True composite lymphoma: non-Hodgkin's lymphoma and Hodgkin's disease.
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Adult↗
Biomedical subjects
R L Stephens
Publications and source records attributed to R L Stephens.
Disparate effects of intracisternal RX 77368 and ODT8-SS on gastric acid and serotonin release: role of adrenal catecholamines.
Intracisternal injection of the thyrotropin releasing hormone (TRH) analogue RX 77368 (100 ng) or the somatostatin analogue ODT8-SS (1 microgram) produced an 82% and 101% increase in gastric acid secretion in 2 h pylorus-ligated rats. In contrast, dissimilar effects were produced by intracisternal injection of these peptides on the secretion of serotonin into the gastric lumen. Intracisternal RX 77368 (100 ng) produced a 496% increase in intraluminal serotonin release, while in contrast, intracisternal ODT8-SS (1 microgram) produced a 78% inhibition in intraluminal serotonin release. Bilateral adrenalectomy reversed the stimulatory effect of intracisternal RX 77368 (100 ng) on serotonin, but not acid release. The data reveal a difference in the ability of the two peptides, which act as gastric secretagogues, to produce intraluminal acid and serotonin release, and suggest that combined activation of the vagus and the adrenal gland are important in mediating basal and RX 77368-stimulated serotonin release into the gastric lumen. In particular, differential effects on adrenal catecholamine release are implicated in the divergent effects of the two peptides.
Adrenal Glands↗
Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study.
Four hundred eleven women with metastatic breast cancer were randomly assigned to receive either 60 mg/m2 doxorubicin (130 patients), 320 mg/m2 bisantrene (146 patients), or 14 mg/m2 mitoxantrone (135 patients). The doses were given intravenously every 3 weeks with a cross-over design to determine their relative efficacy and toxicity. To be eligible, patients must have had one previous chemotherapy regimen, and patients who were estrogen receptor positive must have failed endocrine therapy. There were 365 patients assessable for response and 399 assessable for toxic effects. The median age was 57 years; 18% were premenopausal or perimenopausal. Visceral dominant disease was present in 66% of the patients. Ninety-seven percent of the patients had a disease-free interval from diagnosis to first recurrence of less than 1 year. The response rate was 28% with doxorubicin, 13% with bisantrene, and 14% with mitoxantrone (P = .004). Median time to treatment failure was 133 days with doxorubicin, 66 days with bisantrene, and 68 days with mitoxantrone (logrank P = .06). The median survival was 315 days for doxorubicin, 290 days for bisantrene, and 177 days for mitoxantrone (logrank P = .04), although survival at 2 years was similar for all three agents. There were five responses in the 66 patients crossed over to doxorubicin and one response each for patients crossed over to bisantrene (39 patients) or mitoxantrone (63 patients). Toxicity leading to discontinuance of therapy was more common with doxorubicin, and discontinuance of therapy was due primarily to patient's request or cardiotoxicity. The major dose-limiting toxic effect for all three agents was leukopenia. Nausea and vomiting, mucositis, and alopecia were more severe with doxorubicin. Congestive heart failure developed in nine patients treated with doxorubicin, zero patients treated with bisantrene, and two patients treated with mitoxantrone. A decrease in the left ventricular ejection fraction, as defined by moderate to severe Alexander grade changes, was more common in patients treated with doxorubicin (doxorubicin-treated patients = 20%, bisantrene-treated patients = 5%, and mitoxantrone-treated patients = 10%). This study demonstrates that bisantrene and mitoxantrone have only modest activity in metastatic breast carcinoma. The activity of doxorubicin is greater than that of the other two agents, but at a cost of increased toxicity.
Adenocarcinoma↗
Phase II evaluation of bisantrene in refractory multiple myeloma. A Southwest Oncology Group study.
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Aged↗
Treatment of non-small-cell lung cancer with vinblastine and very high-dose cisplatin. A Southwest Oncology Group study.
Suggestions of a dose-response effect for cisplatin in non-small-cell lung cancer have contributed to the development of very high-dose cisplatin regimens (200 mg/m2 per cycle). We treated 53 eligible patients with metastatic or recurrent non-small-cell lung cancer with a combination of 100 mg/m2 cisplatin and 4 mg/m2 vinblastine, each given on days 1 and 8 of a 28-day cycle. We observed no complete response and 4 partial responses (8%). Median survival was 6 months. Toxicities of grade III or greater included leukopenia (11 cases), nausea/vomiting (6 cases), thrombocytopenia (2 cases), anemia (2 cases), and elevation of transaminase (1 case). Neurotoxicity has been reported to be a major problem in several other very high-dose cisplatin regimens. The low level of neurotoxicity observed in this study may be attributable to the median cumulative cisplatin dose of less than 600 mg/m2. This vinblastine/very high-dose cisplatin regimen showed minor activity against non-small-cell lung cancer. The level of activity did not surpass that of standard-dose (100 mg/m2 per cycle) cisplatin-containing regimens.
Antineoplastic Combined Chemotherapy Protocols↗
Synthesis and antibacterial activities of C-21 functionalized derivatives of (9R)-9-amino-9-deoxoerythromycins A and B.
Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin.
Bacteria↗
Phase II study of fludarabine phosphate (NSC-312887) in patients with advanced endometrial cancer. A Southwest Oncology Group Study.
Nineteen evaluable patients with advanced endometrial cancer refractory to one prior chemotherapeutic regimen were treated with a 5-day schedule of fludarabine phosphate. No responses were noted. The major toxicity was grade 2 or greater leukopenia in 45% of patients. Fludarabine phosphate at this dose and schedule does not appear to be an active agent for patients with refractory endometrial cancer.
Aged↗
A randomized trial of cisplatin, vinblastine, and bleomycin versus vinblastine, cisplatin, and etoposide in the treatment of advanced germ cell tumors of the testis: a Southwest Oncology Group study.
This is a Southwest Oncology Group (SWOG) prospective randomized trial of cisplatin, vinblastine, and bleomycin (PVB) versus vinblastine, cisplatin, and etoposide (VP-16) (VPV) in the treatment of advanced germ cell tumors of the testis. The study objective was to determine what effect the replacement of bleomycin with VP-16 has on complete response (CR), survival, and drug toxicity. One hundred sixty-nine patients were registered and randomized. Of these patients, 160 were assessable for response. All had histologically confirmed disseminated germ cell neoplasms of testicular origin. Forty-six had minimal metastatic disease, and 114 had maximal disease. Seventy-seven were randomized to PVB and 83 to VPV chemotherapy. There was no significant difference in pretreatment characteristics between the two arms with regard to tumor burden, histologic type, and overall performance status. Patients received four courses of induction chemotherapy, either PVB (cisplatin 120 mg/m2 day 3, vinblastine 12 mg/m2 day 1, bleomycin 15 U/m2 twice per week) or VPV (vinblastine 8 mg/m2 day 1, cisplatin 120 mg/m2 day 3, VP-16 50 mg/m2 days 2 to 5). Chemotherapy was given every 3 weeks. Cytoreductive surgery was done postinduction if a chemotherapy CR was not achieved. There was no difference in the percentage of patients achieving a disease-free status between PVB (77%) and VPV (73%). The mean leukocyte nadir was similar for both treatments, but the mean platelet nadir was significantly lower (P = .003) in the VPV arm. All bleomycin-related toxicities (pulmonary, mucositis, skin) were avoided in the VPV arm. We conclude that bleomycin can be replaced in first-line therapy for advanced germ cell tumors without sacrificing efficacy and with the advantage of avoiding unnecessary drug toxicity.
Adolescent↗
Objective antitumor activity of acivicin in patients with recurrent CNS malignancies: a Southwest Oncology Group trial.
Acivicin (AT-125) is a glutamine antagonist with dose-limiting, schedule-dependent CNS toxicity and predictable CSF penetration after intravenous administration. Because of these properties, a trial in CNS malignancies was initiated. Thirty-two patients with recurrent or residual malignant astrocytomas were treated with AT-125. The majority of patients had glioblastoma multiforme (24) and had received prior nitrosoureas (21). The median age was 50 years, and Southwest Oncology Group (SWOG) performance status was 2. The major determinant of response was based upon radiologic criteria using computed tomographic (CT) scanning and/or magnetic resonance imaging (MRI) scans. The tumor mass was measured in two perpendicular planes, which yielded the largest cross-sectional area. Standard solid tumor criteria for response were used. All responding patients also had a stable or tapered dose of corticosteroids with stable or improved performance status and neurologic examination. There were four objective responses (12%): one complete remission (3 1/2+ years) and three partial remissions (57, 86, and 322 days). Two patients had improvement in disease that did not meet requirements for a partial remission. Toxicity was mild and primarily consisted of nausea, vomiting, and lethargy. Two patients were removed from study due to neurotoxicity (depression and hallucinations). The strict response criteria used in this trial were not those that have been used in testing other active agents such as carmustine (BCNU). We conclude that AT-125 has objective antitumor activity in malignant astrocytomas and warrants further study.
Adolescent↗
Antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. IV. Effects on gastric lesions in rats induced by cold-restraint stress and thyrotropin-releasing hormone.
Propyl-methylenedioxyindene (pr-MDI; 30 mg/kg, i.p.), an intracellular calcium antagonist, significantly reduced the number and size of erosions per stomach induced by cold-restraint stress by 69% and 86%, respectively. Our previous findings indicate that the antiulcer activity of pr-MDI is highly correlated with its inhibitory effect on gastric motor activity. Since central TRH is suggested as the brain mediator responsible for cold-restraint stress gastric ulcers in rats, the inhibitory action of pr-MDI was evaluated in the TRH-induced gastric lesion model. Pr-MDI (30 mg/kg) did not reduce the gastric erosions induced by intracisternal administration of 100ng RX77368, a stable thyrotropin-releasing hormone (TRH) analogue, even though it abolished the RX77368-induced stimulation of gastric emptying, gastric acidity, and acid output. Since pr-MDI (30 mg/kg, i.p.) significantly inhibited the stimulation of gastric motility by both cold-restraint stress and TRH, but only cold-restraint stress-induced gastric erosions were effectively reduced by the drug, the present findings suggest a possible dissociation between the ulcerogenic mechanisms of cold-restraint stress and intracisternal administration of TRH.
Animals↗
A phase II trial of continuous infusion vinblastine in patients with gastric carcinoma. A Southwest Oncology Group study.
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Adult↗
Endogenous serotonin produces an inhibitory tone on vagally stimulated gastric function.
The effect of depletion of serotonin stores on vagally stimulated gastric acid secretion and motility was studied in rats. Pretreatment of rats with parachlorophenylalanine (p-CPA) produced a 57% reduction in the intraluminal gastric release of serotonin and a 43-100% potentiation of the gastric acid secretory response elicited by intracisternal injection of the stable TRH analogue RX 77368 in conscious pylorusligated rats or in urethane-anesthetized rats with an acute gastric fistula. p-CPA also enhanced the vagally stimulated gastric acid output produced by intravenous injection of baclofen. In contrast, p-CPA pretreament had no effect on gastric acid secretion stimulated by bethanechol, histamine, or pentagastrin. Selective depletion of central serotonin stores by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) given alone or combined with parachloroamphetamine pretreatment did not alter RX 77368-stimulated gastric acid secretion. In addition, gastric contractility stimulated by intracisternal injection of RX 77368 was significantly enhanced by p-CPA but not by 5,7-DHT pretreatment; whereas the contractile response to carbachol was not altered by p-CPA pretreatment. These results suggest that depletion of peripheral but not central serotonergic stores potentiates gastric acid secretion and contractility stimulated by vagally, but not peripherally, acting gastric stimulants. Thus, peripheral serotonin may exert an inhibitory tone on vagally stimulated gastric acid secretion and motility in the rat.
Animals↗
Examination of the potential antiulcer activity of the calcium antagonist propyl-methylenedioxyindene. III. Lack of effect on cysteamine-induced duodenal ulcers in rats.
Since propyl-methylenedioxyindene (pr-MDI) exhibits significant protective effects against stress-induced ulcers in rats at subcardiovascular doses (10-30 mg/kg, i.p.), the aim of the present study was to explore the effect of this intracellular calcium antagonist on cysteamine-induced duodenal ulcers at the same low doses. Duodenal ulcers were induced in rats with a single dose of cysteamine (425 mg/kg, s.c.), which produced an 80% ulcer incidence within 24 h without affecting gastric acid concentration. Administration of pr-MDI (10 and 30 mg/kg, i.p.) at 0, 6 and 12 h post-cysteamine did not afford protection against ulceration. On the other hand, atropine (10 mg/kg, s.c., administered at 0, 6 and 12 h post-cysteamine) resulted in a 69% inhibition of ulceration, and the antacid Maalox (2 ml, administered p.o. at 0, 2, 4, 6 and 12 h post-cysteamine) completely prevented ulceration. The failure of pr-MDI to protect against duodenal ulceration is discussed in relation to its pharmacological mechanism of action and the pathogenetic mechanism of action of cysteamine.
Aluminum Hydroxide↗
Treatment of small-cell lung cancer with an alternating chemotherapy regimen given at weekly intervals: a Southwest Oncology Group pilot study.
We designed an intensive, weekly treatment regimen for patients with small-cell lung cancer (SCLC) using six of the most active chemotherapeutic agents for this disease (doxorubicin [DOX], cyclophosphamide [CTX], vincristine [VCR], etoposide [VP-16], cisplatin [CDDP], and methotrexate [MTX]). The goal of this program was to gain rapid, repetitive exposure to multiple, active drugs. Treatment was administered weekly for a total of 16 weeks. Seventy-six SCLC patients (limited disease, 34; extensive disease, 42) were treated. The overall complete plus partial response rate was 82%. Complete response rates of 47% and 38% were observed in patients with limited (LD) and extensive disease (ED), respectively. The median survivals for patients with LD and ED were 16.6 and 11.4 months, respectively. Toxicities were tolerable and were primarily hematologic. Twenty-six patients had one or more transient life-threatening toxicities, but only one patient developed a fatal toxicity. Eighty-four percent of the patients received 80% or greater of the intended protocol dosages over the entire 16-week treatment period. We conclude that this intensive, short-duration treatment regimen is at least as good as other "standard" regimens, and we are encouraged aged by the complete response rate and median survival in patients with ED SCLC.
Adult↗
Evaluation of menogaril in renal cell carcinoma. A Southwest Oncology Group phase II study (8504).
The Southwest Oncology Group (SWOG) studied the response rate and toxicity of menogaril (200 mg/m2 i.v. q 28 days) in patients with advanced metastatic renal cell carcinoma. During the early stage of the trial two partial responses were seen in the first 20 treated patients, and an additional 36 evaluable patients were studied. Three of 56 (5%) evaluable patients achieved partial responses. Significant white cell toxicity was observed. Mild or moderate degrees of thrombocytopenia, gastrointestinal side effects, alopecia and phlebitis occurred. No cardiac toxicity was noted. The low response rate suggests that menogaril in this dose schedule has no role in the treatment of patients with advanced metastatic renal cancer.
Antineoplastic Agents↗
Intracisternal injection of TRH precursor, TRH-glycine, stimulates gastric acid secretion in rats.
Intracisternal injection of thyrotropin-releasing hormone (TRH)-Gly (pGlu-His-Pro-Gly) produced a dose-dependent (1-100 micrograms) stimulation of gastric acid secretion in urethane-anesthetized rats implanted acutely with a gastric fistula. The peak response occurred 20-30 min after intracisternal injection and lasted for more than 2 h. Intravenous injection of TRH-Gly (100 micrograms) did not modify gastric acid secretion. Following intracisternal injection of TRH-Gly, a peak elevation of both TRH-Gly and TRH levels is observed in the cerebrospinal fluid (CSF) within 15 min. Thereafter, TRH values are returned to basal levels at 75 min after the injection, whereas TRH-Gly concentrations remain significantly elevated throughout the 2-h period of measurement. Compartmental analysis revealed that CSF conversion of TRH-Gly to TRH was only 0.0072%/min. Medullary coronal sections containing the dorsal vagal complex and the raphé nucleus revealed increased content of TRH-Gly, but not TRH, 40 min after administration of TRH-Gly at an intracisternal dose effective in stimulating gastric acid secretion (100 micrograms). In addition, TRH but not TRH-Gly (10(-7)-10(-5) M) displaced [3H]MeTRH binding from rat medullary blocks containing the dorsal vagal complex. These data suggest that the intracisternal TRH-Gly-induced stimulation of gastric acid secretion is not related to its conversion to TRH in the CSF, or direct activation of TRH receptors in the medulla. The acid secretory response of TRH-Gly may be due to the formation of TRH at the active brain sites, or alternatively to activation of its own specific receptors.
Animals↗
cis-Diamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: a Southwest Oncology Group Study.
A total of 26 patients with biopsy proved epidermoid carcinoma of the penis (Jackson stage III or IV) with measurable disease, no prior chemotherapy and adequate renal function received 50 mg. per M.2 cis-diamminedichloroplatinum intravenously on days 1 and 8 of 28-day cycles. There were 4 partial responses (15.4 per cent), with a response duration of 1 to 3 months. The median survival was 4.7 months. This agent cannot be recommended as treatment for advanced epidermoid carcinoma of the penis using this particular dose and schedule.
Carcinoma, Squamous Cell↗
Central nervous system action of TRH to influence gastrointestinal function and ulceration.
There is clear evidence in rats that TRH acts in the brain to stimulate gastric acid, pepsin, and serotonin secretion, mucosal blood flow, contractility, emptying, and ulceration through activation of parasympathetic outflow to the stomach (TABLE 3). A number of TRH analogues, including some devoid of TSH-releasing activity, mimic the effects of TRH. The most sensitive TRH sites of action to elicit gastric acid secretion and motility are located in the dorsal vagal complex and include the dorsal vagal, nucleus tractus solitarius, and nucleus ambiguus. The gastrointestinal tract is one of the most responsive visceral systems to the central effects of TRH, because doses in the range of 1-10 pmol in the dorsal vagal complex stimulate gastric function, whereas stimulation of cardiovascular and respiratory function on microinjection of the brainstem nuclei requires higher doses. Although fewer investigations have been carried out in other species, evidence from the available data clearly indicates that TRH acts in the brain to increase gastric secretion and motility in the rabbit, sheep, and cat. Lack of stimulation of gastric acid secretion after third ventricle injection in the dog may be related to species difference or to rapid degradation of the peptide before it reaches its site of action. TRH acts centrally to stimulate gastric function and also intestinal secretion, motility, and transit as reported mostly in rabbits (TABLE 3). TRH produces enteropooling and release of serotonin in portal blood, increases duodenal and intestinal contractility and colonic transit, and elicits diarrhea. All these effects were shown to be vagally mediated. Stimulation of intestinal motility and transit by central injection of TRH has been observed in rats and sheep. The biological activity of centrally injected TRH is well correlated with the presence of TRH immunoreactivity and receptors in the dorsal vagal complex containing afferent and efferent connections to the stomach. Moreover, endogenous release of brain TRH in rats mimics the stimulatory effect of centrally injected TRH on gastric function. Although the lack of a specific TRH antagonist has hampered assessment of the physiological role of TRH, converging neuropharmacological, neuroanatomical, and physiological findings support the concept that TRH in the dorsal vagal complex may play a physiological role in the vagal regulation of gastrointestinal function.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗