A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice.

Interleukin 1 (IL-1) is an endogenously produced cytokine that mediates a variety of physiological effects that may be beneficial or deleterious to the host. C57Bl/6 mice treated intravenously with a recently characterized human recombinant receptor antagonist protein to IL-1 (IL-1ra) had improved survival when treated after a lethal Escherichia coli endotoxin (lipopolysaccharide [LPS]) challenge. IL-1ra was effective when treatment was initiated after LPS, and intravenous administration every 4 h for 24 h was required. Serum levels of tumor necrosis factor (TNF) activity after LPS and in vitro TNF cytotoxicity were not altered by treatment with IL-1ra. These experiments provide direct evidence that the lethal effects of LPS may be mediated through the action of IL-1 and that the IL-1ra can provide a new treatment strategy for disease processes mediated via this cytokine.

Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor.

Differentiation factor (D factor), also called leukemia inhibitory factor (LIF), is a glycoprotein that has been increasingly recognized to possess a wide range of physiological activities. We examined the possibility that the administration of D factor may confer beneficial effects and enhance host resistance against lethal endotoxemia. A single intravenous dose of recombinant human D factor completely protected C57/Bl6 mice from the lethal effect of Escherichia coli endotoxin (lipopolysaccharide [LPS]). The protective effects were dose dependent and observed when administered 2-24 h before LPS. Previous work has shown that interleukin 1 (IL-1) and tumor necrosis factor (TNF) also protect against a subsequent LPS challenge in a dose-dependent manner. When human D factor was combined with sub-protective doses of IL-1 beta or TNF-alpha, there was dramatic synergistic protection against a subsequent lethal LPS challenge.

Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals.

Infection with HIV results in an incremental loss of T helper cell (TH) function, which can occur years before CD4 cell numbers are critically reduced and AIDS is diagnosed. All TH function is not affected, however, because B cell activation and hypergammaglobulinema are also characteristic of this period. Recently, in a murine model of AIDS an early loss in production of the CD4 cytokines IL-2 and IFN-gamma was correlated with an increase in the B cell stimulatory cytokines IL-4, IL-5, and IL-10. We therefore assessed the production of IL-4 generated by PBL from HIV-seropositive (HIV+) individuals who did not have AIDS, yet who exhibited different TH functional categories based on their IL-2 production profiles. We observed that the decreases in recall antigen-stimulated IL-2 production were accompanied by an increase in IL-4 production. The loss of recall antigen-stimulated responses in HIV+ individuals could be reversed in vitro by anti-IL-4 antibody. Our results suggest that the TH functions assessed by IL-4 production replace the normally dominant TH function of antigen-stimulated IL-2 production in the progression toward AIDS, and raise the possibility of cytokine cross-regulation in AIDS therapy.

Host defense molecule polymorphisms influence the risk for immune-mediated complications in chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of phagocyte function in which defective superoxide production results in deficient microbicidal activity. CGD patients suffer from recurrent, life-threatening infections, and nearly half develop chronic gastrointestinal (GI) complications (colitis, gastric outlet obstruction, or perirectal abscess) and/or autoimmune/rheumatologic disorders (AIDs). To identify genetic modifiers of disease severity, we studied a cohort of 129 CGD patients, in whom seven candidate genes (myeloperoxidase [MPO], mannose binding lectin [MBL], Fcgamma receptors IIa, IIIa, IIIb, TNF-alpha, and IL-1 receptor antagonist), each containing a physiologically relevant polymorphism predicted to influence the host inflammatory response, were selected for analysis. Genotypes of MPO (P = 0.003) and FcgammaRIIIb (P = 0.007) were strongly associated with an increased risk for GI complications, while an FcgammaRIIa (P = 0.05) genotype was suggestive for an association. Patients with all three associated genotypes had the highest risk for GI complications (P < 0.0001). The risk of AIDs was strongly associated with variant alleles of MBL (P = 0.01) and weakly associated with an FcgammaRIIa genotype (P = 0.04). Patients with variant forms of both MBL and FcgammaRIIa had the highest risk of developing an AID (P = 0.003).

HIV infection--induced posttranslational modification of T cell signaling molecules associated with disease progression.

In attempt to elucidate the mechanism of the HIV infection induced T cell unresponsiveness, we studied signal-transducing molecules proximal to the T cell receptor (TCR) in T lymphocytes of HIV-infected individuals. Total amounts of protein tyrosine kinases (PTKs) Lck, Fyn, and ZAP-70 and the zeta chain of the TCR were found significantly decreased in T cells of symptomatic/AIDS patients as well as in T cells of individuals in acute and early asymptomatic stages of HIV infection. Unexpectedly, the detection of Lck, Fyn, and ZAP-70 was reversed after the treatment of cell lysates with dithiothreitol. This suggests that PTKs Lck, Fyn, and ZAP-70 were modified by a mechanism altering the status of sulfhydryl groups. Moreover, this mechanism seems to affect selectively T cells of HIV infected patients since B cell PTKs Syk and Lyn were detected structurally and functionally intact. Interestingly, similar alterations of signaling molecules were not detected in T cells of HIV-infected long-term asymptomatic individuals. Modification of T cell PTKs may thus underlie the HIV-induced impairment of lymphocyte function and may potentially predict disease progression.

Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection.

BACKGROUND: Genital infection with certain strains of human papillomavirus (HPV) is associated with a high risk of malignant transformation, and HPV-associated cervical intraepithelial neoplasia (CIN) can become invasive cancer. Host factors are critical in regulating tumor growth, and cytokines that modulate immunologic control may be of particular importance. The type 1 cytokines interleukin 2 (IL-2) and interferon gamma (IFN gamma) are immunostimulatory and are thus capable of limiting tumor growth. The type 2 cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are immunoinhibitory and are thus capable of stimulating tumor growth. PURPOSE: We analyzed the production of cytokines by peripheral blood mononuclear cells (PBMCs) in women with CIN associated with localized or extensively spread HPV infection. METHODS: Thirty women diagnosed with CIN and 10 age- and sex-matched healthy control subjects were enrolled in the study conducted at Istituto Nazionale Tumori, Milan, Italy. The following parameters were analyzed: 1) HPV infection of the cervix and other sites of the lower genital tract by colposcopic, cytologic, and histologic examinations; 2) HPV typing; 3) in vitro production of IL-2 by PBMCs in response to stimulation with soluble antigen (influenza [FLU] antigen) or to cell-associated human leukocyte antigen (HLA) alloantigen; and 4) in vitro production of the type 1 cytokines IL-2 and IFN gamma and of the type 2 cytokines IL-4 and IL-10 by PBMCs in response to mitogen stimulation. Statistical significance was determined by nonparametric tests (two-sided). RESULTS: High-grade CIN associated with HPV infection was detected in all case patients, and HPV type 16 or 18 infection was detected in cervical tissue of 21 (70%) of 30 case patients. HPV infection that had spread to other sites of the lower genital tract, thus resulting in more extensive disease, was detected in 16 (53%) of the 30 individuals with CIN, whereas HPV infection was limited to the portio in 14 (47%). IL-2 production by PBMCs in response to stimulation with soluble antigen or HLA alloantigen was reduced in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. In contrast, IL-4 and IL-10 production in response to mitogen stimulation was elevated in the group with extensive disease compared with that in the group with localized disease or with that in healthy control subjects. The highest production of IL-4 and IL-10 was detected in patients with HPV infection that had extended beyond the genital tract. CONCLUSIONS: CIN is characterized by different immunologic profiles, in which HPV infection is or is not confined to the portio. Production of cytokines that mainly enhance potentially protective cell-mediated immunity is defective in the women in whom extended HPV infection was observed. A pronounced shift from type 1 to type 2 cytokine production is associated with more extensive HPV infection. IMPLICATIONS: These data reinforce the need for detailed analyses of immune dysregulation in CIN patients. They also suggest the potential usefulness of the cytokine assays for determining prognosis or deciding whether cytokine-based therapy is indicated.

Lack of in vitro synergy between etoposide and cis-diamminedichloroplatinum(II).

Claims of synergy between etoposide and cisplatin have been based upon preclinical in vivo murine P388 models or upon human clinical trials in tumors such as lung cancer. Such in vivo studies are useful in exploring therapeutic synergy, i.e., an improved therapeutic strategy. The term "synergy" in this context is sometimes, however, taken to imply greater than additive kill of tumor cells. Unfortunately, it is virtually impossible to document supra-additive tumor cell kill in vivo, since in vivo curves of therapeutic effect are not linear and drugs are therefore not additive with themselves. Therapeutic synergy may, in fact, occur when two drugs are merely additive (or even antagonistic) with regard to cytotoxicity if the drugs have nonoverlapping host toxicity. The demonstration of true supra-additive cell kill would imply an interaction of the two agents at a cellular level and would have profound implications for biochemical studies. In order to determine whether the reported therapeutic synergy of etoposide and cisplatin is due, in part, to supra-additive cell kill, we used an in vitro tetrazolium-based colorimetric assay for cytotoxicity (MTT assay) and an isobologram analysis to test combinations of the two drugs against four human small cell and four human non-small cell lung carcinoma lines. Using a rigorous test for in vitro synergy, we could not establish a greater than additive cytotoxic effect on our cell lines. It thus appears that the clinical synergy between etoposide and cisplatin is not due to a supra-additive effect at the cellular level. Our results have implications for a variety of fields in which claims of "synergy" often appear.

Increased level of stromal cell-derived factor-1 mRNA in peripheral blood mononuclear cells from children with AIDS-related lymphoma.

A common polymorphism in the 3' untranslated region of the stromal cell-derived factor 1 (also called pre-B-cell-stimulating factor) beta gene transcript, termed SDF1-3'A, has been associated with an increased risk of non-Hodgkin's lymphoma (NHL) in HIV-1-infected, but not in uninfected, individuals. Because the gene variation is located within the 3' untranslated region, the SDF1-3'A may influence the abundance of SDF-1 mRNA, possibly up-regulating the chemokine expression especially in the presence of HIV-1. In the current study, we investigated the levels of SDF-1 mRNA in peripheral blood mononuclear cells and HIV-1 viral load in 84 HIV-1-infected children (0.7 to 18 years of age; median, 5.8), including 12 children who developed NHL during their illnesses (AIDS-NHL group; 8 with SDF1-3'A, 4 with SDF1-wild-type). High level SDF-1 expression was observed in 15 of 34 children with SDF1-3'A as compared with 10 of 50 with wild type (P < 0.03). More notably, the children with AIDS-NHL had significantly elevated levels of SDF-1 mRNA in peripheral blood mononuclear cells, obtained at the time of presentation in 10 children and 8.5 to 19.4 months before (median, 15 months) in 7 children, as compared with the children in the non-NHL group (P < 0.00001). The amounts of cell-associated HIV-1 DNA and singly spliced HIV-1 mRNA were significantly greater in children with AIDS-NHL than those with non-NHL AIDS (P = 0.0052 and 0.011, respectively; stratified by antiretroviral treatment regimen), whereas their serum HIV-1 RNA levels were comparable. Overexpression of SDF-1 and aberrant HIV-1 expression in circulating lymphocytes appear to be linked to the development of AIDS-lymphoma. Additional studies are required to determine whether excessive SDF-1, together with virally encoded factors, is directly involved in the pathogenesis of AIDS-lymphoma.

A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer.

Phenylacetate has recently been shown to suppress tumor growth and promote differentiation in experimental models. A phase I trial of phenylacetate was conducted in 17 patients with advanced solid tumors. Each patient received a single i.v. bolus dose followed by a 14-day continuous i.v. infusion of the drug. Twenty-one cycles of therapy were administered at four dose levels, achieved by increasing the rate of the continuous i.v. infusion. Phenylacetate displayed nonlinear pharmacokinetics [Km = 105.1 +/- 44.5 (SD) microgram/ml, Vmax = 24.1 +/- 5.2 mg/kg/h and Vd = 19.2 +/- 3.3 L]. There was also evidence for induction of drug clearance. Ninety-nine % of phenylacetate elimination was accounted for by conversion to phenylacetylglutamine, which was excreted in the urine. Continuous i.v. infusion rates resulting in serum phenylacetate concentrations exceeding Km often resulted in rapid drug accumulation and dose-limiting toxicity, which consisted of reversible central nervous system depression, preceded by emesis. Three of nine patients with metastatic, hormone-refractory prostate cancer maintained stable prostatic specific antigen levels for more than 2 months; another had less bone pain. One of six patients with glioblastoma multiforme, whose steroid dosage has remained unchanged for the duration of therapy, has sustained functional improvement for more than 9 months. The use of adaptive control with feedback for the dosing of each patient enabled us to safely maintain stable phenylacetate concentrations up to the range of 200-300 micrograms/ml, which resulted in clinical improvement in some patients with advanced disease.

Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas.

Gastrinomas and insulinomas are frequent in multiple endocrine neoplasia type 1 (MEN1). The MEN1 tumor suppressor gene was recently identified. To elucidate the etiological role of the MEN1 gene in sporadic enteropancreatic endocrine tumorigenesis, we analyzed tumors (28 gastrinomas and 12 insulinomas) from 40 patients for MEN1 gene mutations and allelic deletions. One copy of the MEN1 gene was found to be deleted in 25 of 27 (93%) sporadic gastrinomas and in 6 of 12 (50%) sporadic insulinomas. MEN1 gene mutations were identified in 9 of 27 (33%) sporadic gastrinomas and 2 of 12 (17%) insulinomas and were not seen in corresponding germ-line DNA sequence. A specific MEN1 mutation was detected in one gastrinoma and in the corresponding germ-line DNA of a patient who had no family history of MEN1. Somatic MEN1 gene mutations and deletions play a critical role in the tumorigenesis of sporadic gastrinomas and may also contribute to the development of a subgroup of insulinomas.

Prognostic value of initial fasting serum gastrin levels in patients with Zollinger-Ellison syndrome.

PURPOSE: To assess the value of the initial fasting serum gastrin (FSG) at presentation in patients with Zollinger-Ellison Syndrome (ZES) in predicting primary tumor characteristics and survival. PATIENTS AND METHODS: A total of 239 patients were treated for ZES between December 1981 and September 1998, with a mean follow-up of 9.1 +/- 0.6 years. At initial evaluation, 86 patients (36%) had mild (0 to 499 pg/mL), 61 (25.5%) had moderate (500 to 1,000 pg/mL), and 92 (38.5%) had severe (> 1,000 pg/mL) elevations in FSG. Primary tumor location and size, presence of lymph node or hepatic metastases, and survival were analyzed based on the level of initial FSG. RESULTS: In patients with sporadic ZES, but not in those with multiple endocrine neoplasia type 1 (MEN-1) and ZES, there was a significant relationship between the level of initial FSG and tumor size and location of primary tumor, frequency of lymph node and liver metastases, and survival. The median 5- and 10-year survival decreased with increasing initial FSG (P <.001) in patients with sporadic ZES; MEN-1 patients lived longer than sporadic ZES patients (P =.012), and survival in this group was not associated with the level of initial FSG. Multivariate analysis showed that factors independently associated with death from disease in patients with sporadic ZES were liver metastases (P =.0001), a pancreatic site (P =.0027), and primary tumor size (P =.011) but not initial FSG (P >.30). CONCLUSION: The severity of FSG at presentation is associated with size and site of tumor and the presence of hepatic metastases, factors that are significant independent predictors of outcome. The level of FSG at presentation may be useful in planning the nature and extent of the initial evaluation and management in patients with sporadic ZES.

Parameters affecting the development of non-Hodgkin's lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy.

PURPOSE: To investigate the occurrence of non-Hodgkin's lymphoma (NHL) in human immunodeficiency virus (HIV)-infected patients receiving long-term antiretroviral therapy and factors associated with the development of these lymphomas. PATIENTS AND METHODS: The charts of 55 patients with advanced HIV infection receiving zidovudine (formerly known as azidothymidine [AZT])-based therapy and 61 patients receiving dideoxyinosine (ddI) were examined for the occurrence of NHL. Stored samples from the AZT-based treatment cohort were examined retrospectively for parameters predictive of the subsequent development of lymphoma. RESULTS: Eight of 55 patients receiving AZT-based therapy developed NHL, yielding an estimated probability of 12% (95% confidence interval [CI], 4.7% to 27.1%) after 24 months, and 29.2% (95% CI, 15.2% to 48.7%) after 36 months. Four of 61 patients receiving ddI developed NHL, yielding a 6.2% (95% CI, 2.1% to 17%) estimated probability after 24 months, and 9.5% (95% CI, 3.6% to 22.8%) after 36 months. The difference between these cohorts was not significant (two-tailed P [P2] = .13). Patients with less than 50 CD4 cells/microL developed NHL at a significantly higher rate (P2 = .0085). This was particularly true for patients who presented with primary CNS lymphoma (PCNSL). For patients receiving AZT-based therapy, pretreatment serum interleukin-6 (IL-6) levels were somewhat higher in those who subsequently developed NHL than in those who did not (P2 = .048). CONCLUSION: HIV-infected patients with profound immunodeficiency, especially those with less than 50 CD4 cells/microL, are at substantial risk of developing NHL and particularly PCNSL. Additional studies are needed to define the role of other factors such as IL-6 in the pathogenesis of these opportunistic tumors.

Growth of newly diagnosed, untreated metastatic gastrinomas and predictors of growth patterns.

PURPOSE: The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors. PATIENTS AND METHODS: Nineteen patients with histologically proven metastatic gastrinoma in the liver with Zollinger-Ellison syndrome were studied. Conventional imaging studies were performed initially and at 4- to 6-month intervals before any treatment. Metastases growth rates were calculated and correlated with laboratory and clinical parameters, as well as tumor extent on initial tumor assessment. RESULTS: Twenty-six percent of patients (five of 19) demonstrated no growth over a mean follow-up time of 29 months, 32% (six of 19) had slow growth (1% to 50% increase in volume per month) over a 19-month period, and 42% (eight of 19) had rapid growth (> 50% volume increase per month) over an 11-month period. In patients with rapid growth, 62% died; 0% of the no-growth or slow-growth group died. No clinical or laboratory parameter correlated with growth rate, except the rate increase in fasting serum gastrin and the presence of bilobar liver or bone metastases. The growth rate was highly predictive of death from tumor. CONCLUSION: The growth rate of metastatic gastrinoma varies markedly in different patients and 26% demonstrate no growth. The growth rate needs to considered in the determination of when and in whom antitumor therapy is initiated, as well as in the assessment of response to tumoricidal therapies.

Prospective study of the clinical course, prognostic factors, causes of death, and survival in patients with long-standing Zollinger-Ellison syndrome.

PURPOSE: The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone state is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. PATIENTS AND METHODS: Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8+/-0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushing's syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. RESULTS: Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushing's syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushing's syndrome markedly decreased survival rate. CONCLUSIONS: In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushing's syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches.

Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and magnetic resonance image in their detection, frequency, location, and effect of their detection on management.

PURPOSE: To determine whether bone scan, magnetic resonance imaging (MRI), or somatostatin receptor scintigraphy (SRS) is best for identifying bone metastases in patients with gastrinomas, as well as their frequency and location, whether their detection affects management, and what patient subgroups should be examined. MATERIALS AND METHODS: One hundred fifteen patients with gastrinoma were prospectively studied. Patients were examined yearly and those with liver metastases were reexamined every 3 months. Based on clinical history, histology, growth pattern, and development of new bone lesions, possible bone metastases were classified as to whether they were or were not bone metastases. Imaging results were correlated at different times in the disease course and with disease extent. RESULTS: Bone scan was positive in 52 patients, MRI in seven, and SRS in six. Eight patients (7%) were determined to have bone metastases and MRI was correctly positive in seven, SRS in six, and bone scan in five. SRS or MRI was positive in all patients with bone metastases. Bone scan had significantly lower specificity and sensitivity, and a higher rate (P < .02) of false-negative results than MRI or SRS. Bone metastases occurred in 31% of patients with liver metastases and 0% with only lymph node metastases. The initial bone metastases were in the spine or sacrum (75%) followed in descending order by the pelvis or sacroiliac joints (38%), scapula or shoulder, and ribs. In all cases, detection of bone metastases changed the management. CONCLUSION: SRS and MRI, because of high sensitivity and specificity, are recommended over bone scanning to screen for bone metastases in patients with gastrinomas. However, because bone metastases can occur initially outside the axial skeleton, SRS is the recommended initial localization method of choice. Bone metastases occur in 7% of all patients and 31% of patients with liver metastases, only occur in patients with liver metastases, are usually in the axial skeleton initially, and their detection changes management in all cases. Patients with pancreatic endocrine tumors with liver metastases should undergo SRS every 6 months to 1 year to detect bone metastases.

Risk of second aerodigestive cancers increases in patients who survive free of small-cell lung cancer for more than 2 years.

PURPOSE: Patients who survived small-cell lung cancer (SCLC) for more than 2 years were evaluated to determine the frequency and anatomic pattern of redevelopment of small-cell cancer and development of non-small-cell lung cancer (NSCLC) and aerodigestive cancers with the passage of time. PATIENTS AND METHODS: From April 1973 through December 1991, 578 patients with previously untreated SCLC were entered onto prospective therapeutic trials at the National Cancer Institute (NCI), Bethesda, MD. Sixty-two (11%) were cancer-free 2 years after initiation of therapy and were assessable for redevelopment of SCLC and development of NSCLC, and aerodigestive cancers. RESULTS: Twenty patients redeveloped SCLC 2.0 to 12.2 years after initiation of chemotherapy, of whom two patients were deemed to have a second primary small-cell cancer that involved the aerodigestive tract. Fifteen patients developed 16 cancers in the lung other than SCLC 3.4 to 14.9 years after initiation of therapy. Two developed other aerodigestive cancers that involved the larynx and lip. The risk of a NSCLC and aerodigestive cancer in these patients increased more than sixfold from 2% per patient per year during years 2 to 4 to 12.6% and 14.4%, respectively, after more than 10 years. The cumulative actuarial risk of a second primary NSCLC or aerodigestive cancer at 16 years is 69% and 72%, respectively. CONCLUSION: The increasing risk of second aerodigestive cancers with the passage of time is a mounting problem for patients cured of SCLC. Chemoprevention trials for these patients should be considered.

Pharmacologic variables associated with the development of neurologic toxicity in patients treated with suramin.

PURPOSE: To describe pharmacologic variables correlated with the development of neurologic toxicity in patients treated with suramin. METHODS: Eighty-one patients were treated with suramin in a phase I study. The rate of drug infusion was continuously adjusted to maintain a preassigned plasma suramin concentration (175, 215, or 275 micrograms/mL) for a fixed duration (2 to 8 weeks). RESULTS: Eight patients developed grade III/IV neurologic motor impairment (predominantly motor axonal polyneuropathy). All were treated at the 275-micrograms/mL concentration. One patient treated at the 215-micrograms/mL concentration developed grade II motor dysfunction. In addition, seven of nine patients had sensory symptoms. Pharmacologic variables associated with the development of polyneuropathy included total cumulative suramin dose, duration of exposure to plasma concentrations greater than 200 micrograms/mL, and area under the curve (AUC) greater than 200 micrograms/mL. CONCLUSION: Significant neurologic toxicity can result from therapy with suramin, even when dosing is designed to avoid exposure to plasma concentrations greater than 350 micrograms/mL. Future clinical trials of suramin should be designed in such a way as to limit the total cumulative dose to < or = 157 mg/kg given over a period of > or = 8 weeks, limit the period of exposure to plasma suramin concentrations greater than 200 micrograms/mL to < or = 25 days, and limit the AUC greater than 200 micrograms/mL to < or = 48,000 mg.h/AL.

Severe atypical neuropathy associated with administration of hematopoietic colony-stimulating factors and vincristine.

PURPOSE: We have observed a severe atypical neuropathy (SAN) in patients with small non-cleaved-cell (SNCL) and large-cell lymphoma (LCL) treated with intensive chemotherapy and hematopoietic colony-stimulating factors (CSFs). The present analysis was undertaken in an attempt to identify factors associated with the development of this syndrome. PATIENTS AND METHODS: Fifty-four adult and pediatric patients consecutively treated according to the same chemotherapy protocol were included in the analysis. Low-risk patients received three cycles of cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate (CODOX-M) while in high-risk patients this drug combination was alternated with high-dose cytarabine (ara-C), etoposide, and ifosfamide (IVAC) for a total of four cycles. Twenty-eight patients received a CSF (granulocyte [G]- or granulocyte-macrophage [GM]-CSF), and 26 patients received no CSF. A statistical analysis, which included a logistic regression model, was undertaken to examine the importance of potential contributing factors to the development of SAN. RESULTS: SAN, which consisted of excruciating foot pain, usually associated with marked motor weakness, was observed in 12 patients. There was a highly significant association between the occurrence of this syndrome and the administration of CSFs, and an independent association with the cumulative dose of vincristine given in the first cycle of chemotherapy. Furthermore, the analysis suggested a synergistic effect between administration of the CSFs and vincristine in the genesis of this neuropathy. CONCLUSION: Our results indicate that CSFs can precipitate SAN when given in conjunction with vincristine. The development of SAN was associated most strongly with the cumulative dose of vincristine -- the size of individual doses and the number of doses given in cycle 1 were important to the extent that they influenced the cumulative dose.

Phase I clinical trial of alitretinoin and tamoxifen in breast cancer patients: toxicity, pharmacokinetic, and biomarker evaluations.

PURPOSE: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored. PATIENTS AND METHODS: Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy. RESULTS: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor-positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained. CONCLUSION: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.

Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.

PURPOSE: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS: The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION: r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.