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Biomedical subjects

S B Howell

Publications and source records attributed to S B Howell.

At least 181 records · Page 10Linked to original sources
PubMed1987

Evidence against ras activation in human ovarian carcinomas.

Activation of ras genes in human ovarian carcinomas and ovarian carcinoma cell lines was tested by transfection of NIH 3T3 cells with high molecular weight DNA extracted from fresh tumors or from cell lines. Of 18 ovarian tumors and tumor cell lines that were exhaustively tested, only one yielded DNA active in focus-induction in this assay. Southern blot analysis of DNA in serially transformed NIH 3T3 foci revealed restriction fragments that hybridized with a probe specific for the human N-ras oncogene and with human repetitive (Alu) sequences. Individually transformed foci contained N-ras hybridizing fragments of different sizes. Northern blots of RNA extracted from different transformants revealed the expression of different transcripts hybridizing with the N-ras probe. The transformants also expressed a 700 base RNA that hybridized with a human B-lym probe. The low prevalence of ras activation in ovarian tumors as measured by transforming capability suggests that ras activation does not play an important role in the development of most human ovarian tumors.

Animals↗
PubMed1987

Gene therapy for thioguanine-resistant human leukemia.

The feasibility of using retroviral gene therapy to overcome drug resistance was assessed by determining the efficiency by which a retrovirus containing the human HGPRT gene could sensitize hypoxanthine-guanine phosphoribosyltransferase (HGPRT) negative human promyelocytic leukemia cells to 6-thioguanine. A single three-hour exposure at a virus to cell ratio of 6 X 2:1 restored sensitivity to 70(+/- 18)% of the clonogenic cells. The efficacy varied as a function of virus concentration and duration of viral exposure; the time allowed for integration and expression between one and five days post-infection had little effect. Cells successfully sensitized contained a proviral insert and expressed HGPRT activity that ranged from 1 to 92% of that in the wild-type cells. The mutation rate of the inserted gene varied from the same as that of the endogenous HGPRT gene to 200-fold greater in different clones. Failure of sensitization following viral exposure was associated with absence of an integrated provirus, and clonogenic cells failing to be sensitized by one virus exposure were sensitized with approximately the same efficiency by a second viral exposure. These results demonstrate the feasibility of transferring a drug sensitivity gene to a human leukemia cell line.

Cell Line↗
PubMed1987

Multivesicular liposomes containing cytarabine for slow-release Sc administration.

Sc administration of cytarabine entrapped in multivesicular liposomes to BDF1 mice resulted in slow first-order release from skin, with a half-life of 4 days. The half-life was 10 minutes for unencapsulated free drug. A single-dose sc treatment of BDF1 mice, inoculated iv with 10(5) L1210 leukemia cells 24 hours previously, resulted in long-term survivors over a wide dose range. This study demonstrates that encapsulation of cytarabine in multivesicular liposomes results in slow release from skin and that a single sc dose is often curative for mice with systemic leukemia.

Animals↗
PubMed1986

Cisplatin administered by the intracavitary route as treatment for malignant mesothelioma.

Twenty-one patients with malignant mesothelioma were treated with an experimental intracavitary chemotherapy regimen of weekly intraperitoneal or intrapleural cisplatin (90-100 mg/m2) with simultaneous intravenous sodium thiosulfate delivered to protect against cisplatin-induced nephrotoxicity. One of eight patients (12.5%) receiving intrapleural therapy and nine of 13 patients receiving intraperitoneal therapy demonstrated objective evidence of a clinical response, including three surgically defined major tumor regressions (23%). Patients receiving intrapleural treatment had more advanced disease prior to therapy than those receiving intraperitoneal therapy. It was concluded that intraperitoneal cisplatin is an active treatment program for intra-abdominally localized mesothelioma. Additional investigation of intrapleural cisplatin should be undertaken in a patient population with less advanced disease or following surgical debulking.

Actuarial Analysis↗
PubMed1986

Pharmacologic studies of intra-hepatic artery chemotherapy with degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the pharmacokinetics of 4 drugs administered via the hepatic artery was studied in 5 patients with colon carcinoma metastatic to the liver. The 4 drugs were 99m-technetium diethylenetriamine pentaacetic acid (99mTc-DTPA), an agent which is not metabolized in the liver, and floxuridine, doxorubicin, and mitomycin, agents which undergo hepatic metabolism to varying extents. DSM transiently decreased arterial blood flow to normal liver an average of 64% and to hepatic tumor an average of 78%. DSM increased tumor exposure to DTPA by a mean of 1.71-fold, and increased hepatic exposure by 1.46-fold, but did not affect total plasma exposure. In contrast, DSM did reduce total plasma exposure to floxuridine by a mean of 34%, and to mitomycin by 20%. No information was available on the effect of DSM on plasma doxorubicin levels which never exceeded the limits of detection. Variation in the injection rate of DSM did not appear to influence the relative advantages produced in tumor or plasma AUCs. The estimated increase in tumor exposure produced by DSM was 3.8-fold for floxuridine, and 3.0-fold for mitomycin. These results reflect the differences in extent of hepatic metabolism of these agents, and agree closely with predictions made from mathematical models. Although DSM improved the therapeutic index, the increase in tumor exposure was insufficient to produce significant tumor regression.

Adult↗
PubMed1986

Peritoneal access for intracavitary chemotherapy.

Direct intraperitoneal instillation of many chemotherapeutic agents can markedly increase total peritoneal drug exposure and may be useful for the treatment of ovarian carcinoma and mesothelioma. The use of a totally implanted access system (Port-a-CathTM) reduces the risk of inadvertent bowel damage, and infection associated with repeated intraperitoneal instillation of drugs. In addition, patient acceptance is better in comparison to catheters that protrude through the skin. Catheter failure due to the formation of adhesions around the outside of the catheter remains a major problem.

Antineoplastic Agents↗
PubMed1986

Hypomagnesemia following high-dose intracavitary cisplatin with systemically administered sodium thiosulfate.

Seventy-one patients receiving a minimum of two courses of high-dose intracavitary cisplatin (100-200 mg/m2/course) with i.v. thiosulfate administered to protect against cisplatin-induced renal insufficiency were retrospectively evaluated to examine the influence of thiosulfate and large cumulative doses of cisplatin on the incidence of hypomagnesemia. Only 8% of 50 patients who had normal serum magnesium levels prior to the initiation of the experimental program became hypomagnesemic during the therapeutic trial. Similarly, while 67% of the 21 patients with low initial serum magnesium levels remained hypomagnesemic, 33% had normal serum levels at the completion of therapy. It is suggested that the intravenous administration of thiosulfate might have been responsible for the strikingly low incidence of hypomagnesemia in this patient population. A prospective evaluation of the utility of sodium thiosulfate in preventing cisplatin-induced renal magnesium wasting appears indicated.

Adult↗
PubMed1986

Ip chemotherapy employing a regimen of cisplatin, cytarabine, and bleomycin.

Thirty-seven patients with refractory ovarian carcinoma or other malignancies principally confined to the peritoneal cavity were treated with a combination ip chemotherapy regimen consisting of cisplatin (100 or 200 mg/m2), cytarabine (1,200 mg/m2), and bleomycin (15 or 2 U/m2) repeated at 28-day intervals. Sodium thiosulfate was simultaneously administered iv to protect against cisplatin-induced nephrotoxicity. While only one of 18 patients (6%) with bulky residual ovarian carcinoma experienced a partial remission, two of six evaluable patients with minimal residual disease experienced surgically defined complete remissions. Local abdominal pain was often severe with the higher dose of bleomycin and was occasionally a problem with the lower dose schedule. Fever was common (greater than 70% of courses), but was reduced in degree by pretreatment with steroids. We conclude that combination ip chemotherapy with this three-drug regimen can result in objective tumor regressions and surgically defined complete remissions in patients with minimal residual ovarian carcinoma who have failed to achieve a complete remission following cisplatin-based iv chemotherapy.

Abdominal Neoplasms↗
PubMed1986

Plasma uridine changes in cancer patients treated with the combination of dipyridamole and N-phosphonacetyl-L-aspartate.

Dipyridamole (DP) and N-phosphonacetyl-L-aspartate (PALA) act synergistically in vitro against many cell lines and in vivo against human ovarian carcinoma xenografts. We have conducted a phase I clinical trial of DP p.o. (50 mg/m2, every 6 h) in combination with PALA (starting at 500 mg/m2 i.v. with 300-mg dose escalations). Sixty-five patients were entered into this study, and we have established the maximum tolerated dose of PALA to be 4.5 g/m2 when combined with DP, which is approximately 80% of the previously reported maximum tolerated dose for PALA alone. The observed toxicities of DP plus PALA were mild and were similar to those reported for PALA alone. Bone marrow toxicities were not evident at any PALA dose. Ten patients with a mean pretreatment plasma uridine concentration of 3.49 +/- 1.28 (SD) microM had their plasma uridine reduced to 2.29 +/- 0.70 microM 9 h after DP p.o. A peak plasma DP concentration of 1.86 +/- 0.99 microM was achieved approximately 2 h after p.o. dosing. Nine patients who had a reduced plasma uridine concentration of 2.46 +/- 0.61 microM after 1 week of DP had their plasma uridine further reduced by PALA to 0.87 +/- 0.23 microM 7 h post-PALA. Daily plasma uridine measurements in two patients during their DP treatment confirmed the previously described pattern for Day 1, but the data suggest a slight recovery (15%) in plasma uridine by Day 2. Daily sampling in two other patients after a single PALA dose of 4.2 g/m2 showed that their plasma uridine declined 5 h after the PALA dose and remained depressed for 6 days in one patient and 11 days in the other. These results suggest that DP worked in synergy with PALA to lower circulating uridine in cancer patients. The mechanism for the ability of DP to reduce plasma uridine is not known, but there is evidence that DP can inhibit cellular efflux of uridine as well as its uptake. DP may reduce plasma nucleoside pools in addition to blocking nucleoside salvage and therefore have general applicability in other chemotherapy regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Complications of extensive adhesion formation after intraperitoneal chemotherapy.

The results of modeling studies have suggested and clinical investigations have confirmed a major pharmacokinetic advantage for exposure of the peritoneal cavity to certain chemotherapeutic agents compared with exposure of the systemic circulation when these drugs are delivered through the intraperitoneal route. Objective antitumor responses and significant palliation of symptoms have been demonstrated. One major concern with the use of intraperitoneal therapy is the risk of inducing peritoneal sclerosis and extensive adhesion formation. At the University of California at San Diego (UCSD) Cancer Center, 115 patients with advanced intra-abdominal malignant conditions have been treated with several intraperitoneal chemotherapy programs. To date, with a total of 1,103 patient-months of follow-up study, seven episodes of small intestinal obstruction have developed of which two were definitely and five possibly related to chemotherapy induced adhesion formation. The development of methods to prevent or decrease peritoneal sclerosis will allow for greater application of this innovative therapeutic approach.

Adult↗
PubMed1986

Differential sensitization of human ovarian carcinoma and mouse L1210 cells to cisplatin and melphalan by glutathione depletion.

We have investigated the role of glutathione in determining the macromolecular binding and cytotoxicity of cisplatin (DDP) and melphalan (LPAM) in human ovarian carcinoma cells and DDP-resistant L1210 mouse leukemia cells. Glutathione reacted avidly with DDP in normal saline with a bimolecular rate constant of 16.2 M-1 hr-1. Glutathione had no effect on the rate of hydrolysis of LPAM, consistent with the SN1-like reaction mechanism of LPAM. Glutathione protected calf thymus DNA and bovine serum albumin from DDP platination and LPAM alkylation. Glutathione also protected nuclei isolated from human ovarian carcinoma cells from DDP platination. The importance of intracellular glutathione in determining the cytotoxicity of DDP and LPAM was assessed by depletion of glutathione with buthionine sulfoximine in three cell types. Exposure to 0.5 mM buthionine sulfoximine for 20-28 hr depleted glutathione to levels that were 10-20% of control levels. COLO 316 and 2008 human ovarian carcinoma cells, and ZCR9 mouse leukemia cells were all sensitized to LPAM cytotoxicity by this level of glutathione depletion. The dose modification factors, defined as the IC50 control cells/IC50 depleted cells, were: 2.6 +/- 0.5 for COLO 316 cells, 1.6 +/- 0.1 for 2008 cells, and 2.1 +/- 1.1 for ZCR9 cells. In contrast, glutathione depletion had a minimal effect on DDP cytotoxicity in these cells with dose modification factors of: 1.2 +/- 0.2 for COLO 316 cells, 0.8 +/- 0.3 for 2008 cells, and 1.1 +/- 0.1 for ZCR9 cells. The differential potentiation of DDP and LPAM cytotoxicity by glutathione depletion in these cells, despite the similar protection that glutathione affords macromolecules from drug binding, suggests that there are fundamental differences in the intracellular interaction of these electrophilic drugs with glutathione.

Animals↗
PubMed1986

Lack of synergy between cisplatin and cytarabine against ovarian carcinoma in vitro.

Synergy has been reported for the combination of cisplatin and cytarabine in a murine model and in several human cell lines in vitro. Clinical trials are under way with this combination. However, we were unable to demonstrate any significant synergistic interaction between these two agents in two human ovarian carcinoma cell lines with either 4-hour or continuous concurrent exposure in vitro at drug concentration producing 1-2 logs of cell kill. Synergy between these two drugs may be limited to unique cell lines and tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

High-dose intracavitary cisplatin with intravenous thiosulfate. Low incidence of serious neurotoxicity.

Recent published reports have suggested that cisplatin administered in high doses or in certain combination chemotherapy can cause serious neurotoxicity in a large percentage of patients treated. In several high-dose cisplatin-based intracavitary chemotherapy trials with the simultaneous intravenous administration of sodium thiosulfate, the incidence of clinically relevant neurotoxicity has been extremely low. In addition, several patients with serious preexisting cisplatin-induced neurologic dysfunction were treated without worsening of their clinical condition. It is suggested that thiosulfate might have been responsible for the low incidence of neurotoxicity in this patient population. Further experimental and clinical investigation of the potential of this agent to protect against cisplatin-induced neuropathy appears warranted.

Adolescent↗
PubMed1985

Intraperitoneal chemotherapy for advanced ovarian cancer.

Treatment of patients with advanced ovarian cancer who have failure of first-line chemotherapy is rarely effective. Preliminary pharmacokinetic and phase II clinical studies established the feasibility of delivering relatively high concentrations of cisplatin intraperitoneally via a semipermanent catheter, while using intravenous sodium thiosulfate as a neutralizing agent to decrease the nephrotoxicity of cisplatin. Sixty patients with advanced ovarian cancer, all of whom had failure of first-line chemotherapy (including cisplatin in 56 of 60), were treated with high-dose intraperitoneal cisplatin in combination with doxorubicin and/or cytarabine. Of the 46 patients evaluable for response, 19 (42%) showed an objective response, most often (12/19) disappearance of malignant ascites. No serious drug-associated morbidity was observed aside from three cases of intestinal obstruction which may have been due in part to drug-induced adhesions. It is felt that prospective studies to compare the efficacy of intraperitoneal chemotherapy with other forms of "salvage" therapy, as well as its use as initial chemotherapy for advanced ovarian cancer, need to be done.

Altretamine↗
PubMed1985

Cisplatin and cytarabine administered intrapleurally as treatment of malignant pleural effusions.

Eight patients with histologically-documented malignant pleural effusions received a total of ten courses of intrapleurally administered chemotherapy with cisplatin (100 mg/m2) and cytarabine (10(-2) M). Sodium thiosulfate was simultaneously administered intravenously to protect against cisplatin-induced nephrotoxicity. There was no local toxicity observed and the only significant systemic toxicity (bone marrow depression) developed in a patient with poor marrow reserve prior to the initiation of therapy. Six of seven evaluable patients exhibited major reductions (greater than 75%) in the size of their effusions lasting for 2 to 10 plus months (median: 4 months). We conclude that the intrapleural administration of this chemotherapy regimen results in objective and subjective improvement in patients with malignant pleural effusions with minimal local and systemic toxicity (except for cisplatin-induced emesis) and does not require chest tube drainage or prolonged hospitalization.

Adult↗
PubMed1985

Infectious peritonitis in patients receiving intraperitoneal chemotherapy.

A total of 32 episodes of infectious peritonitis developed in 90 patients receiving intraperitoneal chemotherapy. Staphylococcus epidermidis was the organism most commonly cultured, accounting for 65 percent of isolates. Result of initial gram stain was positive in 35 percent of cases. The development of fever and abdominal pain as well as rising peripheral and peritoneal fluid white blood cell counts was helpful in the making of a diagnosis of infectious peritonitis. Seventy-five percent of patients were cured with antibiotic therapy alone whereas one quarter also required removal of the semi-permanent catheter. Patients treated with intraperitoneal chemotherapy delivered by dialysis exchange over several days exhibited significantly more episodes of infection than patients treated by a single-drug instillation each month. Although the development of bacterial peritonitis remains a problem during intracavitary chemotherapy, the use of subcutaneous ports and meticulous sterile technique during catheter manipulation will hopefully decrease the risk of occurrence of this potentially avoidable complication.

Anti-Bacterial Agents↗