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S B Howell

Publications and source records attributed to S B Howell.

At least 145 records · Page 8Linked to original sources
PubMed1990

A phase I clinical trial of intraperitoneal thiotepa for refractory ovarian cancer.

Treatment options for patients with ovarian cancer who have failed systemic and intraperitoneal (ip) cisplatin-based chemotherapy are limited. We conducted a phase I clinical study of ip thiotepa in patients with refractory ovarian cancer to determine the maximum tolerated dose (MTD). Ten patients were given 39 courses of thiotepa (median number of courses per patient, 3.5; range, 1-10+). All patients had received prior ip cisplatin; 7 also had received iv cisplatin, and 5 had three or more prior regimens. Thiotepa (30-80 mg/m2) was given ip in 2 liters normal saline every 4 weeks. The therapy was well tolerated. There was no vomiting, stomatitis, alopecia, or peritonitis. The dose-limiting toxicity was myelosuppression. With repeated doses, patients had a delayed marrow recovery and required a 1- to 2-week delay in treatment. Six patients had stable disease (duration 2-14+ months; median duration 5 months); 1 patient had a 50% decrease in CA-125 level, and 1 patient with no measurable disease remained clinically disease-free. In summary, ip thiotepa had clinical activity in heavily pretreated patients with refractory ovarian cancer with disease stabilization seen in 6 of 9 evaluable patients and a partial response seen in 1 patient. Myelosuppression was the only toxicity encountered. A dose of 60 mg/m2 ip is recommended for phase II studies.

Adult↗
PubMed1990

Effect of topoisomerase modulators on cisplatin cytotoxicity in human ovarian carcinoma cells.

The in vitro interaction of modulators of topoisomerase I and II with cisplatin in human ovarian carcinoma cells might be synergistic. The interactions were evaluated by median effect analysis of survival data derived from continuous exposure to drug combinations for 10 days in colony-forming assays. The interaction between cisplatin and the topoisomerase I inhibitor camptothecin and the topoisomerase I activator beta-lapachone was additive, as was that between cisplatin and the topoisomerase II inhibitor novobiocin. Despite the clinical efficacy of the combination of etoposide (a topoisomerase II inhibitor) and cisplatin, the combination index at 50% cell kill indicated antagonism between these two drugs. Thus, biochemical synergism at the cellular level is not a prerequisite of improved therapeutic efficacy.

Antibiotics, Antineoplastic↗
PubMed1990

Role of hypoxanthine and thymidine in determining methotrexate plus dipyridamole cytotoxicity.

The nucleoside transport inhibitor dipyridamole can potentiate the cytotoxicity of methotrexate by a mechanism that was thought to be related to the inhibition of thymidine salvage. In human ovarian carcinoma cells thymidine only partly reversed the in vitro cytotoxicity of methotrexate plus dipyridamole at sub-millimolar concentrations, above which the cytotoxicity of thymidine itself became evident. Hypoxathine with thymidine, or hypoxanthine alone at a higher concentration, completely reversed methotrexate and methotrexate plus dipyridamole cytotoxicity. The effects of dipyridamole on cellular cyclic adenosine monophosphate (cAMP) levels and on 3H-methotrexate efflux in 2008 cells were examined. At 10 mumol/l, dipyridamole did not alter cAMP content or methotrexate influx in ovarian carcinoma cells, but reduced the rate of efflux of 3H-methotrexate by 25%. In Chinese hamster ovary cells and their folylpolyglutamyl synthase-deficient variant AUX B1, the reduced methotrexate efflux by dipyridamole was not due to increased polyglutamation, since increased retention was observed in both cell lines. The data support the hypothesis that dipyridamole potentiated the activity of methotrexate by inhibiting the salvage of hypoxanthine, and to a lesser extent, that of thymidine. The ability of dipyridamole to increase the cellular retention of methotrexate was probably a non-specific action of dipyridamole on the cell membrane, and may have a role in the observed synergy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Comparison of the pharmacokinetics of ultrafilterable cisplatin species detectable by derivatization with diethyldithiocarbamate or atomic absorption spectroscopy.

The pharmacokinetics of the cisplatin (DDP) species detected by measurement of diethyldithiocarbamate (DDTC)-reactive species (DDTC-DDP) were compared to the pharmacokinetics of the species detected by measurement of total ultrafilterable platinum in patients receiving DDP alone or in combination with the nephroprotective agent sodium thiosulfate. The doses of DDP studied were 100 mg/m2 (11 courses given to eight patients) and 202.5 mg/m2 (five courses given to four patients) given as 2 h i.v. infusions, the latter with concurrent thiosulfate. When DDP was given alone (100 mg/m2) the two assays yielded the same area under the curve (AUC) values for DDTC-DDP and total ultrafilterable platinum during the first 4 h after the start of infusion; however, beyond 4 h post-infusion, the AUC for total ultrafilterable platinum was consistently greater than that for DDTC-DDP. When DDP was given with thiosulfate (202.5 mg/m2), the AUC for total ultrafilterable platinum was significantly greater than that of DDTC-DDP during the whole sampling period. The ratio of the AUC for total ultrafilterable platinum to DDTC-DDP, when DDP was given with thiosulfate, was barely significantly greater than that when DDP was given alone. These data indicate that during and immediately following a short infusion of DDP the major platinum-containing species present in plasma ultrafiltrate are still capable of reacting with nucleophilic sites on molecules such as DDTC; however, as the reactive species are eliminated, longer half-lived non-reactive ultrafilterable platinum species begin to predominate. They also indicate that although thiosulfate does neutralize a measurable amount of DDP in the plasma on the schedule employed, this degree of neutralization is not sufficient to explain the protection against DDP-induced nephrotoxicity produced by thiosulfate.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Direct cerebrospinal fluid delivery of an antiretroviral agent using multivesicular liposomes.

The use of multivesicular liposomes for administration of antiviral agents into cerebrospinal fluid was explored in a Sprague-Dawley rat model. DDC (2',3'-dideoxycytidine) was encapsulated into multivesicular liposomes made from dioleoyl lecithin, dipalmitoyl phosphatidylglycerol, cholesterol, and triolein. The half-lives of drug leakage in human plasma and in 0.9% NaCl were 15 and 47 h, respectively. After intraventricular injection with a stereotaxic apparatus, DDC levels within the central nervous system decreased exponentially, with a half-life of 1.1 h for the unencapsulated DDC and 23 h for the liposome-encapsulated DDC. There were no abnormalities observed in the behavior of the rats. Encapsulation of a more hydrophilic antiviral agent is expected to increase the half-life even further. The results of this study offer the possibility of a practical intrathecal drug delivery for drugs that do not cross the blood-brain barrier.

Animals↗
PubMed1990

Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin.

Cisplatin (DDP) is the most effective drug for the treatment of human ovarian cancer, but the mechanisms that determine sensitivity to the cytotoxic action of DDP are not well understood. Treatment of two human ovarian carcinoma cell lines with epidermal growth factor (EGF) simultaneously increased sensitivity to DDP and caused a persistent change in morphology in the absence of any mitogenic effect. Sensitization to DDP was shown to be dependent on both EGF concentration and EGF receptor number in C127 mouse fibroblasts expressing the human EGF receptor after transfection with a pBPV plasmid construct containing the human EGF receptor gene under control of the transferrin receptor 3'-inducible regulator. Sensitization of human ovarian carcinoma cells to DDP was not blocked by inhibition of protein synthesis. EGF did not enhance sensitivity to DDP or alter morphology in DDP-resistant human ovarian carcinoma cells despite the presence of functional EGF receptors on these cells. These results showed that elements of the signal transduction pathway activated by EGF determined cellular sensitivity to DDP, and that a DDP-resistant phenotype is associated with a defect in this signal transduction pathway.

Animals↗
PubMed1990

A phase II trial of intraperitoneal cisplatin and etoposide for primary treatment of ovarian epithelial cancer.

We conducted a phase II trial of intraperitoneal (IP) cisplatin (DDP) and etoposide (VP-16) in stage III and IV newly diagnosed ovarian carcinoma patients with residual disease of any size. Twenty-three patients were entered, 19 had stage III and four stage IV disease. DDP 200 mg/m2 and VP-16 350 mg/m2 were given in 2 L saline IP via a Port-A-Cath (Pharmacia-Deltec, St Paul, MN). Sodium thiosulfate 4 g/m2 was given intravenously (IV) just before the start of IP instillation, and continued as a constant IV infusion of 2 g/m2/hr IV for a total of 6 hours. Treatment was given once every 4 weeks; six cycles of therapy were planned. Thirteen patients (56%) were in complete clinical remission at the end of treatment (normal physical exam, computed tomographic [CT] scan, CA-125, and peritoneal cytology). Seven of these 13 underwent a second-look laparotomy: three (13%) were in pathologic complete remission and four (17%) had microscopic disease only. Projected survival is 68% at 27 months, with 10 patients being alive and continuously free of disease. There was a very rapid fall in mean CA-125 to within normal limits at the end of the second course of treatment. The major toxicity was myelosuppression with median nadir WBC, granulocyte, and platelet counts of 2,600, 896, and 205,000/microL, respectively. There was no cumulative renal damage, anemia, hypomagnesemia, or chemical peritonitis. Neurotoxicity was similar to that observed with IV dosing. We conclude that therapy with the IP DDP/VP-16/IV thiosulfate regimen, in which all cytotoxic drugs are given only by the IP route, produces less anemia and renal damage than standard IV DDP-containing regimens, and that survival with this regimen appears to be at least as good as that produced by IV programs.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

The effect of DNA polymerase inhibitors on the cytotoxicity of cisplatin in human ovarian carcinoma cells.

We examined the effect of specific inhibitors of DNA polymerases alpha and delta, and beta, on cisplatin (DDP) cytotoxicity in DDP-sensitive and -resistant human 2008 ovarian carcinoma cells. Under conditions of continuous exposure to drug combinations, neither aphidicolin glycinate (AG) nor dideoxythymidine enhanced the cytotoxicity of DDP in either cell line as determined by clonogenic survival assays. However, when clonogenic survival was determined following short-term drug exposure, AG exhibited strong synergism with DDP in the DDP-resistant, but not the DDP-sensitive cells, as indicated by median effect analysis of the data. DNA polymerase alpha mRNA levels were the same in both cell lines under basal conditions. DDP-sensitive cells, but not DDP-resistant cells, were able to increase their expression of DNA polymerase alpha in response to DDP exposure. Levels of mRNA for DNA polymerase beta and for the human DNA repair gene ERCC-1 were not elevated in resistant cells, either under basal conditions or 18 hr after a 1 hr exposure to IC20 concentrations of DDP. In another human ovarian carcinoma cell line, A2780, AG and DDP were synergistic in both DDP-sensitive and -resistant variants in short-term exposure. We conclude that DNA polymerases alpha and/or delta play a role in the DDP sensitivity of human ovarian carcinoma cells.

Antibiotics, Antineoplastic↗
PubMed1990

Rapid emergence of acquired cis-diamminedichloroplatinum(II) resistance in an in vivo model of human ovarian carcinoma.

We have characterized the acquisition of resistance to cisplatin (DDP) in an in vivo solid tumor model. Human ovarian carcinoma cells (2008 cell line) were grown s.c. as xenografts in athymic mice. Tumors were selected with 3.0 mg/kg of DDP i.p. given once per week for four weeks. One week after the last dose of DDP, cell lines were generated from the tumors. Cells from these lines were then re-inoculated into athymic mice, and the DDP selection process was repeated. This procedure was continued for a total of four passages (16 doses). Although this chemotherapy did not affect the tumors' growth, cell lines derived from these tumors after the first passage displayed low-level resistance to DDP as determined by the concentration causing 50% inhibition of colony formation in a clonogenic assay. The mean resistance (+/- SD) of cell lines derived from tumors treated with four doses of DDP was 1.6 +/- 0.06 (n = 5). A minimum of only two doses of DDP was required to generate significant resistance (1.5 fold). The DDP resistance slowly increased with further selections so that after four passages with chemotherapy, the cells were 3.0-fold resistant. The DDP resistance was not stable; after three passages, resistance slowly declined over 104 days from 2.2- to 1.4-fold. Resistant cells obtained after both three and four passages did not have elevated glutathione as determined by flow cytometry of monochlorobimane-stained cells. After three passages, DDP-resistant cells were not resistant to CdCl2, suggesting that metallothioneins were also not elevated. A key biochemical change found in these cells was a decrease in DDP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cellular pharmacology of cisplatin: perspectives on mechanisms of acquired resistance.

The interactions of cisplatin with DNA have been defined in sophisticated detail; however, the interactions of this drug with other components of the cell are less well understood. There is much interest in how cisplatin gets into cells, how it is transformed and inactivated, how it and its biotransformation products are effluxed from the cell, how the DNA damage is repaired, and how all of these processes can be modulated for therapeutic gain. Recent years have seen much progress toward defining the cellular pharmacology of cisplatin and, in the process, several mechanisms of acquired resistance to this drug have now been elucidated.

Animals↗
PubMed1989

Effect of sodium thiosulfate on the pharmacokinetics and toxicity of cisplatin.

Concurrent administration of sodium thiosulfate (STS) can protect against the nephrotoxic effects of even very-high-dose cisplatin (CDDP) (i.e., 270 mg/m2 given intraperitoneally). The effect of STS on the pharmacology and toxicity of CDDP was investigated in patients receiving at each treatment 90 mg of CDDP/m2 intraperitoneally, with STS given concurrently on alternate cycles by the intravenous route. The patients received a total of 38 courses of therapy, 21 without STS and 17 with STS. STS reduced the total exposure to diethyldithiocarbamate-reactive CDDP for the peritoneal cavity and plasma by 36% and 25%, respectively. When given alone, CDDP caused a statistically significant acute reduction in creatinine clearance levels; this reduction was less evident when STS was given. We conclude that, whereas STS does reduce systemic exposure, the magnitude of this effect was not sufficient to account for the ability of STS to protect against high-dose CDDP.

Cisplatin↗
PubMed1989

Dipyridamole enhancement of etoposide sensitivity.

Dipyridamole (DPM) enhanced the sensitivity of human ovarian carcinoma 2008 cells to etoposide (VP-16) producing a 5.5-fold reduction in 50% inhibitory concentration at a DPM concentration of 20 microM. This interaction was shown to be truly synergistic by isobologram and median effect analysis. DPM increased the steady-state VP-16 content of 2008 cells; a DPM concentration of 4 microM increased VP-16 content by 2-fold. DPM was 25 times less potent when cells were incubated in human plasma. In tissue culture medium 96% of the DPM was free, whereas in plasma only 15% was non-protein bound. DPM did not displace VP-16 from proteins under either condition. DPM did not increase the initial influx of VP-16 but did inhibit the initial efflux, reducing the efflux rate constant by 27%. DPM had no effect on the later stages of drug efflux, nor did it irreversibly bind VP-16 in the cell. The effect of DPM was evident within 1 min; once removed, the effect disappeared within 2 min. DPM is a potent nucleoside membrane transport inhibitor and can also inhibit cyclic AMP (cAMP) phosphodiesterase in platelets. Nitrobenzylthioinosine, another nucleoside transport inhibitor which competes for binding with DPM, did not enhance sensitivity to VP-16 or increase VP-16 cellular accumulation and did not block the effect of DPM. In 2008 cells, DPM did not increase cAMP; when cAMP was increased by incubation with dibutyryl cyclic 3':5'-AMP, there was no synergy with VP-16. The results indicate that enhanced sensitivity to VP-16 was not due to an effect of DPM on the protein binding of VP-16 or on cellular cAMP and suggest that it is not directly related to inhibition of nucleoside transport. This effect appears to be a newly identified mechanism of action for this agent.

Blood Proteins↗
PubMed1989

Comparison of the synergistic potentiation of etoposide, doxorubicin, and vinblastine cytotoxicity by dipyridamole.

Dipyridamole (DPM) enhanced sensitivity to etoposide (VP-16), doxorubicin (DOX), and vinblastine (VBL) in a human ovarian carcinoma cell line that was already relatively sensitive to all three agents. This interaction was shown to be truly synergistic by median effect analysis over a 2 log cell kill. The combination index at 50% cell kill (CI50) was used to quantitate the extent of synergy. The CI50s were 0.42, 0.66, and 0.30 for VP-16, DOX, and VBL, respectively. We compared the effect of DPM on the cellular pharmacology of each chemotherapeutic drug. DPM increased the steady state cellular content of VP-16 by a maximum of 3.2-fold, and that of DOX and VBL by 1.7- and 3.7-fold, respectively. There was a good correlation between the CI50 and the DPM-induced increase in cellular drug content (r = 0.94). DPM had no effect on the initial influx VP-16 or DOX but did increase the initial influx of VBL by 3.5-fold. DPM inhibited the initial efflux of all three compounds. However, there was no relation between the extent of efflux inhibition and the magnitude of the DPM-induced increase in cellular drug content, indicating that DPM must have other effects as well. DPM has chemical characteristics similar to other known modulators of VP-16, DOX, and VBL sensitivity. When compared to verapamil, DPM was as efficacious but twice as potent in its synergistic enhancement of VP-16 sensitivity. These results demonstrate that DPM can markedly increase the cytotoxicity of VP-16, DOX, and VBL and suggest possible clinical applications.

Animals↗
PubMed1989

Pharmacologic basis for the use of dipyridamole to increase the selectivity of intraperitoneally delivered methotrexate.

Dipyridamole (DP) is an attractive agent with which to increase the selectivity of intraperitoneally delivered methotrexate (MTX). We demonstrated that DP synergistically increased the cytotoxicity of MTX to the human OV 2008 ovarian carcinoma cell line in vitro and that this synergy was highly concentration-dependent. DP did not alter MTX binding in plasma, and vice versa. We found that the two drugs were chemically compatible at concentrations of less than 400 microM, which was well above the concentration needed to make continuous i.p. infusion feasible. The ability of OV 2008 cells to accumulate uridine was used as a bioassay for the in vivo activity of DP. When this drug was infused i.p. at 12 mg/m2 per day, the steady-state peritoneal DP concentrations attained in patients were sufficient for maximal inhibition of uridine uptake, indicating concentrations high enough for synergism with MTX. We found no correlation between total peritoneal protein concentration and either free DP concentration or biologic activity. On the basis of these preclinical and pharmacologic measurements, we conclude that it should be possible to produce selective i.p. biochemical modulation of MTX with DP.

Ascitic Fluid↗
PubMed1989

Characterization of cisplatin-resistant COLO 316 human ovarian carcinoma cells.

The biochemical changes responsible for acquired resistance to cisplatin (DDP) are not fully understood. We have developed DDP-resistant sublines of COLO 316 human ovarian carcinoma cells in vitro and characterized a number of biochemical features of these cells. Following selection with either continuous 50 nM DDP (COLO/DDP50 cells) or intermittent 1 microM DDP (COLO/B, COLO/C, or COLO/D cells) the onset of resistance was rapid. The resistance of the COLO/B cells gradually fell from 14-fold to 5-fold over 6 months in drug-free media. Both selection procedures produced cells exhibiting broad cross-resistance to other platinum analogs, natural products and alkylating agents. There was no significant change in the growth rate (doubling time = 36 h, cloning efficiency (28%), protein content (0.55 mg/10(6) cells), or morphology of these cells. Cell cycle distributions of log-phase cells were similar (60% G0/G1, 35% S, 5% G2/M) as determined by flow cytometry. Glutathione (GSH) levels, while not elevated in COLO-B cells at low levels of resistance (2-3-fold), were 30% elevated at higher levels of resistance (9-fold). However, GSH levels in COLO/DDP50 cells with 13-fold resistance were 2.3-fold elevated. The resistance of both cell types could be partially reversed by extended depletion of GSH with D,L-buthionine-S,R-sulfoximine. COLO/D cells had a 48% decrease in DDP accumulation at 1 h while COLO/DDP50 cells had no change in DDP accumulation. The cross-resistance profiles, GSH biochemistry and DDP accumulation data indicate that acquired DDP-resistance is a complex, multifactorial response in these cells. The specific combination of mechanisms expressed in these cells appears to depend upon the selection procedure.

Cell Line↗
PubMed1989

Unexpected synergy between N-phosphonacetyl-L-aspartate and cytidine against human tumor cells.

Cytidine, a non-toxic endogenous nucleoside, was found unexpectedly to augment the cytotoxicity of a pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA) in human ovarian carcinoma cells. The PALA/cytidine synergy is confirmed here in other human tumor cells (T242 melanoma, HL60 promyelocytic leukemia and SKOV3 ovarian carcinoma) in the cytidine concentration range of 1-10 micromolar. The synergy was not observed in Chinese hamster ovary (CHO) cells. Exogenous uridine (5-50 microM) completely reversed the PALA/cytidine cytotoxicity in a concentration-dependent manner. Measurements of cellular ribonucleotide levels revealed that the PALA treated cells had reduced UTP and CTP pools (10% and 40% of control respectively); and the PALA/cytidine treated cells had elevated CTP and GTP levels while their UTP levels remained at 10% of control. Deoxyribonucleotide levels were unremarkable except for a slight elevation of dCTP in the PALA/cytidine treated cells. Uridine competitively inhibited radioactive cytidine transport into 2008 cells, which may explain its ability to antagonize the PALA/cytidine synergy. These results suggest that the ribonucleotide biosynthetic mechanism is the primary cellular target for PALA/cytidine activity, and that the ratio of ribonucleotides to each other is an important determinant of tumor cell viability. The use of non-cytotoxic nucleosides to augment the activity of antimetabolites may have clinical relevance in cancer therapy.

Antimetabolites, Antineoplastic↗
PubMed1989

Selective intraperitoneal biochemical modulation of methotrexate by dipyridamole.

Dipyridamole increases the toxicity of methotrexate in a concentration-dependent manner. We hypothesized that concurrent intraperitoneal administration of both drugs would result in high peritoneal concentrations with much lower plasma concentrations, permitting a selective increase in the activity of methotrexate against intraperitoneal tumors without enhancing systemic toxicity. Initially, 2.16 mg/m2/d methotrexate and 12 mg/m2/d dipyridamole were delivered together as a constant intraperitoneal infusion for 48 hours. With escalation of chemotherapy, eventually 4.32 mg/m2/d methotrexate was administered for 168 hours. Forty-seven courses were administered to 18 patients. The mean peritoneal to plasma concentration ratios of methotrexate and non-protein bound dipyridamole were 71.6 +/- 34.8 and over 2,300, respectively. Chemical peritonitis was the dose-limiting toxicity. Three patients had some evidence of a response (two with decreasing tumor markers, and the third with a reduction in ascites). We conclude that the drug concentrations are in an appropriate range for selective intraperitoneal biochemical modulation of methotrexate, and that it is feasible to expose tumors confined to the peritoneal cavity to these drugs for long periods of time.

Adult↗