Biomedical subjects

I Han

Publications and source records attributed to I Han.

At least 55 records · Page 3Linked to original sources

PubMed1997

Preoperative total parenteral nutrition influences postoperative systemic cytokine responses after colorectal surgery.

Previous human studies have investigated the influences of nutritional routes on the serum kinetics of cytokines following intravenous administration of lipopolysaccharide. However, it is unclear whether preoperative nutritional routes influence responses of systemic cytokines in patients after surgery. This study was designed to investigate whether preoperative total parental nutrition (TPN) influences systemic interleukin-6 (IL-6) and interleukin-8 (IL-8) responses in patients following surgery for colorectal cancer. Patients with colorectal cancer received TPN (TPN group, n = 6) or an oral diet (oral group n = 6) for more than 7 d before the operation. Patients in the TPN group received standard TPN. Patients in the oral group received an ordinary hospital diet. Blood samples were collected before the operation, on postoperative day 1 (POD1), POD3, and POD7. Levels of IL-6, IL-8, and C-reactive protein (CRP) in plasma were determined. The characteristics of patients in the TPN and oral groups were comparable. Mean carbohydrate intake was greater (28 versus 19 kCal/kg), and lipid intake was smaller (0 versus 7 kCal/kg) in the TPN group than in the oral group. Plasma CRP levels did not differ between the two groups. Plasma IL-6 and IL-8 levels were marginally higher before the operation and were significantly higher on POD1 in the TPN group than in the oral group. The IL-6 levels showed a positive regression relation with the amounts of blood loss only in the TPN group (P < 0.05, r = 0.881). The slope of the regression line was steeper in the TPN group than in the total enteral nutrition (TEN) group (P < 0.01). In conclusion, routes of nutritional supply have an impact on the production of systemic cytokines after insult. The postoperative systemic IL-6 and IL-8 responses in patients who received standard TPN preoperatively were greater than in patients who received an oral diet. Preoperative nutrition via the enteral route may provide better regulation of cytokine responses after surgery than parenteral nutrition.

Colorectal Neoplasms↗

PubMed1997

Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility.

Sp1 is a ubiquitously expressed transcription factor that is particularly important for the regulation of TATA-less genes that encode housekeeping proteins. Most growth factors and receptors are also encoded by such genes. Sp1 is multiply O glycosylated by covalent linkage of the monosaccharide N-acetylglucosamine (O-GlcNAc) to serine and threonine residues. Based on an earlier observation that growth factor gene transcription can be regulated by glucose and glucosamine in vascular smooth muscle cells, we determined whether Sp1 glycosylation could be regulated and if this modification altered Sp1 function. We found that Sp1 becomes hyperglycosylated when cells are exposed to 5 mM glucosamine, whereas under glucose starvation, stimulation with cyclic AMP (cAMP) results in nearly complete deglycosylation of this protein. Correlating with this hypoglycosylated state, Sp1 is rapidly proteolytically degraded by an enzyme(s) that can be inhibited by specific proteasome inhibitors, lactacystin and LLnL. Treatment of cells with glucose or glucosamine protects Sp1 from cAMP-mediated degradation, whereas blockade of glucosamine synthesis abrogates glucose but not glucosamine protection. This effect on Sp1 is specific, in that the Stat-3 and E2F transcription factors did not undergo degradation under these conditions. The O-GlcNAc modification of Sp1 may play a role as a nutritional checkpoint. In the absence of adequate nutrition, Sp1 becomes hypoglycosylated and thereby subject to proteasome degradation. This process could potentially result in reduced general transcription, thereby conserving nutrients.

Animals↗

PubMed1996

Multifractionated high-dose-rate brachytherapy with concomitant daily teletherapy for cervical cancer.

BACKGROUND: High-dose-rate (HDR) brachytherapy has been the preferred treatment for cervical cancer at Wayne State University since 1987. The outcome of the first 105 patients treated is analyzed. PURPOSE: To determine clinical efficacy of the HDR modality. METHODS: We reviewed 105 patients and evaluated the 88 patients treated for cervical carcinoma with HDR and external beam radiotherapy (EBRT) from August 1987 to December 1992. Patients received initial external radiation to the pelvis (total dose of 19.8 to 39.6 Gy in 11 to 22 fractions), followed by outpatient HDR brachytherapy (3 fractions/week, 386 cGy/fraction to Point A, total of 8 to 12 fractions) and concurrent daily EBRT (1.8 to 2.0 Gy) to lateral parametria. During the HDR period of treatment, step wedge transmission blocks were used to shield central pelvic tissue while treating peripheral pelvic tissues with EBRT. Patient distributions were as follows: 25, IB/IIA; 35, IIB/IIIA; and 28, IIIB/IVA. There were 56 African American and 32 Caucasian patients with mean age of 55 (range 19-89). The median follow-up was 33 months (range 20 to 76 months). Kaplan-Meier analysis was performed. RESULTS: Three-year survival rates were 88%, IB/IIA; 69%, IIB/IIIA; 56%, IIIB/IVA; and 72% overall. Local control was achieved in 71/88 (80%) of patients. Failure site was cervix or within the pelvis in 12 patients, distant metastasis only 17 patients, and combined local and distant in 5 patients. Of the failures, 82% (28/34) died within 2 years. There were 3 grade III/complications (3.4%). CONCLUSION: Results compare favorably with previous LDR experience.

Adult↗

PubMed1996

Effects of three inhibitors of nitric oxide synthase on host resistance to bacterial infection.

OBJECTIVE: To examine the effects of three nitric oxide synthase inhibitors on survival in a murine sepsis model. DESIGN: Prospective randomized experimental trials. SETTING: Laboratory. SUBJECTS: Female Balb/c mice. INTERVENTIONS: Escherichia coli (10(8) colony-forming-units/body) were injected into the peritoneal cavities of Balb/c mice. NG-nitro-L-arginine-methyl-ester, NG-monomethyl-L-arginine, or N-iminoethyl-L-ornithine was given at various concentrations, intraperitoneally, one hour before bacterial challenge. MEASUREMENTS: One hundred and fifteen animals were observed for survival. RESULTS: These inhibitors provided the mice no protection from the bacterial challenge. Notably, pretreatment with NG-nitro-L-arginine-methyl-ester (100 mg/kg i.p.) actually reduced survival time after E. coli challenge. CONCLUSIONS: Inhibition of nitric oxide production improved neither the survival time nor rate in this murine sepsis model.

Animals↗

PubMed1996

Effects of pancreatic duct ligation and aging on acute taurocholate-induced pancreatitis. Experiments in the perfused pancreas in rats.

CONCLUSION: When taurocholate was injected into the common bile duct, high ductal pressure due to ligation of the pancreatic duct did not produce more damage in the pancreas of both old rats and young adult rats, and levels of pancreatic enzymes in portal venous effluent were lower in old rats than in younger rats. BACKGROUND: The effects of ligation of the pancreatic duct and aging on acute pancreatitis caused by taurocholate are still unclear. METHODS: Young adult and old male Wistar rats were used. Six hours after ligation of the common bile duct in both the duodenum and liver hilus, rats were killed and the pancreata were perfused. Taurocholate or normal saline was injected retrogradely into the common bile duct. The levels of amylase and lipase in the portal venous effluent were determined as markers of damage to the pancreas. The pancreas was also histologically examined after the perfusion experiments using an Image Analysis System. RESULTS: (1) A nonsignificant elevation of pancreatic enzymes was found in portal venous effluent by the retrograde injection of saline into the common bile duct. Injection of taurocholate caused a marked elevation of enzymes in the effluent for the first 30 min after injection, which then gradually decreased. (2) Basal levels of pancreatic enzymes were significantly higher in the ligation group than in the nonligation group. Injection of saline into the common bile duct had no apparent effect on enzymes in the effluent. In contrast, taurocholate injection into the common bile duct produced a marked increase in enzymes in the portal venous effluent. However, no significant difference was found between the ligation group and the nonligation group. (3) Similar findings were obtained when old rats were used. (4) Although basal levels of enzymes were almost the same in nonligated old and young adults rats, taurocholate injection into the pancreatic duct in old rats resulted in a significant depression of enzymes compared to that in young adult rats. In the ligation group, pancreatic enzymes in the portal venous effluent following taurocholate injection tended to be lower in old rats than in young adult rats. The results were histologically supported in that various degrees of fibrosis were found in the pancreata of old rats.

Acute Disease↗

PubMed1996

In vivo antitumor activity of cis-bis-neodecanoato-trans-R,R-1, 2-diaminocyclohexane platinum(II) formulated in long-circulating liposomes.

A lipophilic cisplatin derivative, cis-bis-neodecanoato-trans- R,R-1,2-diaminocyclohexane platinum (II) (NDDP), was formulated in liposomes composed of phosphatidylcholine (PC) and cholesterol (Chol) additionally containing monosialoganglioside (Gm1) or polyethyleneglycol conjugated to phosphatidylethanolamine (PEG-PE). These NDDP-containing long-circulating liposomes were examined for in vivo antitumor activity using the mouse RIF-1 solid tumor as a target residing outside the reticuloendothelial system (RES). Biodistribution studies, using C3H/HeJ mice and 111In-labelled DTPA-SA as a lipid marker, showed that the activity of GM1 and PEG-PE in prolonging the circulation times of liposomes was preserved in the presence of 3.0 mol% of NDDP in the liposome membranes. The high levels of liposomes remaining in the blood for PC/Chol/GM1 and PC/Chol/PEG3000-PE liposomes were associated with high levels of platinum in the blood as determined by atomic absorption spectrophotometry. These NDDP-containing long-circulating liposomes showed approximately a three-fold increase in tumor accumulation as compared to the conventional PC/Chol liposomes. In vitro cytotoxicity studies using RIF-1 tumor cells showed that the presence of PEG-PE, but not Gm1, significantly enhanced the cytotoxicity of liposomal NDDP. RIF-1 tumor-bearing C3H/HeJ mice were treated twice with 25 mg/kp NDDP in various liposomal formulations on days 12 and 16 after tumor cell inoculation. A significant reduction in the tumor growth rate was observed when NDDP was formulated in PC/Chol/PEG3000-PE liposomes which support both efficient tumor accumulation and enhanced cytotoxicity of liposomal NDDP. On the other hand, NDDP formulated in PC/Chol/GM1 liposomes, which display only a high tumor accumulation, had no effect on the tumor growth rate. Furthermore, NDDP formulated in dimyristoylphosphatidylglycerol (DMPG)-containing liposomes, exhibiting in vitro cytotoxicity comparable to NDDP formulated in PC/Chol/PEG3000-PE liposomes, but showing poor tumor accumulation, was also not effective. These results indicate a potential effectiveness of NDDP formulated in PEG-PE-containing liposomes for therapy of tumors in non-RES organs.

Animals↗

PubMed1996

Intraliposomal conversion of lipophilic cis-bis-carboxylato-trans-R,R-1,2-diaminocyclohexane-platinum (II) complexes into cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane-platinum (II).

Cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (NDDP) is a lipophilic platinum complex (Pt complex) developed in a liposomal carrier. Prior studies have suggested that NDDP is a prodrug that exerts its biological activity through activation within the liposome bilayers containing dimyristoyl phosphatidylglycerol (DMPG) before in vivo administration. In order to understand the kinetics of the intraliposomal degradation/activation of different liposomal Pt complexes, we studied the effects of their structure, lipid composition, content of acidic phospholipids and size, and the effects of pH, temperature and the presence of residual chloroform on their stability, in vitro cytotoxicity, and in vivo antitumor activity. The following factors were found to enhance the intraliposomal degradation/activation of Pt complexes: (1) the size and spatial configuration of the Pt complex, (2) an acidic pH, (3) a high temperature, (4) the presence and amount of acidic phospholipids, and (5) the presence of residual chloroform. Liposome size did not affect the intraliposomal stability of different Pt complexes. Good inverse relationships between the extent of drug degradation and in vitro cytotoxicity and between the extent of drug degradation and in vivo antitumor potency were observed, thus confirming that the biological activity of these complexes is exerted through the intraliposomal formation of certain active intermediate(s). The only active intermediate that could be identified was cis-bis-dichloro-trans-R,R-1,2-diaminocyclohexane platinum(II) whose structure was confirmed by 1H, 13C, and 195Pt nuclear magnetic resonance (NMR) spectroscopy.

Animals↗

PubMed1996

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein.

BACKGROUND: The significance of preserving the spleen has recently been shown. However, there are few reports of spleen-preserving distal pancreatectomy for lesions of the body and tail of the pancreas, and this procedure is not generally performed. The aim of this study was to clarify the technique and indications for spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for benign lesions of the distal pancreas. METHODS: Four patients (two each with an endocrine tumor and a cystic lesion) underwent the procedure. We also performed the spleen-preserving Puestow's procedure with removal of the tail of the pancreas in a 22-year-old male patient with familial chronic pancreatitis. An important technique is to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen and to remove the splenic artery from the pancreas in the other direction. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane, which is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas from the body of the pancreas toward the spleen, because it is very difficult to remove it in the other direction. There are many branches from the splenic vein on both sides; these branches should be carefully ligated and cut. The pancreas is removed from the splenic artery from the spleen toward the head of the pancreas. This procedure is much easier than removal of the pancreas from the vein. RESULTS: The postoperative course was uneventful in four of the five patients. A pancreatic fistula remained in one patient for several weeks. The mean and standard deviation of the operative blood loss, the duration of the operation, and the postoperative hospital stay in the four uneventful cases, excluding the one in which Puestow's procedure was performed, were 600 +/- 479 ml, 290 +/- 48 minutes, and 40 +/- 21 days, respectively. No severe complications occurred in any of the five patients. CONCLUSIONS: Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein is easy and safe and should be performed for benign lesions of the distal pancreas.

Adult↗

PubMed1996

Route of nutritional supply influences local, systemic, and remote organ responses to intraperitoneal bacterial challenge.

OBJECTIVE: The authors' aim was to investigate whether antecedent nutritional routes influence immune responses after surgical insult. SUMMARY BACKGROUND DATA: Total parenteral nutrition (TPN) may influence host responses to infection. To the best of the authors' knowledge, however, no study has focused on the mechanisms underlying the influence of nutritional route on local, systemic, and remote organ (lung) responses after surgical insult. METHODS: Sixty-eight rats were divided into TPN and total enteral nutrition (TEN) groups. The two groups received identical nutrients for 7 days and were then challenged intraperitoneally with 3 x 10(8) Escherichia coli. In the first experiment, the rats were observed for survival. In the second experiment, the rats were killed before (0 hours) challenge or 2 or 6 hours after challenge. Peritoneal exudative cells (PEC) and bronchoalveolar cells (BALC) were harvested and cultured in vitro. Colony-forming units of bacteria in the peritoneal lavage fluid (PLF) were determined. Tumor necrosis factor (TNF), interleukin-1 alpha (IL-1 alpha), interferon-gamma (IFN-gamma) levels in serum, PLF, bronchoalveolar lavage fluid (BALF), and cell culture supernatants were measured. RESULTS: The 48-hour survival rate was higher in TEN than in TPN rats. Local immunity was depressed in the TPN group. Bacterial colony counts in PLF were significantly higher in the TPN group than in the TEN group after challenge. The number of PECs was significantly lower, and at 2 hours, local cytokine (TNF and IL-1 alpha) responses were diminished in the TPN group compared with the TEN group at 2 hours. The number of PECs showed a significant positive correlation with levels of local cytokines in the TEN group but not in the TPN group. Elevation of local IFN-gamma was significant from 0 to 6 hours in the TEN group but not in the TPN group. In vitro production of TNF by PEC was impaired in the TPN rats before challenge. Remote organ (lung) responses were suppressed in the TPN group. The number of BALCs and the TNF levels in BALF declined significantly between 0 and 2 hours in the TEN group but not in the TPN group. Interferon-gamma levels in BALF were higher in the TEN group than in the TPN group at 2 hours. Systemic cytokine responses were disturbed in the TPN group. Production of systemic TNF was greater, but the IFN-gamma response was diminished in the TPN group compared with the TEN group after intraperitoneal bacterial challenge. CONCLUSION: Local, systemic, and remote organ (lung) immune responses to intraperitoneal bacterial challenge are suppressed in TPN-treated animals, leading to poor survival after challenge. Enteral nutrition before surgical insult may enhance host immune responses after the insult as compared to parenteral nutrition.

Animals↗

PubMed1996

Growth hormone and insulin-like growth factor I augment Escherichia coli-killing activity of murine peritoneal exudative cells.

Effects of growth hormone (GH) and insulin-like growth factor (IGF)-I on Escherichia coli-killing activity of murine peritoneal exudative cells (PECs) were investigated. Plasma from the mice, injected subcutaneously with saline, GH (4.8 mg/kg/day), or IGF-I(24 mg/kg/day) for 6 days, was mixed with E. coli and pooled murine PECs. Plasma from GH- and IGF-I-treated mice modestly but significantly augmented the E. coli-killing activity of PECs, as compared with that from saline controls. Plasma from IGF-I-treated mice also enhanced PEC interleukin 1 production. In the next experiment, PECs preincubated with medium, GH (10-1000 ng/mL), or IGF-I (50-5000 ng/mL) for 3 h were investigated for E. coli-killing activity. Preincubation of PECs with all concentrations of GH and IGF-I significantly enhanced the E. coli-killing activity of PECs, as compared with the medium control. These results indicate that GH and IGF-I enhance phagocytosis and the E. coli-killing activity of PECs, via a modestly increased plasma capacity to support these activities, as well as by a strong direct action.

Animals↗

PubMed1996

The greater omentum is the primary site of neutrophil exudation in peritonitis.

BACKGROUND: Peritonitis remains a major infectious problem. Neutrophil influx into the peritoneal cavity is one of the most important host defense mechanisms. However, no studies have focused on the site of neutrophil exudation. This study examined the primary anatomic site of neutrophil exudation in bacterial peritonitis. STUDY DESIGN: Fifty-five rats were injected intraperitoneally with saline solution (control group) or 10(7) Escherichia coli (peritonitis group). In experiment 1, 1 x 10(6) fluorescein-labeled neutrophils were infused 3 hours after the challenge. Then, peritoneal-lavaged fluids and peritoneal tissues (the greater omentum, mesentery, parietal peritoneum, colon, and ileum) were obtained. Subpopulations of peritoneal exudative cells and numbers of labeled neutrophils in tissues were counted. In experiment 2, labeled neutrophils were infused at 10 minutes and at 1 and 5 hours after the challenge. Peritoneal tissues were also harvested. The number of labeled neutrophils in each tissue was determined. RESULTS: In experiment 1, numbers of labeled peritoneal neutrophils and exudative neutrophils were higher in the peritonitis group than in the control group. Numbers of exudative neutrophils showed a positive correlation with numbers of labeled peritoneal neutrophil. In experiment 2, at 1 and 5 hours after the challenge, the number of labeled neutrophils was higher in the peritonitis group than in the control group. The number of neutrophils in the omentum was higher than the number in other peritoneal tissues. CONCLUSIONS: Our fluorescence microscopic method is useful for detecting neutrophil adhesion. Neutrophil exudation into the peritoneal cavity was most marked in the omentum. The greater omentum may play an important role in host defense as a source of exudative neutrophils.

Animals↗

PubMed1994

Bone metastasis from cervical cancer.

BACKGROUND: This retrospective analysis examines the frequency, distribution, and the pattern of disease progression of bone metastasis in patients treated for cervical cancer and the use and results of palliative intent radiation therapy. METHODS: Charts, films, and other available records were reviewed for the 41 patients with bone metastasis of the 496 patients with invasive cervical cancer treated at the Gershenson Radiation Oncology Center, Detroit, Michigan, from 1980 through 1989. RESULTS: Several patterns of bone metastasis were observed: (1) direct extension into bone from the parametrial extensions of the primary or recurrent pelvic tumor, (2) direct extension into bone from parenchymal metastasis to distant lymph nodes or lung, (3) regional hematogenous metastasis compatible with Batson's venous plexus distribution, and (4) systemic hematogenous metastasis to distant bones. Eighty percent of the patients were irradiated, and of those, 70% experienced pain relief. CONCLUSIONS: Bone metastasis in patients with cervical cancer is an infrequent but significant occurrence with associated severe dysfunction, other signs of local and distant failure, and short life expectancy. Radiation therapy provides moderate palliation for treatable patients.

Adenocarcinoma↗

PubMed1994

Lipophilic platinum complexes entrapped in liposomes: improved stability and preserved antitumor activity with complexes containing linear alkyl carboxylato leaving groups.

Lipophilic diaminocyclohexane (DACH) platinum complexes have shown significant promise in preclinical studies. One of these compounds, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP), which contains two branched leaving groups of 10 carbons, showed a favorable toxicity profile in a liposomal formulation in early clinical trials. However, like many other DACH platinum compounds with branched leaving groups, it is unstable within the liposomes, thus preventing its widespread clinical evaluation. We studied the effect of the configuration of leaving groups on intraliposomal complex stability by studying a series of DACH platinum complexes containing linear alkyl carboxylato leaving groups of 5-18 carbons. The entrapment efficiency was greater than 90% for all liposomal preparations of the complexes and was independent of lipid composition and length of the leaving group. The drug leakage from the liposomes was minimal, but was directly related to the length of the leaving group. Intraliposomal stability was inversely related to the length of the leaving group and the content of DMPG (dimyristoyl phosphatidylglycerol) in the liposomes. The effect of length of leaving group on intraliposomal stability was minimal in compounds with leaving groups smaller than 10 carbons, but very pronounced in compounds with longer leaving groups. Stable liposomal formulations of selected compounds with leaving groups of 6 and 10 carbons had significant in vivo antitumor activity against both L1210/S and L1210/PDD leukemias. The results indicate (1) that compounds with linear leaving groups are much more stable within DMPG-containing liposomes than compounds with branched leaving groups and (2) that DMPG is required for in vivo antitumor activity. Stable and active liposomal formulations of selected compounds with linear leaving groups have been identified. These formulations are candidates for clinical development.

Animals↗

PubMed1994

Nonanastomotic aneurysm formation in a Dacron arterial graft: report of a case.

Dacron prostheses are the most widely used grafts in replacement procedures for abdominal aortic aneurysms, having been proven as the most reliable substitute for arterial replacement. However, we present herein the rare case of an 82-year-old woman in whom nonanastomotic aneurysm formation occurred in the graft as a complication associated with a Dacron prosthesis. The patient presented with a pulsatile mass in the right inguinal region. She had undergone surgery 13 years earlier for an abdominal aortic aneurysm, at which time an aortobifemoral graft reconstruction had been performed with a double-velour knitted Dacron prosthesis. The pulsatile mass was found to be a nonanastomotic aneurysm of the right limb of the bifurcated graft with an intact distal anastomosis. In this case, the development of the graft aneurysm seemed to result from deterioration of the Dacron prosthesis itself due to mechanical fatigue caused by the inguinal band.

Aged↗

PubMed1994

Cellular accumulation and DNA damage induced by liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum+ ++(II) in LoVo and LoVo/PDD cells.

Liposomal cis-bis-neodecanato-trans-R,R-1,2-diaminocyclohexaneplatinum (11) (L-NDDP) is a liposome-entrapped platinum complex that has shown partial lack of cross-resistance with cisplatin in human colon carcinoma LoVo cells. We studied the drug accumulation and DNA damage induced by L-NDDP and cisplatin in LoVo and LoVo/PDD cells. Our results indicate that the accumulation of L-NDDP in LoVo cells is several-fold higher than that of cisplatin; that the accumulation of L-NDDP is similar in both cell lines, whereas that of cisplatin is reduced by 2- to 3-fold in LoVo/PDD cells; and that the transmembrane transport of cisplatin is highly dependent on temperature while that of L-NDDP is not. We also found that the cytotoxicity of both agents correlates with the extent of DNA-protein cross-link formation, and that DNA interstrand cross-linking does not appear to play a role in the cytotoxicity of L-NDDP, whereas it correlates with cisplatin cytotoxicity.

Antineoplastic Agents↗

PubMed1993

Cellular pharmacology of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum(II) in A2780/S and A2780/PDD cells.

We studied the cytotoxicity, cellular accumulation, and DNA interactions induced by liposome-entrapped NDDP (L-NDDP) and cisplatin in A2780 human ovarian carcinoma cells sensitive (A2780/S) and resistant (A2780/PDD) to cisplatin. L-NDDP was 2-fold more cytotoxic than cisplatin against A2780/S cells with 5-h or 24-h drug exposure. Both cell lines were equally sensitive to L-NDDP, while A2780/PDD cells were 4-fold resistant to cisplatin (resistance indexes, 1.30-1.85 and 4.02-4.50, respectively). Using a drug exposure time of 24 h, L-NDDP cytotoxicity was independent of the liposome composition used, whereas with shorter drug exposure (5 h), the cytotoxicity of L-NDDP was directly related to the relative content of DMPG in the liposome carrier. However, changes in liposome composition or drug exposure time did not alter the resistance index of L-NDDP in this cell system. The cellular accumulation of L-NDDP was similar in both cell lines and 2- to 5-fold higher than that of cisplatin in A2780/S cells, whereas the cellular accumulation of cisplatin was reduced by 2- to 3-fold in A2780/PDD cells. The presence of DMPG in the lipid bilayer enhanced by 2-fold the cellular accumulation of L-NDDP, in good correlation with the direct relation between cytotoxic potency of L-NDDP and the presence of DMPG in the liposome carrier. Pt/DNA levels were determined at different time points after drug exposure for 1 h. Peak Pt/DNA levels were observed at 6 h for cisplatin and at 9 h for L-NDDP. Peak Pt/DNA levels and Pt/DNA over time of L-NDDP were about 1.5- and 3-fold higher than those of cisplatin in A2780/S and A2780/PDD cells, respectively, when equimolar concentrations of both drugs were used. Cisplatin induced significant DNA interstrand and DNA-protein cross-links in A2780/S cells, and a good correlation was observed between cytotoxicity against both cell lines and both types of lesions. In contrast, equimolar concentrations of L-NDDP induced only minimal DNA interstrand cross-links in either cell line.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗

PubMed1991

A preliminary report of combination chemotherapy with cisplatin and mitomycin-C followed by radical hysterectomy or radiation therapy in patients with locally advanced cervical cancer.

Neoadjuvant chemotherapy with cisplatin and mitomycin-C was used in the primary treatment of 17 patients with locally advanced cervical cancer (stages Ib-IIIb; tumor diameter greater than 5 cm) prior to definitive local treatment with radical hysterectomy or radiotherapy. Thirteen of the seventeen patients (76.5%) responded to initial chemotherapy, permitting a radical hysterectomy in ten patients. At histologic examination of the surgically resected primary tumor and lymph nodes, complete pathologic responses were found in 2 patients and partial pathologic responses in 8 patients. The median follow-up time is 14.5 months with a median survival for all patients of 52 weeks. All responders are alive. No therapy-related deaths, major complications, or delay in treatment occurred. Neoadjuvant chemotherapy with mitomycin-C and cisplatin is feasible and may be of benefit for patients with locally advanced cervical cancer.

Adult↗

PubMed1991

High-dose-rate afterloading brachytherapy, external radiation therapy, and combination chemotherapy in poor-prognosis cancer of the cervix.

Fourteen patients with poor-prognosis cervical cancer were treated with concurrent chemotherapy (cisplatin and mitomycin-C), external radiation therapy (RT), and high-dose-rate (HDR) brachytherapy. Pelvic RT was delivered as (a) external-beam radiation (four-field box technique, 40.0 Gy), (b) brachytherapy using HDR 60Co or 192Ir (3.80 Gy/fraction, thrice weekly; total dose, 46.83 Gy) with intrauterine stent, and (c) parametrial boost using an AP field with custom-fabricated step wedges. Post-radical-hysterectomy patients received 50.40 Gy external RT and 3.23 Gy/day vaginal cylinder HDR at 1/2-cm depth (total dose, 16.15 Gy). Complete clinical and radiographic response was noted in all evaluable patients who are alive with no evidence of disease, 3 to 27 months after completion of therapy (median, 9 months). Toxicity consisted of grade 2 to 3 hematologic toxicity (4 patients) and nausea and vomiting in all, but grade 3 in only 2 patients. One patient had grade 2 diarrhea. The only major complication (small bowel obstruction) occurred in a patient with lupus vasculitis. This pilot study demonstrates the feasibility of this regimen in an outpatient setting with acceptable toxicity. More prolonged follow-up of our patients is required to determine its impact on long-term survival.

Antineoplastic Combined Chemotherapy Protocols↗