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Biomedical subjects

P E Postmus

Publications and source records attributed to P E Postmus.

At least 73 records · Page 4Linked to original sources
PubMed2000

Regional pressure volume curves by electrical impedance tomography in a model of acute lung injury.

OBJECTIVE: A new noninvasive method, electrical impedance tomography (EIT), was used to make pressure-impedance (PI) curves in a lung lavage model of acute lung injury in pigs. The lower inflection point (LIP) and the upper deflection point (UDP) were determined from these curves and from the traditional pressure-volume (PV) curves to determine whether the PI curves resemble the traditional PV curves. Furthermore, regional differences in the mentioned determinants were investigated. DESIGN: Prospective, experimental study. SETTING: Animal research laboratory. INTERVENTIONS: In nine anesthetized pigs, repeated lung lavage was performed until a Pao2 <80 torr was reached. Thereafter, an inspiratory PV curve was made using a constant flow of oxygen. During the intervention, EIT measurements were performed. MEASUREMENTS AND MAIN RESULTS: In this study, the LIP(EIT) was within 2 cm H2O of the LIP(PV). Furthermore, it was possible to visualize regional PI curves by EIT. No significant difference was found between the LIP(PV) (21.3+/-3.0 cm H2O) and the LIP(EIT) of the total lung (21.5+/-3.0 cm H2O) or the anterior parts of the lung (21.5+/-2.9 cm H2O). A significantly higher LIP (29.5+/-4.9 cm H2O) was found in the posterior parts of the lung. A UDP(PV) could be found in three animals only, whereas in all animals a UDP(EIT) could be determined from the anterior part of the lung. CONCLUSIONS: Using EIT, determination of LIP and UDP from the regional PI curves is possible. The obtained information from the regional PI curves may help in understanding alveolar recruitment. The use of this new bedside technique for clinical decision making remains to be examined.

Animals↗
PubMed2000

Monitoring of recruitment and derecruitment by electrical impedance tomography in a model of acute lung injury.

OBJECTIVE: To evaluate a noninvasive system for obtaining information about alveolar recruitment and derecruitment in a model of acute lung injury. DESIGN: Prospective experimental study. SETTING: Animal research laboratory. SUBJECTS: Nine anesthetized pigs. INTERVENTIONS: Electrical impedance tomography measurements were performed. Electrical impedance tomography is an imaging technique that can register the ventilation-induced impedance changes in different parts of the lung. In nine anesthetized pigs, repeated lung lavages were performed until a PaO2 of <80 mm Hg was reached. Thereafter, the lungs were recruited according to two different recruitment protocols: the open lung approach and the open lung concept. Five time points for measurements were chosen: healthy (reference), lavage (atelectasis), recruitment, derecruitment, and maintain recruited (final). MEASUREMENTS AND MAIN RESULTS: After lavage, there was a significant increase in the impedance ratio, defined as the ventilation-induced impedance changes of the anterior part of the lung divided by that of the posterior part (from 1.75 +/- 0.63 to 4.51 +/- 2.22; p < .05). The impedance ratio decreased significantly after performing the recruitment protocol (from 4.51 +/- 2.22 to 1.18 +/- 0.51). During both recruitment procedures, a steep increase in baseline impedance change was seen. Furthermore, during derecruitment, a decrease in the slope in baseline impedance change was seen in the posterior part of the lung, whereas the anterior part showed no change. CONCLUSION: Electrical impedance tomography is a technique that can show impedance changes resembling recruitment and derecruitment of alveoli in the anterior and posterior parts of the lung. Therefore, electrical impedance tomography may help in determining the optimal mechanical ventilation in a patient with acute lung injury.

Animals↗
PubMed2000

Prediction of peak oxygen uptake in men using pulmonary and hemodynamic variables during exercise.

PURPOSE: Many attempts have been made to predict peak VO2 from data obtained at rest or submaximal exercise. Predictive submaximal tests using the heart rate (HR) response have limited accuracy. Some tests incorporate submaximal gas exchange data, but a predictive test without gas exchange measurements would be of benefit. Addition of stroke volume and pulmonary function (PF) measurements might increase the predictability of a submaximal exercise test. METHODS: In this study, an incremental exercise test (10 W x min(-1)) was performed in 30 healthy men of various habitual activity levels. Step-wise multiple regression analysis was used to isolate the most important predictor variables of peak VO2 from a set of measurements of PF: lung volumes, diffusion capacity, airway resistance, and maximum inspiratory and expiratory pressures; gas exchange; minute ventilation (V(E)), tidal volume (V(T)), respiratory exchange ratio (RER = carbon dioxide output divided by VO2); and hemodynamics (HR, stroke index (SI) = stroke volume/body surface area, and mean arterial pressure). These measurements were made at rest and during submaximal exercise. RESULTS: Using the set of PF variables (expressed as percentages of predicted), FEV1 explained 30% of the variance of peak VO2. No other PF variables were predictive. After addition of resting hemodynamic data, SI was included in the prediction equation, raising the predictability to 40%. At the 60-W exercise level, 48% of the variance in peak VO2 could be explained by SI and FEV1. At 150 W, the prediction increased to 81%. At this level VCO2/O2 (RER) also entered the prediction equation of peak VO2: 6.44 x FEV1(%) + 13.0 x SI - 1921 x RER + 2380 (SE = 142 mL x min(-1) x m(-2), P < 0.0001). Leaving out the gas exchange variable RER, maximally 64% of the variance in peak VO2 could be explained. CONCLUSION: In conclusion, inclusion of pulmonary function and hemodynamic measurements could improve the prediction accuracy of a submaximal exercise test. The submaximal exercise test should be performed until a level of 150 W is reached. Noninvasive stroke volume measurements by means of EIC have additional value to measurement of HR alone. Finally, measurement of gas exchange significantly improves the predictability of peak VO2.

Adult↗
PubMed2000

Endobronchial lipoma: a series of three cases and the role of electrocautery.

Lipomas are rare endobronchial tumors that may cause severe parenchymal damage due to bronchus obstruction and subsequent pneumonia. Therefore, accurate diagnosis and radical treatment are essential. We describe three cases of endobronchial lipoma. One patient presented with hemoptysis, two patients were initially diagnosed as COPD. They were all treated by electrocautery which achieved complete removal. We recommend electrocautery as an easy and cost-effective alternative for removal of intraluminal tumors including lipoma.

Aged↗
PubMed2000

The degree of branching of the glycans of alpha(1)-acid glycoprotein in asthma. A correlation with lung function and inflammatory parameters.

Alpha(1)-acid glycoprotein (AGP) is a plasma protein belonging to the group of acute-phase proteins. It contains five N-linked glycans which, depending on pathophysiologic state, differ in their degree of branching (i.e., in the relative proportions of di-, tri-, and tetraantennary glycans). Changes in the degree of branching of these glycans have been shown to affect various immunomodulatory properties of AGP. We wanted to investigate whether changes occur in the branching of AGP glycans in plasma and in bronchoalveolar lavage fluid (BALF) in asthma. For this purpose, we selected three groups of patients for study: patients with atopic asthma (AA), atopic nonasthmatic patients, and a group of patients with various interstitial lung diseases (ILDs). The plasma AGP concentration was normal in both atopic study groups, but was increased in ILD patients. In contrast, the branching of glycans of AGP was altered in subjects with AA, whereas it was normal in the other study groups. The presence of asthma symptoms correlated with the increased glycan branching of AGP in both plasma and BALF. Additionally, the degree of branching of AGP in BALF was related to FEV(1), to the provocative dose of histamine causing a 20% decrease in FEV (PD(20)), and to the number of eosinophils. In conclusion, asthma is accompanied by changes in the branching of AGP glycans that indicate an inflammatory reaction that differs markedly from a normal acute-phase response, in which decreased branching of AGP occurs.

Adolescent↗
PubMed2000

Diagnosing acute pulmonary embolism: effect of chronic obstructive pulmonary disease on the performance of D-dimer testing, ventilation/perfusion scintigraphy, spiral computed tomographic angiography, and conventional angiography. ANTELOPE Study Group. Advances in New Technologies Evaluating the Localization of Pulmonary Embolism.

In patients with chronic obstructive pulmonary disease (COPD), differentiating a pulmonary embolism (PE) from an exacerbation of COPD can be difficult, since clinical signs and symptoms of the two conditions overlap. Development of reliable noninvasive or minimally invasive techniques for the diagnosis of PE is, especially in these patients, necessary. In this study we assessed the effect of COPD on the accuracy of the clinical probability estimate (CPE), spiral computed tomographic angiography (SCTA), D-dimer analysis, ventilation perfusion (V/Q) scintigraphy, and pulmonary angiography for the diagnosis of PE. From May 1997 through March 1998, 627 consecutive patients with suspected PE were investigated in six teaching hospitals. In these patients, D-dimer testing, CPE, V/Q scintigraphy, and SCTA and/or pulmonary angiography were performed according to a strict diagnostic protocol. The patients were also independently categorized as having COPD or not. A diagnosis of COPD was established in 91 patients (15%). The prevalence of PE was similar in patients with and without COPD (29% and 31%, respectively), notwithstanding the larger proportion of nondiagnostic V/Q scan results in patients with COPD (46% versus 21%, p < 0.001). The distribution of CPEs, diagnostic value of the D-dimer assay and SCTA, and reproducibility of pulmonary angiography were comparable among patients with and without COPD. The presence of COPD does not affect the diagnostic performance of CPE, D-dimer testing, SCTA, or pulmonary angiography. Furthermore, although more nondiagnostic V/Q scan results can be expected in the presence of COPD, V/Q scintigraphy remains a valuable screening test in patients with COPD.

Acute Disease↗
PubMed2000

Do bullae indicate a predisposition to recurrent pneumothorax?

A relationship between idiopathic spontaneous pneumothorax (ISP) and visible parenchymal bullae and blebs has been reported. The causal relationship between blebs and bullae and ISP is questionable. Consequently, resection of the involved area is only indicated if it predisposes to recurrence of the pneumothorax. CT studies on 101 cases of ISP were analysed. The presence of bullae and their distribution was then related to the first and recurrent pneumothorax. CT demonstrated bullae in 56% of first ISP and in 64% of recurrent ISP, mostly among older patients. Only eight patients had bullae larger than 2 cm on the side of the pneumothorax. The location of the bullae was not a factor in predicting recurrent pneumothorax.

Adult↗
PubMed2000

High-resolution CT in patients with intraluminal typical bronchial carcinoid tumors treated with bronchoscopic therapy.

STUDY OBJECTIVE: To evaluate the extent to which high-resolution CT (HRCT) can predict the clinical outcome of bronchoscopic treatment with curative intent in patients with intraluminal typical bronchial carcinoid tumors. DESIGN: An observational study. SETTING: Bronchoscopy unit and radiology department of a university hospital. PATIENTS AND INTERVENTIONS: Eighteen patients with intraluminal typical bronchial carcinoid tumors in the absence of nodal and distant disease were treated with bronchoscopic electrocautery or Nd-YAG laser as an alternative to surgical resection. Prior to treatment, HRCT was performed. RESULTS: In 10 patients, HRCT showed no peribronchial tumor extension, and 9 of these patients were found to be tumor free after bronchoscopic treatment. So far during follow-up, none of these patients has had a recurrence of the tumor. The median duration of follow-up was 33 months (range, 13 to 68 months). In five patients, HRCT showed signs of peribronchial tumor extension. In three of these patients, specimens taken from biopsies performed after bronchoscopic treatment showed residual tumors, and salvage surgery was carried out. In three patients, HRCT was unable to assess peribronchial tumor extension: in two because of insufficient connective tissue contrast between the hilar structures and in one patient because of suboptimal scan technique. CONCLUSION: HRCT findings were complementary but not conclusive in patients with intraluminal typical bronchial carcinoid tumors treated with bronchoscopic therapy. However, in a category of patients in whom HRCT showed strictly intraluminal tumors, bronchoscopic resection as an alternative for surgical resection seems justified.

Adult↗
PubMed2000

Tissue effects of bronchoscopic electrocautery: bronchoscopic appearance and histologic changes of bronchial wall after electrocautery.

STUDY OBJECTIVES: To study tissue effects of bronchoscopic electrocautery (BE). DESIGN: In six patients with non-small cell lung cancer, a BE procedure was performed immediately before surgery. After patients were placed on ventilation, normal mucosa on different carinae was treated with a cautery probe (2-mm(2) surface area) at a power setting of 30 W with a variable time of application of 1 to 5 s. Bronchoscopic appearance of the treated area was documented photographically, and histologic changes of the bronchial wall were examined. SETTING: Bronchoscopy unit of a university hospital. MEASUREMENTS AND RESULTS: BE resulted bronchoscopically in whitening of the bronchial mucosa with crater-shaped lesions. After longer duration of BE application, deeper craters with more profound charring were seen. Histologic changes of the lesions showed craters containing a variable amount of necrotic tissue. In one case, thin subsegmental carinae were coagulated and measurements could not be performed. In the remaining five cases, microscopic findings revealed 0.2 +/- 0.1-mm necrosis after 1 s; 0.4 +/- 0.2-mm necrosis after 2 s; 0.9 +/- 0.5-mm necrosis after 3 s; and 1.9 +/- 0.8-mm necrosis after 5 s. A variable degree of tissue damage surrounding the necrotic tissue area was found. In one case, cartilage damage appeared after 3 s of coagulation, and extensive damage of the underlying cartilage was seen in four cases after 5 s of application. CONCLUSIONS: Superficial damage was obtained by short duration of BE (< or = 2 s), and longer duration of coagulation (3 s or 5 s) caused damage to the underlying cartilage. Bronchoscopic appearance after endobronchial electrocautery corresponded with the histologic changes.

Adult↗
PubMed2000

Outcome of bronchial carcinoma in situ.

INTRODUCTION: The proportion of patients with carcinoma in situ in whom invasive cancer will develop is not known. It is important for clinical decision making to know the outcome of these lesions. The same applies for studies assessing the effectiveness of chemoprevention treatment or endobronchial therapy. METHODS: The records of patients with a bronchial carcinoma in situ who had undergone autofluorescence bronchoscopic examinations at regular intervals during a follow-up period for at least 6 months were reviewed. Data were examined for the outcome of carcinoma in situ, and for the detection, course, and bronchoscopic findings of neoplastic lesions at other bronchial sites. RESULTS: Progression to carcinoma occurred in five of nine patients (56%) with a carcinoma in situ. Eight neoplastic lesions were detected at other sites in four of the nine patients (44%). In earlier biopsy specimens of two sites that later showed a severe dysplasia and a carcinoma, only normal epithelium was found. Biopsies had been performed at these sites because they were assessed as suspicious during autofluorescence bronchoscopy. CONCLUSION: The majority of sites showing a carcinoma in situ progressed to invasive carcinoma. A considerable portion of the patients had neoplastic lesions at other bronchial sites. The fluorescence pattern of the bronchial mucosa may reflect early changes that are not found at histopathologic examination, but which may progress to neoplastic growth.

Aged↗
PubMed1999

[Role of chemo(radio)theray prior to surgery for stage IIIa non-small cell lung carcinoma (localized non-resectable tumor)].

Neoadjuvant chemotherapy with or without combined radiotherapy followed by surgery may yield a survival profit for selected patients with non-small cell lung carcinoma in stage IIIA. It has not yet been established which is the most efficacious neoadjuvant chemotherapy nor what is the best postneoadjuvant chemotherapy, especially resection or radiotherapy. Comparative clinical studies to find the answer to these two questions are in progress. New forms of treatment are required in order to achieve 5-year survival in more stage IIIA patients than is currently the case.

Carcinoma, Non-Small-Cell Lung↗
PubMed1999

Development of meta-tetrahydroxyphenylchlorin-monoclonal antibody conjugates for photoimmunotherapy.

A limitation of photodynamic therapy is the lack of tumor selectivity of the photosensitizer. To overcome this problem, a protocol was developed for coupling of meta-tetrahydroxyphenylchlorin (mTHPC), one of the most promising photosensitizers, to tumor-selective monoclonal antibodies (MAbs). mTHPC was radiolabeled with 131I to facilitate the assessment of the in vitro and in vivo behavior. After the modification to 131I-mTHPC-(CH2COOH)4, thus increasing the water solubility and creating a functional moiety suitable for coupling, conjugation was performed using a labile ester. Insoluble aggregates were not formed when mTHPC-MAb conjugates with a molar ratio of up to 4 were prepared. These conjugates showed a minimal impairment of the integrity on SDS-PAGE, full stability in serum in vitro, and an optimal immunoreactivity. To test the in vivo behavior of the mTHPC-MAb conjugates, the head and neck squamous cell carcinoma-selective chimeric MAb U36 was used in head and neck squamous cell carcinoma-bearing nude mice. Biodistribution data showed that the tumor selectivity of cMAb U36-conjugated mTHPC was increased in comparison with free mTHPC, despite the fact that conjugates with a higher mTHPC:MAb ratio were more rapidly cleared from the blood. Preliminary results on the in vitro efficacy of photodynamic therapy with MAb-conjugated mTHPC showed that mTHPC coupled to the internalizing murine MAb 425 exhibited more phototoxicity than when coupled to the noninternalizing chimeric MAb U36.

Animals↗
PubMed1999

Combination chemotherapy studies with gemcitabine and etoposide in non-small cell lung and ovarian cancer cell lines.

Gemcitabine (2',2'-difluorodeoxycytidine, dFdC) and etoposide (4'-demethylepipodo-phyllo-toxin-9-4,6-O-ethylidene-beta-D-g lucopyranoside, VP-16) are antineoplastic agents with clinical activity against various types of solid tumors. Because of the low toxicity profile of dFdC and the differences in mechanisms of cytotoxicity, combinations of both drugs were studied in vitro. For this purpose, we used the human ovarian cancer cell line A2780, its cis-diammine-dichloroplatinum-resistant and VP-16 cross-resistant variant ADDP, and two non-small cell lung cancer cell lines, Lewis Lung (LL, murine) and H322 (human). The interaction between the drugs was determined with the multiple drug effect analysis (fixed molar ratio) and with a variable drug ratio. In the LL cell line, the combination of dFdC and VP-16 at a constant molar ratio (dFdC:VP-16 = 1:4 or 1:0.125 after 4- or 24-hr exposure, respectively) was synergistic (combination index [CI], calculated at 50% growth inhibition = 0.7 and 0.8, respectively; CI <1 indicating synergism). After 24- and 72-hr exposure to both drugs at a constant ratio, additivity was found in the A2780, ADDP, and H322 cell lines (dFdC:VP-16 = 1:500 for both exposure times in these cell lines). When cells were exposed to a combination of dFdC and VP-16 for 24 or 72 hr, with VP-16 at its IC25 and dFdC in a concentration range, additivity was found in both the LL and H322 cells; synergism was observed in the A2780 and ADDP cells, which are the least sensitive to VP-16. Schedule dependency was found in the LL cell line; when cells were exposed to dFdC 4 hr prior to VP-16 (constant molar ratio, total exposure 24 hr), synergism was found (CI = 0.5), whereas additivity was found when cells were exposed to VP-16 prior to dFdC (CI = 1.6). The mechanism of interaction between the drugs was studied in more detail in the LL cell line; dFdCTP accumulation was 1.2-fold enhanced by co-incubation with VP-16, and was even more pronounced (1.4-fold) when cells were exposed to VP-16 prior to dFdC. dCTP levels were decreased by VP-16 alone as well as by the combination of both compounds, which may favor phosphorylation of dFdC, thereby increasing dFdCTP accumulation. DNA strand break (DSB) formation was increased for exposure to both compounds together compared to exposure to each compound separately, this effect being most pronounced when cells were exposed to VP-16 prior to dFdC (38% and 0% DSB for dFdC and VP-16 alone, respectively and 97% DSB for the combination). The potentiation in DSB formation might be a result of the inhibition of DNA repair by dFdC. Provided the right schedule is used, VP-16 is certainly a compound eligible for combination with dFdC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

A dose and schedule finding study of gemcitabine and etoposide in patients with progressive non-small cell lung cancer after platinum containing chemotherapy.

BACKGROUND: Combination chemotherapy improves survival in patients with disseminated non-small cell lung cancer (NSCLC). Gemcitabine is active against NSCLC and etoposide has an additive effect in vitro. We describe a dose finding study for the combination of these drugs. PATIENTS AND METHODS: NSCLC patients progressive after chemotherapy received gemcitabine (1000 mg/m2 days 1, 8, 15) and one of five etoposide schedules in doses ranging from 60 to 100 mg/m2 per day administered on days 1-3 (schedules 1-2) or 8-10 (schedules 3-5). RESULTS: 23 patients (median age 59 years) were entered. Number of patients and cycles evaluable for toxicity was 22 and 75. Non-hematological toxicity was mild. In cycle 1 leukocytopenia grade III/IV was observed in 33 and 56% of the patients treated with etoposide 60 and 80 mg/m2 days 1-3 and in 50% treated with etoposide 60 and 80 mg/m2 days 8-10. During cycle 1 thrombocytopenia grade III/IV was observed in 0, 33, 0 and 33% of these patients, respectively. Both patients treated at etoposide 100 mg/m2 days 8-10 experienced febrile leukocytopenia. During cycle 1 single doses of gemcitabine were administered as planned more frequently in patients receiving etoposide 80 mg/m2 per day on days 8-10 compared to etoposide days 1-3 (83 versus 70%). Postponement of combination gemcitabine and etoposide was not necessary. The overall response rate was 21% (95% confidence interval 3-39%) with a median duration of 7.5 + months in this dose finding study. CONCLUSIONS: Combined gemcitabine etoposide is feasible in patients with progressive NSCLC. The optimal combination was gemcitabine 1000 mg/m2 per day on days 1, 8 and 15 and etoposide 80 mg/m2 per day on days 8-10 of each 28-day cycle. The response rate of 21% warrants further investigation in patients with advanced NSCLC.

Adult↗
PubMed1999

Sleep complaints and sleep disordered breathing in hemodialysis patients.

BACKGROUND: The objective of the study was to determine the prevalence of sleep complaints and of sleep disordered breathing (SDB) in hemodialysis patients not selected for sleep complaints and to determine the effect of hemodialysis on SDB. The feasibility of home recording of sleep related respiration in these patients was also studied. METHODS: The patients completed a questionnaire and parameters of SDB were examined in the home setting on nights following dialysis and nights following no dialysis with the Edentrace II Recording System. RESULTS: Six (46%) of 13 patients had sleep complaints. Symptoms suggestive for sleep apnea syndrome were found in four (31%) of these 13 patients. In three (75%) of these four patients SDB was found. Sleep related respiration was monitored in 15 patients. Registrations satisfactory for interpretation were obtained in all patients. SDB was observed in five (33%) of these 15 patients. There were no significant differences in parameters of SDB between nights following dialysis and nights following no dialysis. CONCLUSIONS: Home recording of sleep related respiration in hemodialysis patients is feasible. Sleep complaints and SDB are common in these patients. No clinically significant differences in SDB were found between nights following dialysis and nights following no dialysis.

Adult↗
PubMed1999

Analysis of pleural fluid in idiopathic spontaneous pneumothorax; correlation of eosinophil percentage with the duration of air in the pleural space.

Pleural fluid analysis was performed in patients with idiopathic spontaneous pneumothorax. The objective of the study was to define the cell differentiation, and part of the cytokine profile, in relation to the duration of pneumothorax. In the 23 consecutive patients (19 men, mean age 34.2 years, 17 smokers), pleural fluid was obtained immediately after chest tube drainage (n = 6), or during thoracoscopy (n = 17). Cytospins were carried out, and supernatant analysis of the different cytokines was performed using sandwich ELISA. All concentrations were corrected for dilution. The duration of the pneumothorax was correlated with the rise in eosinophil percentage (r = 0.81, P < 0.00001) in pleural fluid. RANTES, platelet-activating factor (PAF), and monocyte chemotactic protein-1 (MCP-1) were detectable but no relationship with eosinophils or duration of the pneumothorax was found. Granulocyte-macrophage colony stimulating factor (GM-CSF) and interluekin-8 (IL-8) were not detectable. Interleukin-5 (IL-5) concentration correlated with the eosinophil concentration (r = 0.84, P = 0.037) and the eosinophil percentage (r = 0.68, P = 0.005) in the pleural fluid. Idiopathic spontaneous pneumothorax causes a time-related rise in the eosinophil percentage in the pleural space, which correlates with the level of IL-5.

Adult↗
PubMed1999

Scheduling of gemcitabine and cisplatin in Lewis lung tumour bearing mice.

We used the gemcitabine (dFdC) and cisplatin (cis-diamine dichloroplatinum CDDP) resistant murine NSCLC tumour Lewis Lung (LL) in C57/B16 mice to optimise scheduling of both drugs, since in previous in vivo studies no effective combination schedule of both compounds was found to overcome resistance to either drug. dFdC could not be combined at the previously determined maximum tolerated dose (MTD) (120 mg/kg, q3dx4) with CDDP at its MTD (9 mg/kg, q6dx2) (mean weight loss < 15% and < 15% toxic deaths), because of additive toxicity. Therefore, we lowered the dose of dFdC to 60 mg/kg (q3dx4) and of CDDP to 3 mg/kg (q6dx2), which caused an increase in antitumour effect compared with the activity of each compound alone at its MTD (growth delay factor (GDF) = 0.55, 0.13 and 2.56 for dFdC and CDDP alone and the combination, respectively). Changing the CDDP treatment schedule giving the total dose (6 mg/kg) only at day 0 caused unacceptable toxicity. This effect was not seen when mice were treated with the total dose of CDDP on day 9, but, the anti-tumour effect was not enhanced. To decrease toxicity, the dosage of dFdC was lowered to 50 mg/kg and combined with the total dose of CDDP on day 0, which caused a better antitumour effect than the combination of 60 mg/kg dFdC and 3 mg/kg CDDP (q6dx2) with acceptable toxicity. Schedule dependency was found for the combination: dFdC preceding CDDP by 4 h was the best treatment schedule in the LL tumours (GDF: 2.1) with acceptable toxicity. However, when the interval was increased to 24 h, toxicity became unacceptable (> 30% weight loss). The reverse schedule, in which CDDP preceded dFdC, did not lead to an increased antitumour effect or to increased toxicity. Adding amifostine, a selective chemoprotector, to the treatment decreased toxicity of the combination without affecting the antitumour effect. Increasing the CDDP dose to 9 mg/kg (day 0) under amifostine protection led to an improved therapeutic index.

Animals↗