Search PubMed⌕ Search

Biomedical subjects

R L Comis

Publications and source records attributed to R L Comis.

At least 37 records · Page 2Linked to original sources
PubMed1994

Pharmakokinetics and bioavailability study of ethacrynic acid as a modulator of drug resistance in patients with cancer.

Ethacrynic acid (EA) is an inhibitor of the glutathione S-transferases (GSTs), a family of detoxification enzymes the expression of which has been associated with resistance to several classes of anticancer drugs. We performed a two-way randomized crossover study to investigate the pharmacokinetics and bioavailability of EA and describe any toxicities of EA associated with i.v. administration. We administered EA (100 mg) either by the p.o. or i.v. route on days 1 and 2 for pharmacokinetic analysis. After i.v. administration, plasma EA disappearance was biphasic in seven patients and monophasic in two patients with a terminal half-life of 30 and 8 min, respectively. Mean total body clearance was high; 1405 ml/min in patients described by using a one-compartment model and 611 ml/min in those patients described by a two-compartment model. After p.o. administration, peak EA plasma concentrations were less than 10% of i.v. EA and the absolute bioavailability was less than 21% (range, 7-35%). The urinary output as a result of EA treatment was equal following either route of administration and together with the large first-pass effect suggests that a metabolite(s) may be the active diuretic agent(s). Burning at the injection site was the only toxicity unique to the i.v. route of EA administration. We concluded that the systemic availability of EA after p.o. administration is low and variable. This finding supports the potential utility of the i.v. route of administration for the treatment of drug resistance.

Aged↗
PubMed1994

Cisplatin: the future.

Cisplatin is one of the most important anticancer drugs yet developed. It proved critical in the development of curative programs for testicular cancer and in life-prolonging regimens for such diseases as small cell lung cancer, ovarian cancer, and metastatic bladder cancer. Cisplatin currently remains the recommended agent of choice for treatment of several malignancies and is a major reagent in the design of existing clinical trials. Although its analogue, carboplatin, has a constitutional and nonhematologic toxicity profile clearly superior to that of cisplatin, thrombocytopenia associated with carboplatin remains a problem, particularly since it can only be circumvented by means of cellular support, with or without growth factors. Continued laboratory investigations exploring new hypotheses concerning the pharmacodynamics of platinating agents emphasize the importance of the parent compound as well. Thus, in the short term, cisplatin will continue to be used in the therapy of certain major cancers. Ultimately, however, it will be replaced by compounds that both obviate its toxicity and increase its spectrum of activity.

Carboplatin↗
PubMed1993

Intraperitoneal cisplatin and etoposide in peritoneal mesothelioma: favorable outcome with a multimodality approach.

Ten patients with histologically documented peritoneal mesothelioma were treated with intraperitoneal cisplatin 200 mg/m2, sodium thiosulfate rescue and etoposide 65-290 mg/m2 every 4 weeks for a maximum of six cycles. All had epithelial or mixed epithelial-fibrous histology. Toxicity was tolerable, with 50% sustaining grade 3 or 4 granulocytopenia. There was one episode of neutropenic fever. Grade 2 peripheral neuropathy occurred in one patient, grade 1 in five patients. Complete remission occurred in one of five patients with measurable disease. Median survival for patients whose tumors were surgically debulked to < 2 cm residua prior to treatment was 22 months, while it was 5 months for those with measurable, surgically inaccessible disease (P = 0.0731 by Cox regression proportional hazard model). These data suggest that patients who present with resectable disease may benefit from an aggressive adjuvant approach. This possibility warrants prospective testing in a randomized clinical trial.

Adult↗
PubMed1993

Phase I/pharmacokinetic/biochemical study of the nitroimadazole hypoxic cell sensitiser SR2508 (etanidazole) in combination with cyclophosphamide.

SR2508 sensitises certain hypoxic tumor cells in vitro and in vivo to the cytotoxic action of radiation and alkylating agents. The mechanism of sensitisation may derive in part from depletion of glutathione (GSH) and possibly inhibition of GSH-dependent enzymes in target cells. We treated 46 evaluable patients with cyclophosphamide 750-1000 mg m-2 followed by SR2508 at eight dose levels ranging from 2.5 to 15.0 g m-2. Each patient received SR2508 as a single agent initially, followed a week later by the combination of cyclophosphamide and SR2508. Initially, myelosuppression was the major toxicity; potentiation of cyclophosphamide-induced leukopenia by SR2508 required a dose reduction of cyclophosphamide to 750 mg m-2 at SR2508 doses above 7.2 g m-2. At doses above 9.4 g m-2 an acute syndrome of muscle pains and painful paresthesias of the extremities lasting 12-24 h was observed to occur with increasing severity. This side-effect was intolerable in two of three patients treated at 15.0 g m-2. The only other reproducible side-effect was nausea and vomiting which was controllable with antiemetics. Plasma and urine SR2508 concentrations were measured by HPLC in 45 patients. Plasma elimination curves fit a 2-compartment model. The mean terminal half-life at each dose level ranged from 5.1-5.8 h. The mean area under the plasma concentration-time curve was linearly related to dose, and mean total body clearance ranged from 46.6-94.0 ml-1 min-1 m-2; renal clearance accounted for 65.7-79.3%. Pretreatment with cyclophosphamide did not influence the kinetics of SR2508 in individual patients. Examination of the glutathione content of peripheral mononuclear cells and tumour samples showed that depletion to below 50% of control occurred in the majority of patients. GSH transferase inhibition occurred with a similar time-course, but to a lesser extent. These data suggest that the further evaluation of this regimen should be conducted with SR2508 administration preceding that of cyclophosphamide and that its evaluation in cyclophosphamide-sensitive tumours is warranted.

Adult↗
PubMed1993

Carboplatin in the treatment of non-small cell lung cancer: a review.

Cisplatin is among the most active agents available for the therapy of non-small cell lung cancer (NSCLC). Its congener, carboplatin, has been the focus of intense clinical trials over the last several years because of its improved therapeutic index. Results from randomized trials have shown that carboplatin is active in NSCLC, and that it can be effectively integrated into combination chemotherapy programs, with survival benefits comparable to cisplatin-containing regimens. Ongoing trials address critical issues, including: the optimization of platinum dose by either varying the carboplatin dose or combining cisplatin and carboplatin; evaluating the activity of carboplatin-containing programs with stem-cell support; and combining low-dose carboplatin with radiation therapy in an attempt to integrate these effective modalities. Finally, the availability of new active agents such as TAXOL (paclitaxel) and the camptothecin analogs has led to clinical trials to determine the optimal interaction between these agents and carboplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Phase II study of amonafide in advanced and recurrent sarcoma patients.

The activity of amonafide, a benzisoquinoline-1,3-dione, was assessed in 15 patients with advanced or recurrent sarcoma (11 previously treated). Eligible patients had ECOG performance status 0-2, and acceptable renal, hepatic and bone marrow function. Amonafide 300 mg/m2 was given intravenously over one hour daily on five consecutive days, every 3 weeks. Leukopenia and granulocytopenia were the most common and severe toxicities (grade 3 or 4 toxicity in 20% and 27% of patients, respectively). Local irritation and nausea/vomiting, the most common nonhematologic toxicities, were generally mild. No objective responses were seen, though 2 patients had brief stabilization of disease. Amonafide at this dose and schedule has no activity against advanced, recurrent sarcoma.

Adenine↗
PubMed1992

Phase II trials of interferons-alpha and -beta in advanced sarcomas.

Interferons (IFNs)-alpha and -beta were administered to patients with metastatic sarcomas in two different Eastern Cooperative Oncology Group studies. In one study, patients received IFN-alpha 2b, 20 million units/m2 i.v. 5 days/week x 4, then 10 million units s.c.t.i.w. In the second study, patients received IFN-beta ser 180 million units t.i.w. Of 87 patients evaluable for response, there were three responses in 64 patients (5%) treated with IFN-alpha-2b and no responses in 23 patients treated with IFN-beta ser. Severe or life-threatening fatigue with decline in performance status complicated treatment of 37% of patients receiving IFN-alpha 2b and 17% of patients receiving IFN-beta ser. Further investigation of IFNs in sarcomas should depend on evidence from preclinical studies demonstrating synergistic effects of IFNs combined with a cytoreductive modality which has proven activity in these malignancies.

Adult↗
PubMed1992

Oral etoposide in oncology: an evolving role.

Etoposide has been in clinical trials for over 2 decades. From the inception of these investigations, both the oral and intravenous routes have been employed. The oral route has been shown to be convenient, safe, and effective in the trials of diseases such as small cell lung cancer and lymphomas. A recent resurgence of interest has surfaced with its oral application in the elderly and in protracted dosing schedules. Investigations are now under way assessing the relative value of the protracted oral dosing schema in a variety of diseases.

Administration, Oral↗
PubMed1992

Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group.

A total of 248 analyzable patients with Stages III-IV ovarian epithelial cancer (114 with and 134 without prior chemotherapy) were randomized to one of four cisplatin (DDP)-hexamethylmelamine (HMM) regimens. In each, HMM, 200 mg/m2 was given orally daily on days 8-21 of each 21-day cycle. DDP was given i.v. on Day 1 at a dose of 37.5 mg/m2 (regimens A and B) or 75 mg/m2 (regimens C and D). In addition, since pyridoxine administration has been reported to reduce the neurotoxicity of HMM, that agent was given at a dose of 300 mg/m2 orally on Days 1-21 in regimens B and D. Randomization was stratified for performance status (0-1, 2-3) and largest tumor diameter at entry (greater than 2- less than or equal to 10 cm, greater than 10 cm) for previously untreated patients, and for performance status and time from initial diagnosis to entry on study (less than or equal to 1 year, greater than 1 year) for previously treated patients. The overall response rate (PR + CR) was 54%, with 25% of patients achieving a complete response. The 61% response rate with the higher dose DDP regimens was significantly greater than the 47% response rate with the lower dose regimens (p = 0.031). Multivariate analysis identified higher DDP dose, age less than 60 years, no prior chemotherapy, small tumor bulk and favorable tumor grade as significant prognosticators for response. The overall median response duration was 8.3 months (range 1-70 months). Prior chemotherapy, pyridoxine administration, recent diagnosis, and large tumor size were identified by multivariate analysis as factors adversely affecting response duration. Patients treated with the higher dose DDP regimens had more severe nausea, vomiting, and neurotoxicity. This study demonstrates that the combination of DDP + HMM is an effective regimen for advanced ovarian carcinoma that yields response rates comparable to other more complex regimens, and that there is a dose-response relationship for DDP in ovarian cancer. Although pyridoxine administration significantly reduced neurotoxicity, its adverse effect on response duration suggests that the agent should not be administered with DDP or HMM. The mechanism by which pyridoxine may unfavorably affect response duration deserves further investigation.

Altretamine↗
PubMed1992

Developments in therapy for extensive-disease small cell lung cancer.

Developments in the treatment of extensive small cell lung cancer have proven effective in palliative management but have not yielded improvements in the cure rate for this disease. Strategies involving dose escalation of chemotherapy, including de novo and late intensification dose escalation and dose escalation with growth factor support, have had mixed results in this patient population. Alternating chemotherapy, especially with regimens containing etoposide, has achieved better results overall but has not had a significant impact on survival. Current treatment goals should therefore be focused on short-term palliation of symptoms, at least until more effective drugs are developed. Exploration of resistance modulation strategies and biologic approaches, as well as determining the true value of protracted etoposide treatment, may play a role in future treatment endeavors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Bleomycin pulmonary toxicity: current status and future directions.

Bleomycin is a polypeptide antibiotic that has been used in clinical cancer chemotherapy for over 20 years. Risk factors associated with bleomycin include total dose of drug, age of patient, high-dose oxygen therapy during surgery, and prior and concomitant radiation therapy. Attempts at developing predictive and precise monitoring systems have not been completely successful; however, the combined use of clinical and laboratory tests, such as the DLCO test, can be used to permit safe administration of the drug. Recent work has emphasized the development of new analogues, such as liblomycin, that appear to possess less pulmonary toxicity than does bleomycin, and has focused on understanding the pathogenesis of pulmonary toxicity, particularly as it relates to the immune system.

Bleomycin↗
PubMed1991

Phase I study of thiotepa in combination with the glutathione transferase inhibitor ethacrynic acid.

The glutathione transferases comprise a family of isoenzymes, one or more of which are involved in the conjugation of alkylating agents to glutathione (GSH). Increased GSH transferase activity has been shown to underlie acquired resistance to several alkylating agents. Ethacrynic acid inhibits the isoenzymes of GSH transferase with 50% inhibitory concentration values ranging from 0.3 to 6.0 microM and has been shown to restore sensitivity to alkylating agents in drug-resistant animal tumor models. We entered 27 previously treated patients with advanced cancer on a study of ethacrynic acid (25 to 75 mg/m2 p.o. every 6 h for 3 doses) and thiotepa (30 to 55 mg/m2 i.v. 1 h after the second dose of ethacrynic acid). The major toxicity of ethacrynic acid was diuresis, which was observed at every dose level; in addition, severe metabolic abnormalities occurred at 75 mg/m2. At 50 mg/m2, the diuretic effects were manageable. Myelosuppression was the most important effect of the combination. Two of seven courses of ethacrynic acid, 50 mg/m2, and thiotepa, 55 mg/m2, were associated with grade 3 or 4 neutropenia and/or thrombocytopenia. Nausea/vomiting greater than or equal to grade 2 was observed in 16% of courses. GSH transferase activity was assayed spectrophotometrically in the peripheral mononuclear cells of all patients. At each dose level, activity decreased following ethacrynic acid administration, with recovery by 6 h. Administration of ethacrynic acid, 50 mg/m2, resulted in a mean nadir of transferase activity of 37% of control. The pharmacokinetics of thiotepa and its principal metabolite TEPA were studied in 23 patients. The plasma disappearance of thiotepa fit a two-compartment open model with a terminal half-life of approximately 2 h. Plasma TEPA levels peaked at a mean of 2.16 h following thiotepa administration. The harmonic mean terminal half-life of TEPA was 10.4 h, and the TEPA area under the curve (AUC) did not increase with increasing thiotepa dose. The AUC of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA was lower than that previously observed. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA. The severity of the platelet toxicity was correlated with the AUC of thiotepa, but not with that of TEPA. This combination of thiotepa and ethacrynic acid will be tested further in Phase II trials.

Adult↗
PubMed1991

Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine riboside: optimization of 6-methylmercaptopurine riboside dose and schedule through biochemical analysis of sequential tumor biopsy specimens.

Preclinical and clinical studies demonstrate that the selective antitumor activity of fluorouracil (5-FU) is enhanced by agents which perturb certain intracellular nucleotide pools. We previously demonstrated that the combination of N-phosphonacetyl-L-aspartate (PALA), which depletes pyrimidine nucleotide pools, and 5-FU yielded a 43% response rate among 37 assessable patients with colorectal carcinoma. In preclinical tumor models, 6-methylmercaptopurine riboside (MMPR), an inhibitor of purine synthesis, elevates phosphoribosylpyrophosphate (PRPP) pools and promotes the anabolism of 5-FU to fluorinated nucleotides. In vivo, the addition of MMPR enhances the therapeutic efficacy of PALA-5-FU. In a phase I trial, we sought to determine the optimal dose and schedule of MMPR in combination with PALA (250 mg/m2 on day 1) and 5-FU (1300 mg/m2 by 24-hour infusion on day 2). MMPR (75-225 mg/m2) was given intravenously on day 1 to 27 patients with solid tumors (15 colorectal, seven breast, five other). Toxic effects were mild to moderate and included leukopenia, mucositis, nausea, or rash. Two of seven patients given MMPR at 225 mg/m2 had grade 3 diarrhea. PRPP was measured using a [14C]orotic acid 14CO2 release assay in tumor biopsy specimens obtained before and 12 hours and 24 hours after MMPR doses were given to 20 patients. The addition of MMPR elevated PRPP pools in human solid tumors. At 12 hours after treatment, two (50%) of four patients showed a twofold or greater elevation of PRPP at the MMPR dose level of 75 mg/m2; a similar elevation was observed in five (71%) of seven patients given 150 mg/m2 MMPR and in three (43%) of seven patients given 225 mg/m2 MMPR. At 24 hours after treatment, results for the respective dose levels of MMPR were two (33%) of six patients, one (20%) of five patients, and four (57%) of seven patients. Administration of the two highest MMPR dose levels appeared to result in a greater increase in tumor PRPP levels. However, toxicity was greater at the 225 mg/m2 dose level; therefore, the 150 mg/m2 dose level was favored. Tumor levels of PRPP decreased between 12 hours and 24 hours in nine (56%) of 16 patients. This time course indicates that MMPR should be administered at the beginning of the 24-hour infusion of 5-FU.

Adult↗
PubMed1991

Pharmacokinetic study of trimetrexate in combination with cisplatin.

The addition of the antifol methotrexate to cisplatin (DDP) produces supraadditive antitumor effects in preclinical studies, but in the clinic this combination of two nephrotoxic drugs is limited by excessive toxicity. Trimetrexate (TMTX) is a second generation antifol with predominantly nonrenal elimination and antitumor activity superior to that of methotrexate in preclinical models. In early clinical trials TMTX demonstrated promising activity in non-small cell lung cancer, and nephrotoxicity was rare. We performed a Phase I clinical and pharmacological study of TMTX (escalating doses) in combination with DDP (20 mg/m2), both administered i.v. for 5 consecutive days, every 4 wk. The pharmacokinetics of TMTX was determined in 15 patients after administration of the single agent (baseline study) and following the Day 1 and Day 5 doses in the TMTX-DDP combination. The recommended Phase II single-agent dose of TMTX on this schedule, 8 mg/m2, did not produce excessive toxicity when given concurrently with DDP. Significant drug-related nephrotoxicity was not observed, even in patients receiving multiple courses of TMTX-DDP. The mean renal clearance of TMTX increased 1.4-fold and 2.8-fold over baseline on Days 1 and 5, respectively, of TMTX-DDP. Urinary flow was similarly greater on days of TMTX-DDP treatment. The nonrenal clearance of TMTX was unaffected by concurrent DDP. The steady-state volume of distribution, Vdss, and terminal elimination half-life were significantly greater on Day 5 of TMTX-DDP compared to baseline. The plasma protein-binding of TMTX in vitro was not altered by DDP, and the disappearance of ultrafilterable DDP from normal plasma in vitro was unchanged by TMTX. Although a protein-binding interaction of TMTX and DDP was not detected in normal plasma in vitro, the changes in renal clearance, Vdss, and the terminal half-life were consistent with a greater fraction of unbound TMTX in plasma following Day 5 of TMTX-DDP. Effects of DDP on the binding of TMTX to extravascular tissue components, or on the renal handling of TMTX, cannot be excluded. The increase in TMTX renal clearance correlated with increased urinary flow, which may improve the therapeutic index of TMTX as both an antineoplastic and antiparasitic agent.

Antineoplastic Agents↗
PubMed1991

Phase I pharmacokinetic study of intraperitoneal etoposide.

The synergistic interaction of etoposide with cisplatin in certain tumors prompted an evaluation of its potential role in the i.p. treatment of ovarian cancer and other intraabdominal malignancies. We conducted a Phase I evaluation of etoposide as a single agent to determine the maximum tolerated dose i.p., to describe dose-limiting and other toxic effects, and to examine the pharmacokinetics of etoposide in this setting. Etoposide was diluted in 2 liters of normal saline, and instilled i.p. over 10 to 25 min following maximal drainage of ascites. The dwelling time was 4 h, followed by peritoneal drainage. Twenty-two patients received 56 courses at doses which ranged from 100 to 800 mg/m2. The median age was 49, the median performance status was 1, and 18 patients had received prior chemotherapy, with or without radiation. The principal acute toxicity was abdominal pain in 10 patients; this was usually accompanied by signs of peritoneal irritation and was always responsive to nonsteroidal antiinflammatory medications. The major toxicity was dose-related neutropenia; Grade 3 or 4 toxicity affected five of six patients at 800 mg/m2. Thrombocytopenia, nausea and vomiting, and alopecia were also observed. The recommended dose for further study is 700 mg/m2. The pharmacokinetics of etoposide in plasma and peritoneal fluid was measured in 19 patients. Peritoneal levels over the 4-h dwelling time declined monoexponentially with a harmonic mean half-life of 3.5 h (range, 1.9 to 7.8). Plasma levels rose to a peak at 2.9 +/- 1.7 (SD) h and then declined exponentially with a harmonic mean terminal half-life of 7.7 h (range, 4.2 to 15.6). The plasma area under the concentration-time curve increased linearly with respect to dose. The relative pharmacological advantage (ratio of peritoneal to plasma area under concentration-time curve) for i.p. administration was measured as 2.8 and was independent of dose. Based on the high plasma protein binding of etoposide (94%) and the minimal protein binding in the fluid instilled i.p., the ratio of the areas under the concentration-time curves of free drug is estimated to be 4%. These results illustrate that tumor confined to the peritoneal cavity would be exposed to substantially higher free (diffusible) drug concentrations following i.p. than following i.v. administration and support the further evaluation of etoposide by this route.

Adult↗