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Biomedical subjects

W J Slichenmyer

Publications and source records attributed to W J Slichenmyer.

14 recordsLinked to original sources
PubMed2001

Serum prostate-specific antigen decline as a marker of clinical outcome in hormone-refractory prostate cancer patients: association with progression-free survival, pain end points, and survival.

PURPOSE: Validated end points are lacking for clinical trials in hormone-refractory prostate cancer (HRPC). Controversy remains regarding the utility of a posttreatment decline of prostate-specific antigen (PSA). The purpose of this study was to determine whether posttreatment declines in PSA were associated with clinical measures of improvement in a randomized phase III trial of suramin plus hydrocortisone versus placebo plus hydrocortisone. PATIENTS AND METHODS: A total of 460 HRPC patients were randomized to receive suramin plus hydrocortisone (n = 229) or placebo plus hydrocortisone (n = 231). All patients had symptomatic, metastatic HRPC requiring opioid analgesics. Clinical end points evaluated included overall survival, objective progression-free survival (OPFS), and time to pain progression (TTPP). An evaluation of overall survival, OPFS, and TTPP as a function of a PSA decline of > or = 50%, lasting at least 28 days, was undertaken by using a landmark analysis at 6, 9, and 12 weeks. A multivariate analysis of the impact of PSA decline was performed on these clinical end points. RESULTS: A decline in PSA of > or = 50% lasting > or = 28 days was significantly associated with a prolonged median overall survival, OPFS, and TTPP, both in the entire group and the suramin plus hydrocortisone group at all three landmarks in both univariate and multivariate analysis. CONCLUSION: In this prospective, randomized trial of suramin plus hydrocortisone versus placebo plus hydrocortisone, a posttherapy decline in PSA of > or = 50%, lasting 28 days, was associated with prolonged median overall survival, improved median progression-free survival, and median TTPP. This analysis suggests that a posttreatment decline in PSA may be a reasonable intermediate end point in HRPC trials and calls into question the clinical utility of preclinical assays evaluating the in vitro effect of given agents on PSA secretion.

Adenocarcinoma↗
PubMed2001

Anticancer therapy targeting the erbB family of receptor tyrosine kinases.

Several agents that target one or more members of the erbB family of receptor tyrosine kinases are currently undergoing clinical investigation. The monoclonal antibody trastuzumab has been shown effective in erbB2-expressing metastatic breast cancer when administered as a single agent or in combination with cytotoxic chemotherapy. Toxicities associated with trastuzumab include infusion-related fever and chills, hypersensitivity reactions, and congestive heart failure. C225 is a monoclonal antibody directed against the epidermal growth factor receptor, which has shown encouraging antitumor activity in early clinical development. The orally active tyrosine kinase inhibitors show encouraging antitumor activity in preclinical models and early clinical trials. Members of this class currently in clinical development include ZD1839, OSI-774, and CI-1033. Evidence to date suggests that the major role for erbB receptor-targeting drugs will be in combined therapy to enhance response to cytotoxic drugs, and in long-term monotherapy to maintain response and prevent disease progression or recurrence.

Animals↗
PubMed2001

CI-1033, a pan-erbB tyrosine kinase inhibitor.

Overexpression of the erbB family of receptor tyrosine kinases has been implicated in a variety of tumors including breast, lung, prostate, and brain. Most solid tumors express one or more of these receptors, which can often be related to tumor aggressiveness and poor patient prognosis. CI-1033, a pan-erbB tyrosine kinase inhibitor, is a clinically promising agent that is active against all four members of the erbB receptor tyrosine kinase family. In vitro studies of human cancer cell lines indicate that CI-1033 results in prompt, potent, and sustained inhibition of tyrosine kinase activity. This inhibition is highly selective for erbB1 (epidermal growth factor receptor), erbB2, erbB3, and erbB4 without inhibiting tyrosine kinase activity of receptors such as platelet-derived growth factor receptor, fibroblast growth factor receptor, and insulin receptor, even at high concentrations. Treatment of athymic nude mice bearing xenografts of human A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, and SF-767 glioblastoma results in highly significant suppression of tumor growth. The major toxicity in animals is diarrhea, which is more severe at higher doses. In animal models, all side effects are reversible on cessation of treatment. Thus, CI-1033, which is currently undergoing phase I clinical trials, holds significant potential for use in a broad range of solid tumors.

Animals↗
PubMed2000

Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized phase III trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone.

PURPOSE: Suramin is a novel agent that has demonstrated preliminary evidence of antitumor activity in hormone-refractory prostate cancer (HRPC). A prospective randomized clinical trial was designed to evaluate pain and opioid analgesic intake as surrogates for antitumor response in HRPC patients with significant, opioid analgesic-dependent pain. PATIENTS AND METHODS: A double-blind, placebo-controlled trial randomized patients to receive a 78-day, outpatient regimen of either suramin plus hydrocortisone (HC, 40 mg/d) or placebo plus HC. Treatment assignment was unblinded when either disease progression or dose-limiting toxicity occurred; placebo patients were allowed to cross-over to open-label suramin plus HC. In addition to pain and opioid analgesic intake, prostate-specific antigen (PSA) response, time to disease progression, quality of life, performance status, and survival were compared. RESULTS: Overall mean reductions in combined pain and opioid analgesic intake were greater for suramin plus HC (rank sum P =.0001). Pain response was achieved in a higher proportion of patients receiving suramin than placebo (43% v 28%; P =.001), and duration of response was longer for suramin responders (median, 240 v 69 days; P =.0027). Time to disease progression was longer (relative risk = 1.5; 95% confidence interval, 1.2 to 1.9) and the proportion of patients with a greater than 50% decline in PSA was higher (33% v 16%; P =.01) in patients who received suramin. Neither quality of life nor performance status was decreased by suramin treatment, and overall survival was similar. Most adverse events were of mild or moderate intensity and were easily managed medically. CONCLUSION: Outpatient treatment with suramin plus HC is well tolerated and provides moderate palliative benefit and delay in disease progression for patients with symptomatic HRPC.

Adult↗
PubMed1995

Pretreatment H2 receptor antagonists that differ in P450 modulation activity: comparative effects on paclitaxel clearance rates and neutropenia.

Histamine-2 receptor antagonists (H2RAs) are principal components of the premedication regimen used to prevent major hypersensitivity reactions in patients receiving paclitaxel. Several different H2RAs, including cimetidine, ranitidine and famotidine, have been used in clinical trials of paclitaxel, as well as by clinicians in different geographic regions and hospitals primarily because of differences in the availability of the various H2RAs. However, H2RAs have highly variable cytochrome P450-modulating capabilities, and the P450 system appears to play a major role in paclitaxel metabolism and disposition. Therefore, the use of different H2RAs may result in different pharmacologic, toxicologic and antitumor profiles due to differential effects on paclitaxel metabolism. This study evaluated whether cimetidine and famotidine, which possess disparate P450-modulating capabilities, differentially affect paclitaxel clearance rates and the agent's principal toxicity, neutropenia. Women with advanced, platinum-refractory ovarian carcinoma received two courses of treatment with 135 mg/m2 paclitaxel over 24 h while participating in the National Cancer Institute's Treatment Referral Center Protocol. A crossover design was employed in which consecutive patients received either 300 mg cimetidine i.v. or 20 mg famotidine i.v. before their first course of paclitaxel and the alternate H2RA before their second course. In order to evaluate the differential effects of cimetidine and famotidine on pertinent pharmacologic and toxicologic parameters in the same individual, paclitaxel concentrations at steady-state (Css), paclitaxel clearance rates, and absolute neutrophil counts (ANCs) were obtained during both courses. Paclitaxel Css values were not significantly different in individual patients when either cimetidine or famotidine preceded paclitaxel (p = 0.16). Mean paclitaxel clearance rates were 271 and 243 ml/min per m2 following cimetidine and famotidine, respectively. These clearance rates were not significantly different in paired analysis (p = 0.30). The likelihood of subsequently requiring granulocyte-colony stimulating factor (G-CSF) for severe neutropenia during course 1 did not differ significantly between the two H2RAs (p = 0.9). Among patients who did not require G-CSF, mean percentage decreases in ANC were 87.7% and 84.2% after paclitaxel cycles preceded by cimetidine and famotidine, respectively. These measures of neutropenia did not differ significantly in paired analysis (p = 0.13). These results show that the H2RAs cimetidine and famotidine do not differentially affect the pharmacologic and toxicity profiles of paclitaxel when used in the premediation regimen to prevent major hypersensitivity reactions, and may be interchanged.

Adult↗
PubMed1994

Camptothecin analogues: studies from the Johns Hopkins Oncology Center.

The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5-2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily x5 schedule has been developed further with dose escalation using granulocyte-colony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.

Antineoplastic Agents↗
PubMed1993

Loss of a p53-associated G1 checkpoint does not decrease cell survival following DNA damage.

Cell cycle checkpoints regulate progression through the cell cycle. In yeast, loss of the G2 checkpoint by mutation of the rad9 gene results in increased genetic instability as well as increased sensitivity to ionizing radiation. In contrast, comparing clonogenic survival of cells which are isogeneic except for p53 functional status, we find that loss of a G1 checkpoint in mammalian cells is not associated with increased sensitivity to the lethal effects of ionizing radiation or a topoisomerase I inhibitor, camptothecin. These results indicate that increased sensitivity to DNA-damaging agents is not necessarily a defining feature of a mammalian cell cycle checkpoint. Furthermore, in light of a recent link of p53 function to radiation-induced apoptosis in hematopoietic cells, these observations suggest that p53-dependent apoptosis is a cell type-specific phenomenon and thus predict that the biological consequences of loss of p53 function will be cell type specific.

Camptothecin↗
PubMed1993

The current status of camptothecin analogues as antitumor agents.

The nuclear enzyme topoisomerase I (topo I) has been recently recognized as the target for the anticancer drug camptothecin (CPT) and its derivatives. Two of the agents that target this enzyme--topotecan (TPT) and CPT-11--appear to be active against a broad range of human tumors. In the following presentation, we review 1) the role of topo I in normal cells, 2) the chemistry and proposed mechanism of action of CPT and its analogues, 3) the results of preclinical and clinical testing of TPT and CPT-11, and 4) mechanisms of resistance to these agents. In normal cells, topo I is thought to be involved in gene transcription and DNA replication. During the course of its normal catalytic cycle, topo I transiently forms a covalent bond with DNA. CPT and its derivatives slow the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. In S-phase cells, advancing replication forks convert these topo I-DNA adducts into double-strand breaks that appear to be responsible for the cytotoxicity of these agents. Preclinical studies demonstrate antineoplastic activity for TPT and CPT-11 in a variety of tumor models. Phase I studies have identified neutropenia as the dose-limiting toxicity for both drugs. Gastrointestinal effects might also be dose-limiting for CPT-11 administered on some schedules. CPT-11 has shown antitumor activity in phase II trials for patients with carcinomas of lung, cervix, ovary, colon, and rectum and for patients with non-Hodgkin's lymphoma. Phase II studies of TPT are in progress. Resistance to the cytotoxic effects of these agents might result from decreased production of topo I or from production of a mutated form of topo I. In addition, decreased metabolic activation of CPT-11 (which is a pro-drug) and active efflux of TPT by P-glycoprotein-mediated transport might contribute to resistance. As agents with a novel mechanism of action, tolerable toxicity, and encouraging antitumor activity in early clinical trials, TPT and CPT-11 are undergoing further clinical development. If these agents can be successfully combined with other active chemotherapy agents, the topo I-directed agents offer the potential for significant advances in the treatment of patients with a variety of malignancies.

Animals↗
PubMed1992

Response of metastatic adenoid cystic carcinoma and Merkel cell tumor to high-dose melphalan with autologous bone marrow transplantation.

Two patients with metastatic spread of unusual tumors responded to treatment with high-dose Melphalan and autologous bone marrow transplant. One patient had adenoid cystic carcinoma of a minor salivary gland and the other had Merkel cell tumor of the scalp. Both patients had undergone prior surgery and radiotherapy, but later relapsed with distant metastases. Both patients had progression of their disease despite conventional and salvage chemotherapy. Treatment with high-dose Melphalan and autologous bone marrow transplant resulted in partial responses for both patients. High-dose Melphalan should be considered for therapy earlier in the course of patients with these unusual cancers.

Adult↗
PubMed1991

Taxol: a new and effective anti-cancer drug.

Taxol is a new anti-cancer drug that is a natural product derived from the bark of the Pacific Yew tree. The drug promotes polymerization and stabilization of tubulin to microtubules and interferes with the mitotic spindle. Clinical trials indicate that taxol is effective in the treatment of patients with refractory ovarian cancer, breast cancer, malignant melanoma and probably other solid tumors. Toxicities include anaphylactoid reactions, leukopenia, peripheral neuropathy and oropharyngeal mucositis. Increased supplies of the drug are required to support further phase II and III testing.

Alkaloids↗
PubMed1990

New natural products in cancer chemotherapy.

Four new and clinically relevant antineoplastic natural products are reviewed. Taxol is derived from the bark of the western yew. It promotes the formation of microtubule bundles which deform the cytoskeleton and interfere with mitosis. Although phase II efficacy testing is incomplete, taxol is effective in the treatment of patients with ovarian carcinoma and has some activity in patients with non-small cell lung cancer and melanoma. It remains untested against several other neoplasms. The chief toxicities of taxol are myelosuppression, mucositis, anaphylactoid reactions, and peripheral neuropathy. Homoharringtonine is the most active and abundant of the cephalotaxine esters derived from the genus Cephalotaxus. This agent appears to act at the ribosome to inhibit protein synthesis and has clinical activity in patients with acute myelogenous leukemia. The dose limiting toxicities of homoharringtonine are hypotension and myelosuppression. SKF 104864 and CPT-11 are derivatives of camptothecin which are still in early clinical trials. They are cytotoxic in vitro, acting through an interaction with topoisomerase I to induce DNA fragmentation. The spectra of activity and toxicity of SKF 104864 and CPT-11 are still undefined. All four of these new natural products offer possibilities for clinical activity for patients with a variety of malignancies.

Adenocarcinoma↗
PubMed1988

Chronic vasculitis causing unilateral ureteral stenosis.

We report a case of chronic vasculitis causing unilateral ureteral stenosis as an isolated phenomenon in an otherwise healthy forty-three-year-old man. Other causes of chronic vasculitis and ureteral stenosis are reviewed.

Adult↗
PubMed1986

The effect of cauterization of the rabbit ovary on adhesion formation.

A new treatment modality that involves laparoscopic electrocautery of the ovary has been described as an alternative to ovarian wedge resection. The authors investigated the effect of multiple cautery of the rabbit ovary on adhesion formation. Twenty animals were studied after being divided into four groups of five animals each. Group 1 animals underwent a control operation that involved opening and closing of the peritoneum only. All other animals underwent cautery of the right ovary, with the left ovary used as a control. Group 2 animals had no intraperitoneal substance instilled. Group 3 animals had 2.5 ml/kg of sterile normal saline instilled intraperitoneally. Group 4 animals had 2.5 ml/kg of 32% dextran 70 instilled intraperitoneally. Two weeks later, adhesions were evaluated with a macroscopic and a microscopic scoring system. Cautery of the ovaries was associated with the formation of a significant amount of adhesions. The mean macroscopic adhesion score for a cauterized ovary was 2.73 +/- 0.38 and for the control ovary was 0.00 +/- 0.00 (P less than 0.01). According to the microscopic scoring system, the adhesion scores were 1.86 +/- 0.16 and 1.20 +/- 0.28, respectively (P less than 0.05). The 32% dextran 70 group had the lowest mean macroscopic adhesion score, but this was not statistically significant.

Animals↗