PubMed Health⌕ Search

Biomedical subjects

C J Logothetis

Publications and source records attributed to C J Logothetis.

At least 19 recordsLinked to original sources
PubMed1995

NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension.

OBJECTIVE: To evaluate the role of NG-methyl-L-arginine as a modulator of the hyperdynamic shock induced by the administration of interleukin-2 (IL-2). DESIGN: A prospective, pilot clinical study. SETTING: Intensive care unit of a tertiary care center. PATIENTS: Three sequential patients with metastatic renal cell carcinoma who developed hypotension during their first course of treatment with high-dose IL-2 (18 x 10(6) IU/m2/day by continuous infusion for 5 days). INTERVENTIONS: Upon developing hypotension during their subsequent therapy with IL-2, patients were administered 12 mg/kg of NG-methyl-L-arginine. Thereafter, a dose of 4 mg/kg was given every 4 hrs, as needed, to maintain the systolic blood pressure above 100 mm Hg. MEASUREMENTS AND MAIN RESULTS: Invasive hemodynamic monitoring was instituted before the initiation of treatment with IL-2. Differences noted before, and 15 mins after, the administration of NG-methyl-L-arginine were analyzed using the paired t-test. NG-methyl-L-arginine (12 mg/kg) induced a significant antihypotensive effect (mean blood pressure increased from 87 +/- 4 to 121 +/- 7 mm Hg), accompanied by an increase of the systemic vascular resistance (549 +/- 51 to 860 +/- 167 dyne.sec/cm5) and pulmonary vascular resistance (81 +/- 16 to 117 +/- 29 dyne.sec/cm5). A decrease in the cardiac index was also documented (4.5 +/- 0.5 to 3.6 +/- 0.3 L/min/m2). No significant changes in pulmonary artery occlusion and central venous pressures were observed. Maintenance doses of 4 mg/kg of NG-methyl-L-arginine induced similar hemodynamic results, although the duration of the antihypotensive effect of NG-methyl-L-arginine decreased with sequential doses. CONCLUSIONS: The hemodynamic effects induced by IL-2 administration are reversed by NG-methyl-L-arginine, a nitric oxide synthesis inhibitor. These results provide evidence for the biological activity of NG-methyl-L-arginine when administered alone to hypotensive patients. While no adverse effects were observed in this preliminary study, issues of toxicity and effectiveness need to be defined further in formal clinical trials. NG-methyl-L-arginine may play a therapeutic role in the modulation of the extreme vasodilation induced by cytokine administration or in septic shock.

Adult↗
PubMed1995

Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.

PURPOSE: Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. PATIENTS AND METHODS: A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). RESULTS: The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. CONCLUSION: The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.

Adult↗
PubMed1995

The results of a phase II randomized trial comparing 5-fluorouracil and 5-fluorouracil plus alpha-interferon: observations on the design of clinical trials for androgen-independent prostate cancer.

The therapeutic benefit of chemotherapy in androgen independent prostate cancer is limited. 5-Fluorouracil has been reported to have modest antitumor activity in androgen independent prostate cancer. Although alpha-interferon is inactive as a single agent in prostate cancer, preclinical data indicate that it increases the in vitro cytotoxicity of 5-fluorouracil against a variety of malignant cells. We evaluated the relative antitumor activity and tolerance of 5-fluorouracil versus 5-fluorouracil plus alpha-interferon in 50 patients with histologically confirmed metastatic adenocarcinoma of the prostate. These patients had progressive disease in the presence of castrate levels of testosterone. A prospective randomized phase II open labeled trial was performed because of the difficulty in measuring responses in patients with metastatic prostate cancer. Of 23 patients treated with 5-fluorouracil alone and 28 treated with 5-fluorouracil plus alpha-interferon 17 and 23, respectively, were evaluable for response and toxicity, and 5 and 5, respectively, were evaluable for toxicity only. Only 2 of 17 (11.7%) and 4 of 23 (17%) patients, respectively, showed a greater than 50% decrease in serum prostate specific antigen (no significant difference). There was no difference in duration of response or duration of survival between the 2 groups (mean duration of response 8.64 and 6.17 weeks, respectively, and mean duration of survival 33.70 and 38.65 weeks, respectively). Both regimens caused significant morbidity (mucositis and neurotoxicity) and 3 treatment related deaths at the high 5-fluorouracil doses. 5-Fluorouracil alone and with alpha-interferon at the doses used have minimal antitumor activity against androgen independent prostate cancer and, therefore, should not be tested further in these patients. Androgen independent prostate cancer selected using our criteria is a rapidly progressive disease, and these patients are an ideal target population for phase II studies.

Adenocarcinoma↗
PubMed1995

Paclitaxel, cisplatin and methotrexate combination chemotherapy is active in the treatment of refractory urothelial malignancies.

PURPOSE: We investigated the activity of combination chemotherapy consisting of paclitaxel, cisplatin and methotrexate in patients with advanced urothelial cancers. MATERIALS AND METHODS: A total of 25 consecutive patients with metastatic refractory urothelial malignancies was treated with a combination of 200 mg./m.2 paclitaxel, 30 mg./m.2 methotrexate and 70 mg./m.2 cisplatin in a pilot study. RESULTS: There were no complete responses. Of 25 patients 10 (40%), including 3 of 7 with liver metastases, had a partial response. Hematological and nonhematological toxicity was tolerable. CONCLUSIONS: The combination chemotherapeutic regimen of paclitaxel, cisplatin and methotrexate is active in patients with advanced urothelial cancer and warrants further study.

Adult↗
PubMed1995

Growth-inhibitory effects of serotonin uptake inhibitors on human prostate carcinoma cell lines.

Growth stimulation of a variety of cell types by the neurotransmitter serotonin has been reported. We have examined the effects of three serotonin-uptake inhibitors, 6-nitroquipazine, zimelidine and fluoxetine (Prozac, Eli Lilly Co., Indianapolis, Indiana) on human prostate carcinoma cell lines. In vitro, all 3 of these compounds inhibited the proliferation of PC-3, DU-145 and LNCaP cells in a dose-dependent manner. Also, all 3 compounds blocked the uptake of a radiolabeled analog of serotonin by the prostate carcinoma cell lines. The order of potency for inhibition of growth as well as for serotonin uptake was fluoxetine > zimelidine > 6-nitroquipazine. The growth of subcutaneous, PC-3 xenografts in athymic nude mice was significantly inhibited by fluoxetine. These results implicate biogenic amines such as serotonin in the growth of prostate carcinoma cells and indicate the potential use of serotonin-uptake inhibitors for the treatment of prostate cancer.

Animals↗
PubMed1994

Neoadjuvant cisplatin and interferon-alpha 2B in the treatment and organ preservation of penile carcinoma.

We investigated the antitumor activity and toxicity of cisplatin and interferon-alpha 2B as the primary treatment of penile carcinoma. A total of 13 consecutive patients with nonmetastatic, histologically confirmed invasive squamous cell carcinoma of the penis underwent treatment consisting of 20 mg./m.2 cisplatin intravenously and 5 x 10(6) mu./m.2 interferon-alpha 2B subcutaneously daily for 5 consecutive days. An equivalent dose of interferon was then administered subcutaneously every 2 days for 3 weeks and the regimen was repeated at 28-day intervals. Of 12 evaluable patients 9 responded: 4 achieved a pathologically confirmed complete remission of 38+, 21+, 10 and 7 months in duration (2 with relapse were treated with local therapy and remain with no evidence of disease), and 5 achieved a partial response, underwent surgical removal of residual disease and remained disease-free for 14+ to 24+ months. The most significant toxicities were anemia in 5 patients and reversible renal impairment in 3 but no patient had neutropenic fever or required platelet transfusion. We conclude that primary treatment with cisplatin and interferon-alpha 2B induced responses in 75% of 12 patients with penile carcinoma and allowed for a less radical operation than originally scheduled. A larger number of patients and longer followup will be required to confirm these encouraging preliminary results.

Adult↗
PubMed1994

Phase II trial of low dose gamma-interferon in metastatic renal cell carcinoma.

We conducted a phase II trial to confirm the activity of fixed, low dose gamma-interferon in metastatic renal cell carcinoma. A total of 35 patients with metastatic renal cell carcinoma, who had not received prior immunotherapy and who had a Zubrod performance status of 2 or less, was enrolled in this study. Primary tumors were controlled by nephrectomy or embolization before treatment began. gamma-Interferon was administered weekly as a subcutaneous injection at a fixed dose of 100 micrograms. Toxic effects were limited to low grade fever, chills and myalgias within 24 hours of injection. There were no incidences of grade 3 or 4 toxicity. Responses could be evaluated in 34 patients. There were 1 complete and 4 partial responses, for an objective response rate of 15% (95% confidence interval 5 to 32%). Durations of response to date are 21+, 17+, 13+, 9 and 2 months. We conclude that gamma-interferon is an active agent for metastatic renal cell carcinoma when administered according to this dose and schedule. The response rate compares favorably with those of alpha-interferon and interleukin-2, and toxicity is minimal. gamma-Interferon has excellent potential for use in combination with other biological or chemotherapeutic agents and in the adjuvant setting.

Adult↗
PubMed1994

Phase I study of interleukin-2 combined with interferon-alpha and 5-fluorouracil in patients with metastatic renal cell cancer.

Interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) each has produced a 15%-20% response in metastatic renal cell cancer. Combining IFN-alpha with either IL-2 or 5-fluorouracil (5-FU) enhanced IFN-alpha activity. We have therefore conducted a Phase I Study combining IL-2, IFN-alpha, and 5-FU. The patients were continuously infused with IL-2 (1-3 x 10(6) u/m2) and 5-FU (600-750 mg/m2) for a 5-day period every 28 days, and IFN-alpha (4-5 x 10(6) u/m2) was injected subcutaneously daily. Lymphokine-activated killer (LAK) and natural killer (NK) cell activity was measured on days 0 and 8. Twenty-one patients received 76 courses. All primary tumors were controlled by surgery (81%) or angioinfarction. Hematologic toxicity was mild; median nadir of platelets was 117 K/microL and of granulocytes was 1.2 K/microL. Dose-limiting toxicity included mucositis, liver damage, and hypotension. No treatment-related death occurred, and only one patient required intensive-care-unit support. Two patients had an objective response, one of which was a complete response. Increased LAK cell and NK cell activity occurred at all IL-2 dose levels. Simultaneous delivery of IL-2, IFN-alpha, and 5-FU is safe and shows antitumor and biologic activity. 5-FU did not appear to suppress IL-2-induced LAK and NK cell activation. Maximum tolerated dose of the three-drug combination is IL-2, 2 x 10(6) u/m2, 5-FU 600 mg/m2, and IFN-alpha, 4 x 10(6) u/m2.

Adult↗
PubMed1994

Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.

PURPOSE: A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) in patients with androgen-independent prostate cancer (AI PCa). PATIENTS AND METHODS: Thirty-nine consecutive patients whose disease progressed following castration were treated with oral ketoconazole (1,200 mg) daily and Adriamycin (20 mg/m2 in a 24-hour infusion) once weekly. Antitumor activity was assessed by the level of prostatic-specific antigen (PSA) decline. RESULTS: PSA levels decreased > or = 50% from baseline in 21 (55%; 95% confidence interval, 38% to 71%) of 38 assessable patients. We observed partial responses (PRs) in seven (58%) of 12 patients with measurable soft tissue disease (in the lung, lymph nodes, and liver). Two patients with history of atherosclerotic heart disease had a sudden cardiac death. Serious toxic reactions included grade III to V stomatitis and grade III to IV acral erythema in 11 patients (29%), and grade III to IV anal and urethral mucositis in five patients (13%). Grade III to IV neutropenia occurred in 11 patients (29%). Seventeen patients (45%) required hospitalization for complications. Fifteen patients (39%) developed hypokalemia, and 24 patients (63%) developed clinical adrenal insufficiency. CONCLUSION: The combination of ketoconazole and Adriamycin has a 55% PSA response rate in patients with AI PCa and is worthy of additional study. This treatment results in frequent adrenal insufficiency. Therefore, future studies should incorporate routine corticosteroid replacement. The cardiac complications caused by this combination should be studied further before it is widely used.

Administration, Oral↗
PubMed1993

Differential effects of peptide hormones bombesin, vasoactive intestinal polypeptide and somatostatin analog RC-160 on the invasive capacity of human prostatic carcinoma cells.

The effects of bombesin, vasoactive intestinal polypeptide (VIP), and a somatostatin analog (RC-160) on the in vitro invasion of reconstituted basement membrane (Matrigel) by two human prostatic carcinoma cell lines were examined. Aggressively growing PC-3 cells were found to be invasive in this assay in contrast to the relatively indolent LNCaP cells. Bombesin increased penetration of basement membrane by both cell lines. Although VIP had no effect on invasion by PC-3 cells, it enhanced invasion by LNCaP cells in a dose-dependent manner. In agreement with these results, VIP stimulated adenylate cyclase activity only in LNCaP cells. In contrast to bombesin and VIP, RC-160 did not alter invasion by either cell line. Our results suggest that certain neuroendocrine peptides can increase the invasive potential of prostatic carcinoma cells and may thereby contribute to the rapid progression and aggressive clinical course of prostate tumors containing neuroendocrine elements.

Adenylyl Cyclases↗
PubMed1992

Altered expression of retinoblastoma protein and known prognostic variables in locally advanced bladder cancer.

BACKGROUND: The clinical behavior of the tumor in patients with locally advanced bladder carcinoma is unpredictable. Current predictors of clinical behavior include depth of muscle invasion, presence of vascular invasion, proliferation rate, and loss of blood group antigens. Treatment selection would be facilitated by the development of a reliable marker of tumor progression. Functional retinoblastoma (RB) gene loss has been reported to occur in bladder carcinoma, but the significance of this loss is unknown. PURPOSE: We have evaluated the frequency of functional loss of the RB gene in locally advanced bladder carcinoma and have compared the results to known prognostic factors in the same cohort. METHODS: Forty-three study patients with pathologically well-characterized, locally advanced bladder carcinoma, who were placed in a protocol incorporating surgery and chemotherapy, were studied for known clinical and pathological prognostic indicators as well as for their Rb status. Formalin-fixed and paraffin-embedded archival primary tumor tissues were used for histological and immunohistochemical analyses. RESULTS: Altered Rb protein expression was documented in 37% of the tumor specimens. The high rate of altered Rb expression found in this cohort with advanced urothelial tumors strongly suggests that RB functional loss may be associated with tumor progression in this malignancy. Altered Rb protein expression was found to be independent of other known prognostic variables. A significantly poorer tumor-free survival rate also was noted for those patients who had a tumor with an altered Rb protein with or without vascular invasion. CONCLUSION: The high frequency of Rb alteration in locally advanced bladder carcinomas, plus the fact that a significant correlation could not be found between the Rb status and other known prognostic markers in this preliminary study, suggests that altered RB expression may be an independent prognostic marker of tumor progression in bladder cancer.

Gene Expression Regulation, Neoplastic↗
PubMed1992

Small cell carcinoma of the urinary bladder. A clinicopathologic analysis of 22 cases.

Small cell carcinoma of the urinary bladder is an uncommon tumor. The authors report the clinicopathologic findings in a series of 22 cases. Fifteen men and 7 women were studied; their ages ranged from 51 to 87 years (mean, 62.4 years). The most frequent presentation was hematuria (94.4%). At diagnosis, three patients had Stage B disease, six had Stage C, and ten had Stage D (unknown stage in three). Histologically, 6 were oat cell type tumors, 11 were of intermediate cell type, and 5 were of combined cell type. Immunohistochemical studies demonstrated positivity for neuron-specific enolase in ten of ten cases, cytokeratin in seven of ten cases, chromogranin in eight of nine cases, serotonin in seven of nine cases, and S-100 protein in four of ten cases. Neuroendocrine differentiation was seen in five of seven cases examined by electron microscopy. Treatment and follow-up data were available for 19 patients: 10 (52.6%) were dead of disease, 5 (26.3%) were alive and well, 3 (15.8%) were alive with disease, and 1 (5.3%) died of an unrelated cause. The 2-year survival rate was 50% for patients with Stage B, 25% for patients with Stage C, and 33% for patients with Stage D disease. Although overall survival was poor, some cases responded well to therapy. Based on the authors' experience, radical cystectomy with adjuvant chemotherapy appears to be the treatment of choice.

Aged↗
PubMed1992

Human prostate cancer model: roles of growth factors and extracellular matrices.

A human prostate cancer model was established by inoculating a prostate specific antigen (PSA)-producing LNCaP cell line with either prostate or bone fibroblasts. Alternatively, this human prostate cancer model can also be established by inoculating LNCaP cells with growth factor(s) (GFs) and extracellular matrix (ECM) immobilized on Gelfoam. The resulting LNCaP tumors were used to evaluate PSA production and excretion in athymic hosts. This model was also employed to examine the biochemical nature of mesenchymal cell-derived growth-promoting protein(s) and to assess the efficacy of potential chemotherapeutic agents. Because of the propensity of human prostate cancer to metastasize to the bone, this study defined a 1.0 M NaCl-eluted fraction, MS1, from the conditioned medium of a bone stromal cell line (MS) by heparin-affinity column chromatography. The growth-promoting activity was assayed both in vivo (e.g., tumor formation) and in vitro (e.g., soft agar colony formation). We found that the growth-promoting activity was trypsin- and heat-sensitive, and partially degraded by acid and dithiothreitol. Immunochemical studies indicated that the polyclonal antibody raised against MS1 blocked the growth-promoting effect elicited by the bone-conditioned media. This growth-promoting factor was found to be immunochemically dissimilar to KGF, HGF, and bFGF. However, addition of bFGF, HGF and NGF, but not aFGF, TGF beta, IGF1, IGF2, PDGF, EGF, TGF alpha and KGF, stimulated anchorage-independent growth of prostate cells, a condition closely parallel to tumor formation in vivo. We found that the MS1 fraction also contained fibronectin and tenascin but not laminin or collagen IV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chemotherapy resistant transitional cell carcinoma as a target for chemoprevention.

alpha-Interferon combined with 5-fluorouracil results in significant antitumoral activity in metastatic bladder carcinoma refractory to standard MVAC chemotherapy. As a single agent, alpha-interferon is ineffective for invasive or metastatic disease, but appears to contribute to the increased response rate of patients with invasive chemotherapy-refractory disease. Although most patients with superficial bladder carcinoma will not develop invasive disease, patients in complete remission from invasive disease are at high risk for relapse. In vitro assays indicate that fenretinide (4-HPR), alpha-interferon, and 5-fluorouracil possess significant antitumoral activity in human transitional cell carcinoma (TCC) lines. Some features of postchemotherapy-refractory TCC are similar to those of initial superficial disease (sensitivity to biological therapy). The biological study of patients with residual postchemotherapy disease may permit the development of strategies which will prevent the recurrence of malignancy within the bladder following an initial complete remission, in addition to developing strategies for the selection and treatment of patients with high risk superficial disease.

Antineoplastic Combined Chemotherapy Protocols↗