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Biomedical subjects

R J Morgan

Publications and source records attributed to R J Morgan.

At least 127 records · Page 7Linked to original sources
PubMed1995

5-Fluorouracil and high-dose calcium leucovorin for hepatocellular carcinoma: a phase II trial.

A phase II trial of 5-fluorouracil (5-FU) [250-450 mg/m2/day x 5 days as an intravenous (IV) bolus] combined with calcium leucovorin (500 mg/m2/day x 5 1/2 days by continuous IV infusion) administered on a 28-day schedule was performed in 15 patients with advanced hepatocellular carcinoma. The median age was 58 years; performance status ranged from 50 to 100%. Of 15 evaluable patients, 1 (7%) had a partial response lasting 2.4 months; 8 (53%) had stable disease with a median duration of 5.7 months; and 6 (40%) had progressive disease with a median time to progression of 2.7 months. Median survival was 3.8 months. Treatment with 5-FU and calcium leucovorin was moderately well tolerated; 9% of the treatment courses were complicated by grade 3 or 4 hematological toxicity, and 10% of the courses were complicated by grade 3 or 4 gastrointestinal toxicity. Despite the efficacy of the combination of 5-FU and leucovorin in advanced colorectal cancer, our results document the general resistance of hepatocellular carcinoma to modulated 5-FU.

Adult↗
PubMed1995

Effects of papaverine and vasointestinal polypeptide on penile and vascular cAMP and cGMP in control and diabetic animals: an in vitro study.

Adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) mediate penile erection. We have previously established that adenylate and guanylate cyclase activity is elevated in the diabetic rat penis and aorta. This study investigates the action of papaverine and vasoactive intestinal polypeptide (VIP) on these cyclases. The aortae and penes of Sprague Dawley rats (n = 7) were stimulated with VIP and papaverine. Diabetes mellitus (DM) was induced in Sprague Dawley rats (n = 7) with streptozotocin and the penile and aortic tissues were treated with VIP. The penes, aortae and carotid arteries of New Zealand White rabbits were similarly processed. cAMP and cGMP generation was measured by radioimmunoassay. In all tissues: VIP stimulated cAMP synthesis; VIP did not increase cGMP levels; papaverine was without effect on either cAMP or cGMP synthesis. VIP-stimulated cAMP was significantly enhanced in the diabetic rat penis and aorta; there was also a significant elevation in the basal levels of cGMP in these tissues. These data: (1) consolidate that cAMP is a mediator of penile erection, (2) indicate that papaverine and VIP elicit erection by different mechanisms, (3) suggest that an enhanced penile capacity to generate cAMP in DM may constitute an adaptive response to counteract the previously reported reduction in VIP content and VIP receptors, and (4) indicate that the penile and vascular tissues of the rabbit respond in a similar manner to VIP and papaverine.

Animals↗
PubMed1994

High-dose doxorubicin, etoposide, and cyclophosphamide with stem cell reinfusion in patients with metastatic or high-risk primary breast cancer. City of Hope Bone Marrow Oncology Team.

BACKGROUND: Chemotherapy with a doxorubicin-containing regimen results in high overall response rates in the treatment of metastatic adenocarcinoma of the breast; the combination of doxorubicin, etoposide, and cyclophosphamide has produced a response rate of 84% in untreated patients with stage IV disease. Recent data suggest that selected groups of patients with metastatic disease treated with high-dose chemotherapy and stem cell support may enjoy unmaintained, long-term remission. This study was designed to establish the feasibility of administering the combination of high-dose infusional doxorubicin, etoposide, and cyclophosphamide followed by autologous stem cell rescue in patients with responsive metastatic, or high-risk primary breast cancer. METHODS: Criteria for patient enrollment included the presence of high-risk primary breast cancer (stage II with > or = 10 involved axillary nodes or stages III A or B) or stage IV disease in complete or partial response; Karnofsky performance status of 80% or more; no prior radiation therapy to the left side of the chest; exposure to a 150-mg/m2 or smaller cumulative dose of doxorubicin, and a ventricular ejection fraction of 55% or more. Chemotherapy consisted of escalating doses of doxorubicin given by a 96-hour continuous intravenous infusion, followed by 60 mg/kg of etoposide and 100 mg/kg cyclophosphamide, both given intravenously. On Day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused. RESULTS: Thirty-five patients were treated in this study. There were no treatment-related deaths. No patient had a decrease in cardiac ejection fraction below 50% as a consequence of high-dose chemotherapy. Two patients suffered grade 3 mucositis at the highest level of doxorubicin (200 mg/m2). Of 21 patients treated for primary high-risk breast cancer, 19 are recurrence free, with a median follow-up of more than 8 months (> or = 4-36 months). Five of fourteen patients with stage IV disease remain progression free at greater than or equal to 5, 7, 9, 15, and 42 months. For patients with stage IV breast cancer, the median progression-free survival after high-dose chemotherapy was 9 months; the median overall survival had been reached at 22 months. CONCLUSIONS: The phase II dose of doxorubicin in this combination therapy has been established at 165 mg/m2, with dose-limiting toxicity defined as mucositis. Further trials to define the role of this safe and effective high-intensity regimen in the treatment of breast cancer are indicated.

Adenocarcinoma↗
PubMed1994

High-dose cisplatin, etoposide, and cyclophosphamide with autologous stem cell reinfusion in patients with responsive metastatic or high-risk primary breast cancer.

BACKGROUND: This study was designed to establish the feasibility of combining high-dose cisplatin, etoposide, and cyclophosphamide followed by stem cell rescue in patients with responsive metastatic or high-risk primary breast cancer. METHODS: Eligibility criteria included the presence of high-risk primary breast cancer (Stage II with 10 or more involved axillary nodes or Stage IIIA or B) or Stage IV disease in complete or partial response; physiologic age 50 years or younger; Karnofsky performance status of 80% or greater; and creatinine clearance of 80 ml/minute or greater. Chemotherapy consisted of escalating doses of cisplatin (50-150 mg/m2 intravenously [IV]) given on days -12 and -5, etoposide (30 mg/kg IV) given on days -12 and -5, and cyclophosphamide (100 mg/kg IV) on day -3. On day 0, autologous bone marrow with or without peripheral stem cells, or granulocyte colony-stimulating factor primed peripheral stem cells alone were reinfused. RESULTS: Thirty patients were enrolled in this study. Twenty-eight patients demonstrated no evidence of persistent renal damage after treatment. Two patients suffered symptomatic peripheral neuropathy, and one patient required a hearing aid 3 months after therapy. Hematopoietic toxicities were acceptable. There were two fatalities; Streptococcus viridans bacteremia and adult respiratory distress syndrome developed in one patient; and one patient who received 262 mg/m2 of cisplatin died of renal failure. Twelve of 18 assessable patients with Stage IV disease are without evidence of progression; 3 of these patients are progression-free at 11+, 12+, and 32+ months. With a median follow-up of 16+ months (range, 4-31 months), 7 patients of the group of 11 treated with high-risk primary breast cancer are without evidence of disease. CONCLUSIONS: The Phase II dose of cisplatin when given on a day -12 and day -5 schedule in combination with etoposide and cyclophosphamide has been established at a total of 250 mg/m2. Dose-limiting toxicity has been defined as renal failure, and response rates were comparable to previously reported high-dose chemotherapeutic regimens.

Adenocarcinoma↗
PubMed1994

Phase I study of 5-day continuous infusion fluorodeoxyuridine and high-dose folinic acid with oral hydroxyurea.

Fluorodeoxyuridine (FUdR), the deoxynucleoside metabolite of 5-fluorouracil (5-FU), can be converted in a single step to fluorodeoxyuridine monophosphate (FdUMP), which binds covalently to thymidylate synthase (TS). Ribonucleotide reductase, an obligatory enzyme in the synthesis of deoxynucleotides, can be inhibited by hydroxyurea. Recognizing the well-established synergism between 5-FU and folinic acid (leucovorin), we hypothesized that the simultaneous administration of FUdR, leucovorin, and hydroxyurea might afford more effective inhibition of TS. Thirty-six patients with neoplastic disease considered refractory to standard therapy were entered into this phase I protocol. Treatment was administered on days 1 through 5 of a 28-day cycle and consisted of folinic acid (500 mg m-2 day-1) and FUdR at escalating doses of 0.1, 0.15, or 0.2 mg kg-1 day-1 both administered by continuous i.v. infusion, and hydroxyurea given p.o. once per day at doses ranging from 0 to 250o mg in 500-mg increments. The hydroxyurea and FUdR levels were escalated in a sequential fashion. The majority of patients had refractory breast or lung cancer. Dose-limiting toxicities were mucositis and diarrhea at the maximally tolerated dose of 0.15 mg/kg FUdR and 2000 mg hydroxyurea per day in conjunction with high-dose folinic acid. Hematological toxicity was minor. Of the 18 patients in whom response could be evaluated, none had evidence of objective disease regression. Mucositis and diarrhea are the dose-limiting toxicities when continuous infusions of FUdR and high-dose folinic acid are combined with oral hydroxyurea, effects that are consistent with the observed toxicities for FUdR when administered alone or in combination with leucovorin.

Administration, Oral↗
PubMed1994

Phase II trial of 5-fluorouracil and high-dose folinic acid as first- or second-line therapy for advanced breast cancer.

The use of leucovorin to modulate 5-fluorouracil (FUra)-mediated inhibition of thymidylate synthase has been shown both in vitro and in vivo to improve the antitumor activity of FUra. Based on the activity of this combination in previously untreated patients, we performed a study of FUra and high-dose leucovorin (HDFA) in patients with metastatic breast cancer and minimal prior chemotherapy. Patients were stratified by prior chemotherapy (or relapse within 12 months of completing adjuvant chemotherapy) versus no prior chemotherapy (or relapse at greater than 12 months since completion of adjuvant chemotherapy). FUra was given daily for 5 days at 370 mg/m2/day with HDFA, 500 mg/m2/day, beginning 24 hours before and continuing 12 hours beyond the first and last FUra doses, respectively. Two objective responses occurred among 21 patients in the pretreated group (10%; 95% confidence interval: 1-30%). Four of 36 eligible patients (11%) in the "no prior therapy group" had complete responses (95% confidence interval: 3-26%). The major toxicities were moderate leucopenia and mucositis. We conclude that FUra plus leucovorin has modest antitumor activity in metastatic breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Acute paraplegia following intrathecal phenol block in the presence of occult epidural malignancy.

A 68-year-old woman with an invading adenocarcinoma of the lung underwent intrathecal phenol block for chest wall pain. Acute paraplegia resulted immediately following the procedure. Subsequent CT scan showed dural compression from an epidural metastasis five segments above the site of the phenol injection. This was confirmed at surgical decompression of the spinal cord and by histological findings. The cause of the paraplegia, which has not recovered, was probably spinal coning.

Acute Disease↗
PubMed1994

Adenylate and guanylate cyclase activity in the penis and aorta of the diabetic rat: an in vitro study.

OBJECTIVE: To investigate the role of adenylate and guanylate cyclases in the mediation of erection in diabetic rats. MATERIALS AND METHODS: Hyperglycaemic diabetes mellitus was induced in 35 rats using streptozotocin. Two months later the penises and aortae of these rats were excised and cut into rings or segments before being treated with varying concentrations of acetylcholine (Ach), sodium nitroprusside (NaNP), prostaglandin E1 (PGE1) and adrenaline (AD). The levels of adenosine 3'5'-cyclic monophosphate (cAMP) and guanosine 3'5'-cyclic monophosphate (cGMP) so generated were measured by radioimmunoassay and the results compared with those from seven age-matched control rats that had not been given streptozotocin. RESULTS: Ach-stimulated cGMP synthesis was impaired in the aortae in diabetic rats. Ach-stimulated cGMP synthesis was undetectable in the penis. NaNP-stimulated cGMP and PGE1-stimulated cAMP synthesis was enhanced in both the penises and aortae in diabetic rats compared with controls. AD-stimulated cAMP synthesis was enhanced in the aorta in diabetic rats compared with controls, but AD had no effect on cAMP synthesis in the penis. CONCLUSION: Ach-stimulated nitric oxide (NO) synthesis is impaired in the vasculature of diabetic rats and an Ach-NO axis may not be present in the penis of the rat. The enhanced capacity of the penis and vasculature to generate cAMP and cGMP may constitute an adaptive response to counteract the reduction in receptor-linked NO release. Impaired adenylate or guanylate cyclase activity does not contribute to erectile dysfunction in diabetic rats.

Adenylyl Cyclases↗
PubMed1992

Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer.

Twenty-seven patients with advanced cancer were entered in a phase I study of bolus i.v. 5-fluorouracil at a dose of 370 mg/m2/day for 5 days combined with a continuous i.v. infusion of (6S)-folinic acid for 5.5 days, starting 24 h in advance of the first 5-fluorouracil dose. The dose of (6S)-folinic acid was escalated in cohorts of patients from 250 mg/m2/day to a maximum of 1000 mg/m2/day. The pharmacokinetics of (6S)-folinic acid were studied in the 3 patients given 250 mg/m2/day and in 6 patients given 1000 mg/m2/day. The mean steady-state plasma concentrations of (6S)-folinic acid and its principal metabolite (6S)-5-methyltetrahydrofolate at the 250 mg/m2/day dose were 2.7 and 5.1 microM, respectively. Both concentrations were comparable to the concentrations produced when (6S)-folinic acid was administered as half of a (6R,S)-folinic acid mixture (E. M. Newman et al., Cancer Res., 49:5755-5760, 1989). At the 1000 mg/m2/day dose of (6S)-folinic acid, the concentration of (6S)-folinic acid was 15.3 microM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 microM. The change in the ratio of the parent compound to its metabolite was accounted for by a decrease in the nonrenal clearance of (6S)-folinic acid, probably indicating saturation of its metabolism. The toxicities observed in this phase I trial, including stomatitis, diarrhea, neutropenia, and anemia, did not differ in nature or severity from those produced by 5-fluorouracil and (6R,S)-folinic acid when administered on the same schedule. Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested.

Adult↗
PubMed1992

Phase I trial of interleukin-2 plus gamma-interferon.

Interleukin-2 (IL-2) and gamma interferon (gamma-IFN) may be synergistic in inducing cell-mediated antitumor cytotoxicity. In order to determine the dose-limiting toxicities and define a maximum tolerated dose of these two agents in combination, we performed a Phase I clinical trial of intravenous IL-2 plus intramuscular gamma-IFN. Patients received both agents on a thrice-weekly schedule consisting of 4 weeks of treatment followed by 2 weeks of rest. Twenty-five patients were treated and received gamma-IFN doses between 0.05-0.25 mg/m2 (1-4 x 10(6) U/m2) with IL-2 doses from 0.33 mg/m2 to 2.33 mg/m2 (6-42 x 10(6) IU/m2). Two patients had partial responses of melanoma and adenocarcinoma of the lung lasting greater than 11 and 8 months, respectively. The toxicities of the combination were those expected from each agent, with no unusual effects, no irreversible organ toxicities, and no patient deaths. The doses recommended for outpatient administration on this schedule are IL-2, 2.0 mg/m2 plus gamma-IFN, 0.25 mg/m2, a dose combination that is unassociated with significant organ toxicity.

Adenocarcinoma↗