV2 DNA, RNA, and protein syntheses after coinfection with either adenovirus type 5 or HSV-1 revealed that, in each case, the onset of synthesis and attainment of maximal synthesis rate occurred earlier in coinfections with HSV-1. These findings demonstrate the linkage of AAV macromolecular synthesis to an event(s) in the helper virus cycle. Aside from this temporal association, helper-related differences in AAV macromolecular synthesis were not apparent.
DNA, Viral↗
Elevations in serum soluble interleukin-2 receptor levels predict relapse in patients with hairy cell leukemia.
PURPOSE: Interferon-alfa, 2'-deoxycoformycin, and 2-chlorodeoxy-adenosine (2-CdA) are effective in the management of patients with hairy cell leukemia. These agents produce remissions in most patients, but relapses occur with all three drugs. The optimal means to follow patients for relapse after treatment has not been determined. METHODS: We retrospectively examined serial serum soluble interleukin-2 receptor levels (sIL-2R) and absolute granulocyte counts in eight patients with relapsed hairy cell leukemia. All were treated with 2-CdA at the time of relapse. Serum samples were available at 3- to 6-month intervals from 5 to 9 years before relapse and 2-CdA treatment RESULTS: sIL-2R levels increase only in patients who go on to relapse. sIL-2R levels doubled a mean of 17.1 months (range, 4-36 months) before absolute granulocyte count decreased by 50%. DISCUSSION: Demonstration of a rising serum sIL-2R level in patients with hairy cell leukemia identified those with an increased risk of relapse who need more frequent observation than patients who maintain a stable sIL-2R level. Early intervention may ameliorate the toxicity of salvage therapy because disease-related neutropenia may be anticipated.
Antineoplastic Agents↗
Combination chemotherapy followed by an immunotoxin (anti-B4-blocked ricin) in patients with indolent lymphoma: results of a phase II study.
The purpose of this article was to evaluate the antitumor effects of a combination chemotherapy program based on ProMACE (prednisone, methotrexate, doxorubicin [Adriamycin], cyclophosphamide, etoposide) followed by a B cell-specific immunotoxin in the treatment of patients with advanced-stage indolent histology non-Hodgkin's lymphomas. We performed a prospective phase II clinical trial in a referral-based patient population. After confirmation of diagnosis and staging evaluation, 44 patients (10 small lymphocytic lymphoma, 27 follicular lymphoma, 7 mantle cell lymphoma; 30 without prior therapy, 14 previously treated) received six cycles of ProMACE-CytaBOM (cytarabine, bleomycin, vincristine [Oncovin], mechlorethamine) combination chemotherapy (with etoposide given orally daily for five days) followed by a 7-day continuous infusion of anti-B4-blocked ricin immunotoxin at 30 microg/kg/day given every 14 days for up to six cycles. A complete response was achieved in 25 of 44 patients (57%), 21 from the chemotherapy alone, 3 converted from partial to complete response with the immunotoxin, and 1 patient became a complete responder after a surgical procedure to remove an enlarged spleen that was histologically negative for lymphoma. With a median follow-up of 5 years, 14 of 25 complete responders have relapsed (56%); median remission duration was 2 years, and overall survival was 61%. Forty-two percent of the complete responders have been in continuous remission for more than 4 years. The median number of courses of immunotoxin delivered was two usually because of the development of human anti-ricin antibodies. ProMACE-CytaBOM plus anti-B4-blocked ricin does not produce durable complete remissions in the majority of patients with indolent lymphoma. However, the remissions appear quite durable (> 4 years) in about 40% of the complete responders.
Adult↗