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Biomedical subjects

R H Wheeler

Publications and source records attributed to R H Wheeler.

At least 73 records · Page 4Linked to original sources
PubMed1984

Combination cisplatin and dichloromethotrexate in patients with advanced or recurrent cervical cancer: a preliminary report.

The chemotherapy combination of cisplatin and dichloromethotrexate was administered to 14 patients with measurable cervical cancer. Six (46%) have had a complete response for 6+, 7, 11, 14, 15, and 21 months. Four (30%) have had a partial response for 1, 6, 10, and 11 months. Two patients (15%) have had stable disease for 6 and 11 months. Only one patient failed to respond to this combination. In six of these patients, the measurable mass was located in a previously radiated area. This combination was well tolerated with only three instances of severe toxicity. No irreversible renal dysfunction was seen in any patient.

Adult↗
PubMed1984

Radionuclide localization of intraarterial infusions in head and neck cancer.

The therapeutic advantage of intraarterial infusion chemotherapy depends upon delivery of a high drug concentration to the entire tumor bulk with maximum sparing of critical normal tissues. It is clear that successful application of regional therapy must include methodology to assess quantitatively and qualitatively the infused area. 99mTc macroaggregated albumin (Tc-MAA) injected intraarterially is held on first pass in the arteriolar capillary bed, thus providing a map of blood flow distribution. Analog and digital planar images and single photon emission computed tomography (SPECT) after Tc-MAA injections provide static and transaxial tomographic images of head and neck intraarterial infusions. SPECT can be viewed as an endless movie-type display, thus producing a "rotating cimematic display." These radionuclide localization techniques provide a three-dimensional delineation of the tissues infused, including subsurface details not appreciated with dye injection alone. These procedures should be considered an integral part of intraarterial therapy of head and neck cancer.

Head and Neck Neoplasms↗
PubMed1984

A phase I-II trial of cisplatin and dichloromethotrexate in squamous cell cancer of the head and neck.

Dichloromethotrexate, a dihalogenated analog of methotrexate, is excreted and metabolized by the liver; therefore, blood levels are not dependent on renal function. The possibility that dichloromethotrexate could be given at its maximally tolerated dose in combination with high-dose cisplatin has been evaluated in 30 patients with advanced squamous cell cancer of the head and neck. Overall, this regimen was well tolerated, and 13 of 24 evaluable patients had an objective response to therapy (25% complete response and 29% partial response). The maximum dose of dichloromethotrexate that could be delivered was related to the serum albumin. Patients with an albumin less than 3.8 g/100 mL rarely tolerated doses of 500 mg/m2 or greater. Cisplatin plus dichloromethotrexate is an active drug combination in squamous cell cancer of the head and neck, and deserves further evaluation in randomized studies and in an adjuvant setting.

Adult↗
PubMed1984

Phase II trial of ICRF-187 in squamous cell carcinoma of the head and neck.

A phase II trial of ICRF-187 (1.0 g/m2/48 hours by continuous infusion every 3 weeks) was conducted in 25 patients with advanced squamous cell cancer of the head and neck. There were two partial responders for an overall response rate of 8%. Sixteen of the patients had not received prior chemotherapy and both responding patients were in this group. The major side effect of ICRF-187 was reversible leukopenia.

Aged↗
PubMed1983

Intensive sequential chemotherapy with bleomycin, Oncovin, mitomycin C, and methotrexate followed by adriamycin, cisplatin, and cyclosphosphamide in squamous cell cancer of the head and neck.

Twenty-six patients with advanced squamous cell cancer of the head and neck were treated with bleomycin, Oncovin, mitomycin C, and methotrexate (BOMM) for ten weeks. Partial and nonresponders then received adriamycin, cisplatin, and cyclophosphamide (APC) in a planned sequential program. The response rate to BOMM was 65% (19% complete remission, CR). The overall response rate to APC was 20%. Only three of eight nonresponders to BOMM could receive APC and non responded. Six of seven partial responders received APC and only one responded. One complete responder to BOMM received APC at relapse and attained a partial response. The major side effects of BOMM were mucositis and myelosuppression. Patients receiving methotrexate 60-72 hours following the bleomycin infusion had less myelosuppression than patients who were treated 36-42 hours after bleomycin. The toxicities with APC included nausea, vomiting, and myelosuppression. Including a prior series, a total of 45 patients have been treated with BOMM with a 71% response rate (69% in previously irradiated patients). Twenty-eight percent of previously treated patients achieved complete remission, and two of these patients are disease free at 31 and 37 months. Methotrexate dose-rate alteration to low dose twice weekly followed by a single dose of oral leucovorin did not improve the complete or partial response rate when compared to weekly methotrexate administration. The complete remission rate and response duration were also not improved by the planned sequential use of this cisplatin-containing regimen.

Adult↗
PubMed1983

The cytokinetic and cytotoxic effects of ICRF-159 and ICRF-187 in vitro and ICRF-187 in human bone marrow in vivo.

The cytotoxic and cytokinetic effects of ICRF-159 and its d-enantiomer ICRF-187 have been examined in vitro. The effects of both agents were identical. Cytotoxicity is dependent on both the drug concentration and the duration of drug exposure. Drug exposure for twice the cell cycle time is necessary for maximum effect. Cytotoxicity is also dependent upon the rate of cell proliferation. A rapidly growing cell population is more sensitive to brief drug exposure than a slowly growing population. The cytokinetic effects were studied using flow cytometry, determination of [3H]-thymidine incorporation and mitotic index. ICRF-159/187 appears to act only during the G2 phase of the cell cycle. There is no detectable delay in cell passage through the G1/S boundary or in transit through S phase. Inhibition of DNA synthesis occurs only after the G2 block prevents subsequent entry of cells in S phase. A fraction of the cells, depending upon drug concentration, undergo further DNA synthesis without cell division, resulting in a tetrapoid cell population. The cytokinetic effects were determined in the bone marrow of patients receiving ICRF-187. All dose-rates produced G2/M accumulation in the marrow with depletion of S phase cells. One patient was given a single injection of 1.0 gm/M2 . G2/M accumulation was observed 24 h after treatment, with recovery to a pretreatment DNA cycle distribution 24 h later. These studies suggest that a continuous drug infusion, or intermittent infusions timed to allow the normal cell population to recover, may produce superior clinical activity with this agent. A Phase I study of such an intermittent schedule is indicated.

Antineoplastic Agents↗
PubMed1983

Phase I evaluation of semustine in a weekly schedule.

A phase I study of weekly semustine was conducted in 32 patients with advanced cancer. Doses were escalated from 18 to 36 mg/m2/week. At a dose of 36 mg/m2/week, 43% of the patients developed platelet counts less than 100,000/mm3 after a median of 20 weeks on study, and 25% developed wbc counts less than 3000/mm3 after a median of 16 weeks on study. Drug-related nausea was reported by only one patient and was the only subjective toxic effect reported. Tumor regressions were noted in patients with adenocarcinoma of the colon, melanoma, and mixed adenocarcinoma and squamous cell lung cancer. A reasonable starting dose for phase II studies is 36 mg/m2/week, with dose adjustments based on platelet and wbc counts.

Dose-Response Relationship, Drug↗
PubMed1982

Combination chemotherapy of refractory lymphoma with cis-dichlorodiamineplatinum, vinblastine, and bleomycin.

Therapy of advanced lymphomas after failure of chemotherapy with cytoxan and adriamycin containing combinations remains poor. We have treated 17 patients with refractory lymphomas of various histologies with an intensive regimen of cisplatin, vinblastine and bleomycin. These were three complete clinical responses (6, 10+, 8 months, respectively) and five partial responses (2.5, 3, 4, 7, 18 months, respectively) for a total of 8/17 responders. Four of the eight responders had bone or bone marrow involvement. In addition, three patients had dramatic shrinkage of measureable lesions, but the duration (less than 1 month) was too short to allow classification as a response. Toxicity included severe myelosuppression requiring that patients be hospitalized to the majority of cases, mild to moderate rise in serum creatinine levels in 41% of patients and one case of fatal pulmonary fibrosis. This regimen may be useful in patients with refractory or relapsing lymphoma; alternatively, it may be useful as part of an initial treatment protocol utilizing non-cross-resistant regimens for the management of patients with poor prognosis lymphomas.

Adult↗
PubMed1982

Cytokinetic evaluation of the four-drug combination of bleomycin, vincristine, mitomycin C, and methotrexate (BOMM) in cultured Burkitt's lymphoma cells and human bone marrow.

The four-drug combination of bleomycin, vincristine, mitomycin C and methotrexate produces a high response rate in patients with squamous cell carcinoma. In this study we have examined the cytokinetic effects of this drug combination in vitro and in human bone marrow in vivo. The in vitro analysis revealed that mitomycin C produces a concentration dependent slowing of S-phase transit with partial G2/M and G1/S blocks in cell cycle progression. A partially synchronized S-wave occurs 4-8 and 16-20 hours following a two-hour drug exposure. Bleomycin produces a dose dependent G2/M block during a 14-hour drug exposure. Drug removal did not result in appreciable cell cycle synchrony. In vitro exposure to the two drug combination resulted in loss of both the marked G2/M accumulation seen with bleomycin, and the partially synchronized S-phase waves seen following mitomycin C exposure. The sequential changes in bone marrow cytokinetics were determined in eight patients during and following administration of vincristine, mitomycin C and a continuous four-day infusion of bleomycin. The major cytokinetic changes observed were an increase in G2/M phase cells 18 hours following vincristine, and an increase in thymidine incorporation and S-phase cells 24 and 48 hours following the end of the bleomycin infusion. The clinical course of 24 patients was reviewed. Eleven patients who received methotrexate 36 to 42 hours following bleomycin had a subsequent median leukocyte nadir of 1.8 x 10(3)/mm3. Thirteen patients receiving methotrexate 60 to 72 hours after bleomycin had median leukocyte nadir of 3.9 x 10(3)/mm3. The objective response rates in the two groups was 75% and 80%, respectively. This study demonstrates that bone marrow cytokinetic analysis may allow schedule modification to avoid myelosuppression without loss of therapeutic activity.

Antineoplastic Agents↗
PubMed1982

Innovative regional therapy for head and neck cancer.

A totally implantable infusion pump (infusaid) has been developed to achieve continuous drug delivery for long periods of time. The recent availability of a dual-catheter totally implantable infusion pump permits the infusion of both external carotid arteries simultaneously. This has obvious advantages for the treatment of extensive tumors of the head and neck that extend across the midline. Likewise, for the first time, unilateral local-regional disease that extends inferiorly beyond the nutrient field of the external carotid artery may be treated with intra-arterial infusion chemotherapy without the need to infuse the common carotid or innominate arteries. Unilateral infusion of the entire head and neck is accomplished by using the dual-catheter pump to infuse both the thyrocervical trunk and the external carotid artery.

Antineoplastic Agents↗
PubMed1982

Long-term intraarterial chemotherapy infusion of ambulatory head and neck cancer patients.

The complications of percutaneous intraarterial infusion chemotherapy of the head-and-neck-cancer patient has dampened enthusiasm for this approach. A totally implantable infusion pump system circumvents many of these complications and will in the long term enhance the opportunity to expand upon the advantages of infusion chemotherapy for the benefit of all cancer patients.

Adult↗
PubMed1982

High-dose doxorubicin: an exploration of the dose-response curve in human neoplasia.

Twenty-seven patients with advanced solid tumors (ten with lung cancer, eight with sarcoma, five with melanoma, four with miscellaneous tumors) were treated with high-dose doxorubicin (120 mg/m2) every 3 weeks for a total of 75 courses. As expected, marked myelosuppression was observed, with all patients having a granulocyte count nadir of less than 500 cells/mm3. The median platelet count nadir was 91 X 10(3)/mm3 following the first cycle and 50 X 10(3)/mm3 following the fourth cycle. Moderate or severe stomatitis was seen with 65% of the courses, and 46% of the courses were complicated by fever greater than 101 degrees F. Congestive heart failure was observed in only one patient after five cycles (600 mg/m2) of high-dose therapy. This patient has received 540 mg/m2 of doxorubicin 2 years previously. Radionuclide ventriculography (MUGA) performed serially in 12 patients (eight of whom received 480 mg/m2) and clinical evaluation did not suggest an increased risk of cardiotoxicity at this dose rate. Overall, 11 of 24 (46%) evaluable patients responded (58% if patients with malignant melanoma are excluded). Responses included one complete and three partial responses in eight evaluable patients with lung cancer, one complete and two partial responses in seven evaluable patients with sarcoma, and no objective responses in five patients with malignant melanoma. With appropriate supportive care, repetitive courses of doxorubicin at a dose of 120 mg/m2 can be given to patients of good performance status without a major increase in cardiotoxicity. However, the low complete remission rate, considering the observed toxicity, does not justify routine use of this regimen in patients with solid tumors.

Adult↗
PubMed1981

Glucocorticoid receptor activation and inactivation in cultured human lymphocytes.

Although glucocorticoids are not cytolytic for and do not inhibit the growth of the IM-9 line of cultured human lymphoblasts, these cells have a high steroid-binding capacity. We have used IM-9 cells in order to examine whether unoccupied glucocorticoid receptors are inactivated and activated in intact cells. when IM-9 cells are incubated in glucose-free medium in a nitrogen atmosphere, both their ability to bind triamcinolone acetonide and their ATP levels decline and, when glucose and oxygen are reintroduced, ATP levels and receptor activity return. The specific glucocorticoid-binding activity of cytosol prepared from cells exposed to various degrees of energy limitation is directly correlated with the ATP content. Receptor activation in intact cells is rapid and independent of protein synthesis. Cytosol prepared from inactivated cells cannot be activated by addition of ATP. The inactivation of glucocorticoid receptors that occurs when cytosol from normal IM-9 cells is incubated at 25 degrees C is inhibited by molybdate, vanadate, fluoride, ATP, and several other nucleotides. The experiments with intact human lymphoblasts suggest that assays of specific glucocorticoid-binding capacity do not necessarily reflect the cellular content of receptor protein.

Adenosine Triphosphate↗
PubMed1981

Mesenteric angiopathy, intestinal gangrene, and midgut carcinoids.

Twenty-six cases of carcinoid-related mesenteric angiopathy and intestinal infarction (three from our institution and 23 previously reported cases) were reviewed. Twenty patients presented with acute abdominal findings, including peritonitis (13 cases), intestinal obstruction (five cases), and bleeding per rectum (two cases). Fifteen patients (75%) experienced antecedent symptoms of abdominal pain and/or diarrhea, averaging 2.5 years in duration. Twelve patients (46%) exhibited symptoms of carcinoid syndrome. Mesenteric angiography in three cases demonstrated encasement and segmental branch narrowing or occlusion of major mesenteric vessels. Eleven patients underwent resection and primary bowel anastomosis with an early survival rate of 91%. Four additional patients who underwent lesser surgical procedures and five patients who did not undergo operation all died. Elastic vascular sclerosis (EVS) was identified in 19 of 22 cases with available histologic material (86%). These changes were observed in proximity to as well as distant to the primary tumor. In general, the severity of EVS did not correlate with the likelihood of gut ischemia. Although not the sole cause of intestinal gangrene in patients with midgut carcinoids, EVS may contribute significantly to the evolution of these ischemic changes.

Adult↗
PubMed1979

Effect of hyperbaric oxygen on the cytotoxicity of adriamycin and nitrogen mustard in cultured Burkitt's lymphoma cells.

The effects of hyperbaric oxygen (HPO) exposure on the cytotoxicity of Adriamycin (ADM) and nitrogen mustard have been examined in Burkitt's lymphoma cells (P3J) in vitro. Exposure of cells to 3 atmospheres of pressure HPO for 2 hr produces inhibition of DNA synthesis and mitosis. Simultaneous exposure to HPO and ADM results in decreased cytotoxicity compared to drug treatment alone. However, exposure to ADM (0.15 microgram/ml) 2 to 8 hr before or after HPO produces an increase in drug effect. There is no potentiation of lower ADM concentrations. Cytotoxicity is increased when cells are exposed to HPO during, before, or after exposure to nitrogen mustard (NSC 762) (0.15 and 0.25 microgram/ml). Lower nitrogen mustard (NSC 762) concentrations are not potentiated. HPO potentiation of antineoplastic agents appears to depend upon the agent studied, the concentration of the agent, and the scheduling of the drug and HPO exposure.

Burkitt Lymphoma↗