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Biomedical subjects

H I Robins

Publications and source records attributed to H I Robins.

At least 55 records · Page 3Linked to original sources
PubMed1993

Phase I clinical trial of carboplatin and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes in a phase I clinical trial. PATIENTS AND METHODS: Thirty assessable patients with cancer refractory to conventional therapy were treated. During induction therapy, patients received WBH alone in week 1, WBH plus carboplatin in week 2, and carboplatin alone in week 5. Carboplatin dose was escalated (three patients per group) as follows: 100, 150, 200, 250, 300, 350, 400, 480, and 575 mg/m2; three additional patients were entered at 480 mg/m2. Carboplatin was administered at target temperature. RESULTS: Comparisons of the mean/median WBC and platelet nadirs for carboplatin alone and carboplatin plus WBH demonstrated no enhancing effect by WBH. Toxicities including nausea and/or vomiting, as well as myelosuppression, were within acceptable limits, allowing for escalation to a dose of 575 mg/m2; three of three patients at this dose level experienced grade 4 myelosuppression with no associated infection or bleeding. No renal toxicity was observed. Analysis of platinum in plasma ultrafiltrate and urine showed only slight effects of WBH on the pharmacokinetics and renal excretion of platinum. Responses included the following: lung--minor response (200 mg/m2); gastrointestinal neuroendocrine--complete response (CR) (400 mg/m2); pancreatic--partial response (PR) (480 mg/m2); small bowel--PR (575 mg/m2); ovarian--CR, two patients (575 mg/m2), with marker data suggesting WBH enhancement of carboplatin cytotoxicity. Another three patients experienced clinical improvement after WBH plus carboplatin, but progression with carboplatin alone (lung, 400 mg/m2; gastrointestinal neuroendocrine, 480 mg/m2; melanoma, 480 mg/m2). CONCLUSION: We conclude that carboplatin with WBH is well tolerated even at conventional carboplatin doses. Clinical results are consistent with preclinical predictions of an increased therapeutic index for this combination, which encourages future clinical studies.

Adult↗
PubMed1993

Response of "benign" metastasizing leiomyoma to progestin withdrawal. Case report.

We report a rare case of a benign metastasizing leiomyoma in which progestin therapy permitted or promoted pulmonary metastases, but progestin withdrawal induced a marked tumor regression. The significance of these observations is discussed relative to the estrogen and progesterone receptor positivity of this patient's tumor.

Female↗
PubMed1991

Effect of hyperthermia in vitro and in vivo on adenine and pyridine nucleotide pools in human peripheral lymphocytes.

Hyperthermia has been shown in vitro and in vivo to potentiate the effects of ionizing irradiation. Previous studies found that hyperthermia alters the metabolism of adenosine diphosphate (ADP)-ribose polymers required for recovery from DNA damage and that poly(ADP-ribose) polymerase activity is very sensitive to cellular nicotinamide-adenine dinucleotide (NAD) levels. Thus, the effect of 41.8 degrees C hyperthermia in vitro and in vivo on NAD and adenosine triphosphate (ATP) levels was studied in human peripheral lymphocytes. In vitro studies showed significant decreases in oxidized NAD (NAD+) and ATP levels after heating that simulated a clinical whole-body hyperthermia (WBH) treatment. This nucleotide depletion could not be attributed to nucleotide leakage or increased enzymatic NAD+ consumption. As the reduction of NAD observed was sufficient to decrease poly(ADP-ribose)polymerase activity by 50%, the studies were extended to clinica cases. Cellular NAD+ and ATP were measured in previously stored lymphocytes obtained from four patients before and after WBH; a statistically significant decrease in NAD+ was observed after WBH which quantitatively agreed with the in vitro results. Based on these results a prospective study was done in three patients; NAD+ was extracted immediately on sample collection, and the kinetics of WBH-induced NAD depletion were studied. These data, which agree quantitatively with the laboratory results, are presented.

Adenosine Triphosphate↗
PubMed1991

Thymidine-cisplatin vs thymidine-carboplatin interactions in human T-cell acute leukemia.

Thymidine is shown to sensitize JM human T-cell acute leukemia cells to cisplatin killing in vitro with dose modifying factors of 1.72, 1.62, and 1.76 at 200, 500, and 1000 micrograms thymidine/ml x 24 h. The magnitude of thymidine-cisplatin sensitization increases with longer thymidine exposures (500 micrograms/ml) up to 16 h but is not further increased at 24 h. For a 25 h thymidine exposure, enhancement is greater for cisplatin (3 micrograms/ml x 1 h) starting 12-24 h into the thymidine exposure vs starting at 0-8 h (p less than or equal to 0.0004). Results are precisely the same for simultaneous studies using carboplatin except that (1) thymidine enhances carboplatin cytotoxicity more than cisplatin killing, (2) enhancement of carboplatin killing varies little with the timing of carboplatin administration during a 25 h thymidine exposure. These findings are discussed relative to their clinical applicability.

Carboplatin↗
PubMed1991

Combined modality clinical trials for favorable B-cell neoplasms: lonidamine plus whole body hyperthermia and/or total body irradiation.

Favorable B-cell neoplasms provide an excellent clinical model to evaluate the use of systemic multimodality therapy as an approach to the problem of tumor cell heterogeneity. Inherent in this concept is the use of multiple antineoplastic agents to produce supra-additive cytotoxicity without sacrificing therapeutic index. The results of three completed clinical studies and complementary laboratory investigations are reviewed to illustrate an innovative approach to the nodular lymphomas and chronic lymphocytic leukemia. The clinical trials summarized include: A) the combination of 41.8 degrees C whole body hyperthermia (WBH) and the chemotherapeutic drug lonidamine; B) the use of total body irradiation (TBI) (12.5 cGy twice a week, every other week--total planned dose 150 cGy) and daily oral lonidamine; C) the juxtapositioning of TBI (with the same fraction schema) and 41.8 degrees C WBH x 75 min--initiated 10 min after TBI. Also presented is the laboratory rationale and early clinical results for combining lonidamine, TBI, and WBH.

Animals↗
PubMed1991

Radiosensitization of human T-cell leukemia by thymidine and 41.8 degrees C hyperthermia in vitro.

This study tested whether thymidine, a naturally occurring nucleoside metabolite, could increase the sensitivity of human T-cell neoplasms to ionizing irradiation and whether adding 41.8 degrees C hyperthermia (X 1 h) to the combination of thymidine and irradiation would further enhance killing of cells by radiation. The magnitude of cytotoxicity induced directly by thymidine was also evaluated. Finally, the ability of 2'-deoxycytidine to prevent thymidine-induced cytotoxicity and radiosensitization was studied. Using JM and MOLT3, two human T-cell acute lymphoblastic leukemias, it was found that thymidine itself was cytotoxic and the toxicity appeared rapidly upon exposure to the drug (i.e., at 4 h). Thymidine caused significant radiosensitization, and thymidine plus 1 h of 41.8 degrees C hyperthermia enhanced radiation-induced killing significantly more than did thymidine or hyperthermia separately. The addition of 2'-deoxycytidine only partly reversed thymidine-induced killing and did not prevent thymidine-induced radiosensitization. The applicability of these results to the clinical management of T- and null-cell malignancies is discussed, as is the presumed mechanistic basis for these observations relative to deoxyribonucleoside metabolism, NAD metabolism, and inhibition of poly(ADP-ribose) polymerase.

Cell Survival↗
PubMed1990

Thymidine enhancement of carboplatin cytotoxicity: in vivo studies in normal B6D2 F1 mice.

Our laboratory has previously demonstrated that 4-24-h thymidine exposures (50-1000 micrograms/ml) will enhance carboplatin cytotoxicity 2-3.3-fold in vitro. In order to show that these results are clinically applicable, we performed 24-h thymidine infusions with and without carboplatin in B6D2 F1 mice. The mice were evaluated for myelosuppression, weight loss and development of diarrhea. Results obtained demonstrated that thymidine did not enhance systemic carboplatin toxicity. The clinical relevance of these results is discussed.

Animals↗
PubMed1990

Radiant heat systemic hyperthermia clinical trials.

Results of a Phase I study led our group to the conclusion that a radiant heat system provides a safe and effective method of inducing 41.8 degrees C whole body hyperthermia (WBH) which is suitable for combination therapy. The review to follow summarizes our progress in combining WBH with other cancer-treatment modalities, including ionizing irradiation, chemotherapy and immunotherapy.

Clinical Trials as Topic↗
PubMed1990

Whole body hyperthermia and intraperitoneal carboplatin in residual ovarian cancer.

Intraperitoneal (IP) cisplatin-based chemotherapy provides prolonged disease-free survival in some women with residual peritoneal ovarian cancer following systemic chemotherapy. This review presents several considerations which support the combined use of IP carboplatin and whole body hyperthermia in this patient population. This novel treatment approach is predicated on projected advantages which relate to improved therapeutic index.

Carboplatin↗
PubMed1990

Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine.

Thymidine (a nucleoside metabolite) and 41.8 degrees C hyperthermia were used to sensitize C6 glioma cells to carboplatin cytotoxicity in vitro. Clinically achievable thymidine concentrations (0, 200, 400, or 1000 micrograms/ml X 24 hours) significantly enhanced carboplatin killing. Clinically achievable hyperthermia exposures (40.5 or 41.8 degrees C X 1 hour) also enhanced carboplatin killing; 41.8 degrees C was more effective than was 40.5 degrees C. Thymidine and 41.8 degrees C hyperthermia together enhanced carboplatin killing significantly more than did the thymidine-carboplatin or hyperthermia-carboplatin combinations. These results illustrate the concept of 'combination chemosensitization' for simultaneously addressing the divergent drug resistance mechanisms of malignant gliomas.

Animals↗
PubMed1990

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines.

Diethyldithiocarbamate (DDTC) and other dithiocarbamates are currently receiving attention as potential adjuncts to traditional chemotherapy. In vitro studies with rodent cancer cell lines have consistently shown that DDTC concentrations of 0.1-1.0 micrograms/ml are highly cytotoxic. Paradoxically, however, concentrations of 10-100 micrograms/ml have been significantly less toxic. In the present study, such a 'biphasic' pattern was reproduced when 3 rodent cell lines were exposed for 1 hour to 0.001 to 1000 micrograms DDTC/ml. In contrast, in 7 human cell lines survival decreased steadily with increasing DDTC concentration (in the same dose range) without evidence of a biphasic pattern. These data might have implications for studies in which rodent cell lines are used to model the effects of dithiocarbamates in human tissues.

Animals↗
PubMed1990

Phase II study of lonidamine in patients with metastatic breast cancer. An Eastern Cooperative Oncology Group study.

The Eastern Cooperative Oncology Group conducted a phase II study of lonidamine in patients with metastatic breast cancer. The drug was given orally to a maximum daily dose of 340 mg/m2. Forty-two patients were entered on study. One partial response was observed; there were no life-threatening toxicities. The results of this study are compared to two similar phase II trials.

Adult↗
PubMed1990

Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B-cell neoplasms: a report of two pilot clinical trials and laboratory investigations.

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Adult↗
PubMed1990

Radiosensitization of C6 glioma by thymidine and 41.8 degrees C hyperthermia.

The cytotoxic, antiproliferative, and radiosensitizing effects of thymidine (a nucleoside metabolite) were studied using the C6 glioma cell line in vitro. Radiosensitization by a combination of thymidine and 41.8 degrees C hyperthermia was also evaluated. Thymidine concentrations above 100 micrograms/ml completely inhibited C6 proliferation while concentrations of 100 to 1000 micrograms/ml (for up to 24 hours) decreased C6 cell survival to as little as 7.4% compared to untreated control cells. Radiosensitivity was enhanced by the administration of thymidine alone (400 micrograms/ml x 24 hours before irradiation); sensitization by 41.8 degrees C hyperthermia alone (1 hour ending immediately before irradiation) was less pronounced. Thymidine and hyperthermia together produced greater radiosensitization than did heat alone or thymidine alone. These data support the further investigation of thymidine as a neuro-oncology radiosensitizer.

Animals↗
PubMed1989

Preferential binding of radiolabeled poly-L-lysines to C6 and U87 MG glioblastomas compared with endothelial cells in vitro.

This report describes the preparation of polylysine-diethylene triamine pentaacetic acid (DTPA)-metal ion complexes and of iodinated polylysine derivatives and the preferential binding of these polymers to glioblastomas in culture. Synthetic polylysines (DP88 and DP299) were modified covalently either with the chelator DTPA or with 125I-Bolton Hunter reagent. The polylysine (DP88) was modified initially with fluorescein to permit fluorescence cytological studies and quantitative measurements of polylysine concentrations. The polylysines contained an average of one DTPA per 16 lysyl moieties. The polylysine-DTPA derivatives were then modified with a mixture of 153Gd and stable Gd. A copolymer (DP120) of lysine and tyrosine (4:1) was modified with 125I using chloramine T as catalyst. C6 (rat) and U87 MG (human) glioblastoma cells, in culture, bound six to seven times more polylysine-DTPA-Gd than endothelial cells from either aorta or brain. Each of the tumor cell types bound 10(8) molecules of the modified polylysine per cell when 2.5 x 10(5) cells were reacted with 50 micrograms or greater of the polylysine-DTPA-nuclide complex. The higher molecular weight polylysines delivered more radionuclide to the cells in culture. Although the tumor cells bound more [125I]polylysine and [125I]poly(lysine HBr,tyrosine) than they bound polylysyl-DTPA-Gd, the endothelial cells and the plastic culture dish also bound more of the iodinated polymers. The stoichiometry of polylysine bound per cell suggests that the sialic acid moieties on the cell surface are the primary binding sites for polylysine derivatives. Fluorescence microscopy studies revealed that the fluorescein polylysine (DP88) and the fluorescein polylysine-DTPA nuclide complex bound the tumor cells primarily at branch points along the neuritic processes, at the edge of the perikaryon and at the terminal regions of the outgrowth process. The polylysyl-DTPA-Gd can be used, with magnetic resonance imaging, to provide measurable contrast of the margin between C6 glioblastomas and normal brain in vivo in Wistar Furth rats.

Animals↗