Gene expression of insulin-like growth factors and receptors in neoplastic prostate tissues: correlation with clinico-pathological parameters.

The insulin-like growth factor (IGF) system has been shown to regulate prostate cancer cell growth in vitro and, possibly, in vivo. In this study we examined RNA expression of IGF ligands and their receptors in 23 paired benign and neoplastic prostate tissues. In addition to comparing gene expression of IGF ligands and receptors between benign and neoplastic tissue samples, we correlated IGF-I, IGF-II, IGFR-1, and IGFR-2 RNA levels in tumor samples with prognostic clinico-pathological parameters such as stage, grade, Gleason score, perineural or extraprostatic invasion. We found higher IGF-I RNA levels in benign vs. malignant tissues (p = 0.014), whereas IGF-II RNA expression was higher in tumors with high Gleason score (GS) (p = 0.045). Using the Spearman rank correlation test we also found a positive correlation between IGFR-2 RNA levels and GS (p = 0.01). No correlation was found between expression of IGF ligands and receptors and tumor grade, stage perineural invasion, or extraprostatic involvement. We conclude that differential expression of certain IGF system components may be important in the biology and clinical behavior of prostate cancer.

Effect of HER2/neu expression on survival in non-small-cell lung cancer.

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).

Estrogen and progesterone receptors in non-small cell lung cancer in 248 consecutive patients who underwent surgical resection.

CONTEXT: Different authors have reported estrogen receptor (ER) expression between 0% and 96.8% and progesterone receptor (PR) expression between 21.8% and 34.7%. OBJECTIVE: To examine the discrepancies in the literature regarding the expression of ERs and PRs in non-small cell lung cancer. DESIGN: Retrospective analysis. SETTING: A referral tertiary care center. PATIENTS: We reviewed 248 consecutive cases of stage I and II non-small cell lung cancers. METHODS AND RESULTS: Sections of formalin-fixed and paraffin-embedded tumor tissue were stained with ER and PR monoclonal antibodies using the avidin-biotin complex detection system with antigen retrieval. Men represented 66.1% of the patients, and women represented 33.9%. Large cell (undifferentiated) carcinoma constituted 10.4% of the entire population; squamous cell carcinoma, 39.1%; adenocarcinoma, 33.0%; and bronchoalveolar carcinoma, 17.3%. Patients with stage I disease represented 77.0% of the population. In this patient population, we found no nuclear or cytoplasmic expression of either ERs or PRs (95% confidence interval, 0%-1.2%). CONCLUSIONS: The absence of expression of ERs and PRs differs from previous articles, which use a variety of techniques, impairing a meaningful comparison of data. In addition, the presence of ER and PR expression in a lung carcinoma is supportive of a nonpulmonary primary tumor metastatic to the lung. The absence of their expression in non-small cell lung cancer does not support a role of these transcription factors in initiating and maintaining this neoplastic process.

Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience.

PURPOSE: We have completed a phase I study, followed by three phase I/II studies, in patients with metastatic melanoma, renal cell carcinoma (RCC), and sarcoma in order to evaluate the safety, toxicity, and antitumor activity of Leuvectin (Vical Inc, San Diego, CA), a gene transfer product containing a plasmid encoding human interleukin (IL)-2 formulated with the cationic lipid 1, 2-dimyristyloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide/dioleyl-phosphatidyl-ethanolamine (DMRIE/DOPE) and administered intratumorally. PATIENTS AND METHODS: Twenty-four patients were treated in the phase I study. Leuvectin doses were 10 microg, 30 microg, or 300 microg weekly for 6 weeks. In three subsequent phase I/II studies, a total of 52 patients (18 with melanoma, 17 with RCC, and 17 with sarcoma) were treated with further escalating doses of Leuvectin: 300 microg twice a week for 3 weeks, 750 microg weekly for 6 weeks, and 1,500 microg weekly for 6 weeks. RESULTS: There were no drug-related grade 4 toxicities and only one grade 3 toxicity, but the majority of patients experienced mild constitutional symptoms after treatment. In the phase I/II studies, 45 patients were assessable for response (14 with RCC, 16 with melanoma, and 15 with sarcoma). Two patients with RCC and one with melanoma have achieved partial responses lasting from 16 to 19 months and continuing. In addition, two RCC, three melanoma, and six sarcoma patients had stable disease lasting from 3 to 18 months and continuing. The plasmid was detected by polymerase chain reaction assay in the posttreatment samples of 29 of 46 evaluated patients. Immunohistochemistry studies on serial biopsy specimens showed increased IL-2 expression and CD8(+) infiltration after treatment in the tumor samples of several patients (12 and 16, respectively). CONCLUSION: Direct intratumoral injection of Leuvectin is a safe and possibly effective immunotherapeutic approach in the treatment of certain tumor types.

Pituitary component of the aromatic hydrocarbon-mediated expression of CYP2B and CYP2C11.

1. The aim was to determine if the ethylbenzene (EB)-mediated expression of CYP2B and CYP2C11 involved a hormonally controlled component. 2. The hypophysectomized (HX) and intact rats were treated with EB for 1 or 2 days, and the effects on specific CYP levels measured. 3. Differences were observed in the inducibility of CYP2B by EB in the HX rat when compared with intact controls. Whereas significant elevations of CYP2B-dependent activities and protein levels were observed after both 1 and 2 days of EB injection in intact controls, CYP2B levels were significantly elevated in the HX rat only after 2 days of hydrocarbon treatment. 4. Both CYP2C11-dependent activities and protein levels were decreased after EB administration to the intact rat. In contrast, CYP2C11 levels were unaffected by EB in the HX rat at any of the time points indicated. 5. CYP2C11 protein levels were unaffected by treatment with EB for 24 h in cultured hepatocytes, also supporting the hypothesis that hormones are involved in CYP2C11 expression. 6. This study indicates that pituitary input influences the EB-mediated changes in both CYP2B and CYP2C11. CYP2C11 is affected by EB administration in a manner similar to other xenobiotics such as phenobarbital. On the other hand, the smaller induction of CYP2B1/2 in response to EB differs from that observed with phenobarbital where HX augmented the response of the inducer.

Differential expression of insulin-like growth factor binding proteins in high versus low Gleason score prostate cancer.

PURPOSE: The insulin-like growth factor (IGF) system appears to be important in human prostate cancer biology. Expression of specific IGF binding proteins (IGFBPs) by prostate cancer tissues may modulate IGF cellular actions, and possibly determine both IGF-dependent tumor growth and biological aggressiveness in vivo. The purpose of this study was to examine the differential expression of all six IGFBP genes in benign and malignant prostate tissue samples. MATERIALS AND METHODS: Using RNAse protection assays, we examined expression of IGFBPs 1 through 6 in 23 paired benign and neoplastic prostate tissue samples obtained from the same prostatectomy specimen. RNA expression levels on each tissue sample were determined densitometrically and groups compared using standard Student's t test. RESULTS: We found expression of IGFBPs 2 through 6, but not IGFBP-1, in both malignant and benign tissues. A statistically significant differential expression of IGFBPs 2, 3 and 5 was found between tumors with high Gleason score and those with low scores and benign tissues. Expression of IGFBPs 2 and 5 was higher (p = 0.002 and 0.04, respectively) while that of IGFBP-3 was lower (p = 0.05) in high versus low Gleason score cancer specimens. Expression of IGFBPs 4 and 6 was no different between tumors (p = 0.052 and 0.25, respectively). No significant differences in IGFBP expression were evident between benign and tumor tissues when tumor grade was not considered. CONCLUSION: Our results indicate that differential expression of certain IGFBPs in human prostate cancer correlates with tumor Gleason score. Thus, expression of certain IGFBPs in prostate cancer may be used as a surrogate marker of aggressive clinical behavior.

Reduction in carboplatin hematopoietic toxicity in tumor bearing mice: comparative mechanisms and effects of interleukin-1 beta and corticosteroids.

Increasing clinical evidence suggests that treatment of certain cancers is more effective with high dose chemotherapy compared to standard dose chemotherapy. Efforts at reduction of high dose chemotherapy hematotoxicity have focused on post-chemotherapy administration of hematopoietic growth factors or stem cells. A pretreatment strategy to induce hematopoietic resistance has not been extensively examined experimentally or clinically. Pretreatment with agents can provide an alternative or additional method to reduce high-dose chemotherapy hematotoxicity. We have previously described a murine model in which normal mice were injected with high dose carboplatin (CB, 600 mg/m2, intravenously). Within 7-12 days post-therapy, severe granulocytopenia and thrombocytopenia were induced and resulted in a granulocytopenic mortality of 70-80%. Utilizing this model, we observed that pretreatment of mice with interleukin (IL)-1 beta and/or a corticosteroid effectively reduced CB hematotoxicity. In the current studies, we demonstrated that C3H/HeJ mice bearing 0.25-0.5 cm RIF-1 tumors, exhibited a tumor associated decrease in hematopoietic tolerance to CB compared to normal mice. However, IL-1 beta (1 ug/mouse/day for 7 days), cortisone acetate (CA 0.5 mg/mouse/day for 7 days) or both CA and IL-1 beta, decreased CB induced mortality rates (control = 73%, IL-1 beta = 46%, CA = 30%, IL-1 beta + CA = 5%). Pretreatment with IL-1 beta, CA, or both ameliorated CB-induced absolute granulocyte, lymphocyte and platelet count nadirs. Bone marrow granulocyte-macrophage colony forming units (CFU-GM) from mice treated with IL-1 beta demonstrated increased ex-vivo resistance to cisplatin, without altering its sensitivity to high specific activity 3H-thymidine (a measure of cell fraction in S-phase). Bone marrow CFU-GM from mice treated with CA exhibited increased resistance to both cisplatin and to high specific activity 3H-thymidine. Pretreatment with IL-1 beta, CA or both did not alter tumor sensitivity to CB in vivo. These data suggest that IL-1 beta, CA or the combination may be clinically useful in reducing the hematotoxicity of CB.

Effects of endotoxin on proliferation of human hematopoietic cell precursors.

In examining the effects of corticosteroids on hematopoiesis in vitro, we observed that results were highly dependent on the lot of commercial fetal calf serum (FCS) utilized. We hypothesized that this variability correlated with the picogram (pg) level of endotoxin contaminating the FCS. Randomly obtained commercial lots of FCS contained 0.39 to 187 pg/ml of lipopolysaccharide (LPS). Standard FCS concentrations in hematopoietic precursor proliferation assays (granulocyte-marcrophage colony forming units [CFU-GM]) resulted in final LPS levels as high as 40 pg/ml. LPS (2-5 pg/ml) added to essentially endotoxin-free cultures, induced human mononuclear cell release of interleukin (IL)-1, IL-6 and granulocyte colony stimulating factor (G-CSF). Lots of FCS induced the release of IL-1, IL-6, and G-CSF from human mononuclear cells and the release of these factors correlated with the level of contaminating LPS. Human bone marrow CFU-GM proliferation, in response to granulocyte-macrophage colony stimulating factor (GM-CSF), positively correlated with the level of LPS contaminating the FCS and the FCS-induced release of IL-6 from mononuclear cells. CFU-GM proliferation of human bone marrow cluster of differentiation (CD) 34+CD14-cells were not affected by the presence of endotoxin. These data suggest that LPS at 2-5 pg/ml may induce bone marrow accessory cell release of hematopoietic growth factors, thus altering proliferative response of hematopoietic precursors and confounding the study of exogenously added cytokines to culture systems.

Evaluation of cisplatin, carboplatin, and etoposide in metastatic nonsmall cell lung carcinoma. A phase II study of the Southwest Oncology Group.

BACKGROUND: The combined use of cisplatin and carboplatin chemotherapy offers a unique means of platinum dose intensification. Response rates using either of these agents in combination with etoposide are comparable. In a Phase II trial, the authors investigated the combination of cisplatin and carboplatin with etoposide for the treatment of patients with advanced nonsmall cell lung carcinoma. METHODS: Eligible patients were chemotherapy naive and had histologically confirmed, evaluable, or measurable selected Stage IIIB and Stage IV nonsmall cell lung carcinoma. Based upon the results of an earlier Phase I and II pilot study, patients received carboplatin, 225 mg/m2, on Day 1; cisplatin, 50 mg/m2, on Days 2 and 3; and etoposide, 75 mg/m2, on Days 1, 2, and 3 every-4-weeks. RESULTS: Eighty-three patients (75 eligible patients) received chemotherapy with cisplatin, carboplatin, and etoposide. Two patients refused therapy after registration and were not analyzable. Thirty-six of the remaining 75 patients had Grade 4 toxicities, mostly hematologic, and 6 patients died of toxicity. The confirmed response rate was 24% (95% confidence interval, 15-35%). Median progression-free survival was 4 months and the median survival was 8 months. CONCLUSIONS: Combination cisplatin, carboplatin, and etoposide chemotherapy appears to be no better than cisplatin/etoposide or carboplatin/etoposide for the treatment of patients with nonsmall cell lung carcinoma. The toxicity of this regimen may be higher, and therefore it cannot be recommended for general use.

Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study.

PURPOSE: To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS: Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS: At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION: Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.

Phase II trial of dimethyltriazenoimidazole carboxamide in patients with metastatic carcinoid. A Southwest Oncology Group study.

BACKGROUND: The use of chemotherapy in patients with metastatic carcinoid tumors has been of limited value, and investigation of new agents is necessary. Previous reports have suggested that dimethyltriazenoimidazole carboxamide (DTIC) may have antitumor activity. METHODS: A Phase II trial to investigate the clinical response rate to DTIC in patients with metastatic carcinoid tumors was performed. DTIC was administered at low (650 mg/m2) or high (850 mg/m2) doses every 28 days. RESULTS: Sixty-three patients were entered into the study, and 56 were evaluable for toxicity and response. Toxicity was moderate, with the most common side effect being nausea and vomiting (88%). Nine patients (16%; 95% confidence interval, 8-28%) had partial responses, 5 of 25 receiving 850 mg/m2 and 4 of 31 receiving 650 mg/m2 of DTIC. Median survival time of all patients was 20 months. CONCLUSIONS: DTIC has minimal activity in patients with metastatic carcinoid tumors.

GM-CSF, carboplatin, doxorubicin: a phase I study.

Dose intensification has the potential to increase the response frequency of chemosensitive tumors to chemotherapy. G-CSF and GM-CSF offer the possibility of dose-intensifying chemotherapy without prohibitive myelosuppression. A phase I study was undertaken to identify the maximum tolerated dose (MTD) of carboplatin that could be administered with a fixed dose of doxorubicin, 60 mg/m2, administered every 28 days. Further escalation of the carboplatin dose was then attempted, with the concomitant addition of GM-CSF 10 mg/kg per day on days 1-21. We had 21 patients, 13 with prior therapy, who were eligible. In all, 60 courses of therapy were delivered, all with doxorubicin and with carboplatin doses of 250 mg/m2, 325 mg/m2 and 400 mg/m2. At carboplatin 400 mg/m2 and doxorubicin 60 mg/m2, thrombocytopenia was dose limiting. The addition of GM-CSF did not allow further escalation. Of the 6 patients treated with carboplatin 400 mg/m2, doxorubicin 60 mg/m2, and GM-CSF, grade 4 granulocytopenia and thrombocytopenia were seen in 4 and 5 patients, respectively. The severity of thrombocytopenia was related to the calculated carboplatin AUC and also to baseline platelet count and prior therapy. In addition, the interaction of GM-CSF and chemotherapy, especially carboplatin-based, may be more complex than originally anticipated.

Aci-reductones enhance interleukin-2-induced lymphocyte cytotoxicity.

Arachidonic acid (AA) metabolites and reactive oxygen species (ROS) are implicated in the suppression of interleukin-2 (IL-2) activity. We investigated the effects of aci-reductones, compounds that function both as inhibitors of AA metabolism and as scavengers of ROS, on the generation of IL-2-induced, lymphokine activated killer (LAK) activity. Aci-reductones belonging to the 4-aryl-2-hydroxytetronic acid system improved the in vitro generation of LAK activity from IL-2-treated human peripheral blood mononuclear cells (PBMC) approximately 4-fold. Those aci-reductones belonging to the 3,4-dihydroxyhenzofuranone class were less effective. LAK activity improvement was comparable to that produced by indomethacin with superoxide dismutase plus catalase and comparable to the improvement produced by depleting PBMC of monocytes. Aci-reductones completely suppressed the production of prostaglandin E2 from PBMC in response to IL-2 and partially suppressed superoxide anion production. Daudi cell and lymphocyte subset proliferation and monocyte viability were not affected. Less improvement in LAK activation was observed when PBMC depleted of monocytes were exposed to IL-2 and aci-reductones. We conclude that aci-reductones improve LAK generation from PBMC in vitro. This property may be mediated via effects on monocyte AA and ROS metabolism.

Lack of significant changes in nutrition-related parameters with tumor necrosis factor treatment of cancer.

Cancer and its therapies frequently produce anorexia and cachexia. In this study, the acute (3 days) and chronic (4 wks) nutrition-related effects of cancer therapy with recombinant human tumor necrosis factor (rHuTNF) were investigated and described. Nutritional status, as measured by body weight and body composition (body fat and lean-to-fat ratio) with use of bioelectrical impedance, did not appear to deteriorate. None of the serum lipids changed significantly, but triglycerides did rise modestly over four weeks of therapy. Glucose and the peptide hormones (insulin, C-peptide, glucagon, and pancreatic polypeptide) thought to affect appetite did not change with rHuTNF therapy. Therefore, although TNF is thought to contribute to wasting in animal models, it had no negative effect on nutritional status in our small sample. The lack of adverse effect noted in this study is possibly due to the low dose level of rHuTNF or to adaptation.

Modulation of leukemic cell sensitivity to lymphokine-activated killer cytolysis: role of intercellular adhesion molecule-1.

The role of CD11/CD18 leukocyte adhesion molecules and their ligands in mediating non-major histocompatibility complex (MHC) restricted lymphocyte cytotoxicity is controversial. In order to examine the role of target cell intercellular adhesion molecule-1 (ICAM-1; CD54), a ligand of lymphocyte function-associated antigen (LFA-1) (CD11a/CD18), we exposed the human leukemia cell line, HL-60, to a variety of agents implicated in modulating ICAM-1 expression and/or sensitivity to lymphocyte cytolysis. Exposure of HL-60 cells to retinoic acid (RA), interferon (IFN)-alpha, IFN-beta, and IFN-gamma induced protection from lymphokine-activated killer (LAK) cytolysis. Only RA and IFN-gamma induced ICAM-1 expression. Tumor necrosis factor and vitamin D3, which also induced ICAM-1 expression, increased HL-60 sensitivity to LAK lysis. Granulocyte-macrophage colony-stimulating factor also increased sensitivity to LAK lysis; ICAM-1 was not induced. The state of cellular differentiation and expression of class I and II MHC antigens also did not correlate with sensitivity to LAK cytolysis. Exposure of untreated HL-60 cells and HL-60 cells expressing ICAM-1 to monoclonal antibody (mAb) versus ICAM-1 did not modulate LAK sensitivity. Exposure of LAK cells to mAb versus LFA-1 partially inhibited cytolysis; mAb versus CD18 inhibited cytolysis more completely. HL-60 cells were resistant to natural killer lysis; exposure to the various experimental agents did not alter sensitivity. We conclude that leukemic cell sensitivity to LAK cytolysis can be modulated by a variety of agents. Although our results suggest a role for leukocyte CD11/CD18 adhesion molecules in LAK cytolysis, the poor correlation between ICAM-1 expression and sensitivity to LAK lysis suggest that interactions other than LFA-1/ICAM-1 conjugation may be more central to the processes involved.

Modulation of hematologic and immunologic effects of high dose chemotherapy by interleukin-2 in a murine tumor model.

To determine if intensive chemotherapy consisting of cyclophosphamide (C), etoposide (E), and cisplatin (P) (CEP) may be usefully combined with recombinant human interleukin-2 (rhIL-2), we examined a murine tumor model designed to approximate a common clinical situation: macroscopic, drug-resistant cancer. Using C57BL/6 mice with extensive tumor burden 10 days after intravenous B16 melanoma cell injection, we observed (1) C, E, and P synergize to enhance survival but do not cure mice at the highest tolerable dose (C = 200 mg/kg, E = 60 mg/kg, and P = 3 mg/kg); (2) rhIL-2 at 3 x 10(5) U (subcutaneously) daily for 4 days administered 10-18 days after B16 injection significantly improves survival; (3) CEP plus rhIL-2 is more effective than CEP alone only when rhIL-2 is administered before CEP; (4) CEP suppresses IL-2-induced lymphokine-activated killer cell activity in the spleen; and (5) rhIL-2 protects mice incompletely from the immunologic and hematologic suppression of CEP. Our results suggest that intensive chemotherapy combined with rhIL-2 may be beneficial. The success of any such combination may be schedule dependent.

A Southwest Oncology Group Phase I study of the sequential combination of recombinant interferon-gamma and recombinant interleukin-2 in patients with cancer.

Thirty-seven patients with advanced malignancies were treated sequentially with recombinant interferon-gamma (rIFN-gamma) and recombinant interleukin-2 (rIL-2) in an outpatient dose escalation clinical trial. rIFN-gamma (0.1 or 0.25 mg/m2/day) was administered by intramuscular injection, days 1-7 and rIL-2 (12, 18, or 24 x 10(6) IU/m2/day) was administered by a 15-min intravenous bolus, days 8-12. Common toxicities encountered included fever, chills, fatigue, neutropenia, and elevations of SGOT, bilirubin, or creatinine. Hypotension and cardiac and pulmonary toxicities were rare. With repeated cycles of therapy, nausea/vomiting and diarrhea associated with the administration of rIL-2 were seen in greater frequency. There were no treatment-related deaths, and no patient required intensive care unit admission for toxicity management. A complete response was observed in one of 11 patients with renal cancer and a partial response was observed in one of seven patients with malignant melanoma. Due to problems with drug supply, further dose escalation could not be continued, and maximum tolerated doses (MTD) were not determined by strict criteria. However, the combination of rIFN-gamma, 0.25 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day, appeared to be beyond the MTD, as three of six patients at this dose level could not complete one cycle of therapy due to toxicity. It is unlikely that higher doses of either agent would be tolerated, and for further study using this schedule, we recommend the doses: rIFN-gamma, 0.1 mg/m2/day, and rIL-2, 24 x 10(6) IU/m2/day.

Modulation of adhesion molecules on human large granular lymphocytes by interleukin-2 in vivo and in vitro.

The modulation of adhesion molecules on human large granular lymphocytes (LGL) by interleukin (IL)-2 was investigated both in vivo and in vitro. Intercellular adhesion molecule-1 (ICAM-1; CD54) expression increased on LGL of cancer patients receiving IL-2 adoptive immunotherapy. ICAM-1 expression on LGL isolated by Percoll gradient centrifugation, LGL purified, and expanded by adherence to plastic surfaces and LGL identified by Leu 19 (CD56) monoclonal antibody were increased significantly in response to IL-2 in vitro. Exposure of LGL to IL-1, interferon (IFN)-gamma, and tumor necrosis factor (TNF) in vitro did not induce ICAM-1. The expression of LFA-1 (CD11a/CD18), a receptor for ICAM-1, and other leukocyte adhesion molecules, including Mac-1 (CD11b/CD18) and p150,95 (CD11c/CD18), was only maintained by IL-2. IL-2 induction of ICAM-1 and the maintenance of CD18 complex expression on small lymphocytes separated by Percoll gradients were similar to that on LGL. We conclude that IL-2 enhances the expression of ICAM-1 on multiple human lymphocyte populations including LGL effectors. Expression of the CD18 complex on LGL does not appear to be highly regulated by IL-2. These findings may have implications relevant to the role of these adhesion molecules in the activities of LGL modulated by IL-2.

Phase II studies of recombinant human tumor necrosis factor alpha in patients with malignant disease: a summary of the Southwest Oncology Group experience.

From June 1988 to November 1990 the Southwest Oncology Group initiated nine protocols for the phase II evaluation of recombinant human tumor necrosis factor alpha (rhuTNF alpha) in cancer patients. Patients with diverse metastatic malignancies including breast, colon, gastric, pancreatic, endometrial, and bladder cancers, as well as multiple myeloma and various sarcomas received 150 micrograms/m2 of rhuTNF alpha daily for 5 days every other week. Of 147 patients entered in the study, 127 were eligible and were evaluated for toxicity and response. Of 124 patients known to have completed treatment, 92 (74%) went off study for progression, 21 (17%) for toxicity, and 12 (10%) for other causes, mainly that of worsening medical condition. Thirteen percent of patients experienced grade 4 or fatal toxicity. The most serious toxicities were pulmonary failure and coagulopathies. The predominant grade 3 toxicities were symptomatic (chills, fever, malaise, headache, myalgia, and nausea or vomiting). Only one partial remission was seen in a patient with metastatic bladder cancer lasting 4 months (rate 0.8%, exact 95% confidence interval 0-4%). At the study dose and schedule, rhuTNF alpha does not appear to have significant antitumor activity. The biological basis for this finding is discussed.