Biomedical subjects

R Bugat

Publications and source records attributed to R Bugat.

At least 37 records · Page 2Linked to original sources

PubMed2001

Carcinocythemia as the single extension of breast cancer: report of a case and review of the literature.

Carcinocythemia (carcinoma cell leukemia) has been previously described as a rare, late and dramatic event occurring in widespread tumoral disease. We report a case of carcinocythemia occurring in a patient with a particularly indolent breast cancer. When a large amount of circulating tumor cells (CTC) appeared in the blood smears, neither visceral macrometastases nor massive bone marrow infiltration could be detected. We isolated CTC to perform cell cycle analysis and to study the expression of adhesion molecules. A fraction of the CTC was proliferating in the bloodstream but we detected no relevant anomaly of adhesion properties in the CTC. A post-mortem biopsy disclosed an exclusive sinusoidal infiltration of the liver. We propose that in this case, carcinocythemia resulted from the release of CTC from the visceral microcirculation where the proliferation occurred.

Autopsy↗

PubMed2001

Combination of oxaliplatin and irinotecan on human colon cancer cell lines: activity in vitro and in vivo.

The in vitro and in vivo combination of oxaliplatin and irinotecan was investigated in a panel of four human colon cancer cell lines and their counterpart xenografts. In vitro and in vivo experiments demonstrated a synergistic or additive interaction in three cell lines (HCT-116, HCT-8 and HT-29) and an antagonism in SW-620 cells. Since there were clearly opposite interactions depending on the cell line, we further investigated cellular determinants possibly involved in the interaction between the two drugs in HCT-8 and SW-620 cells. Irinotecan slowed down the early platinum-DNA adducts repair (1 h after oxaliplatin exposure) in the presence of irinotecan only in HCT-8 cells (p=0.03, n=3). Moreover, a decrease of the expression of two proteins of the nucleotide excision repair (NER) system, ERCC1 and XPA, was observed. None of these effects was seen in SW-620 cells. Irinotecan induced apoptosis with an increase of poly(ADP-ribose) polymerase (PARP) cleavage in SW-620 cells (60 versus 7% basal level). Pretreatment of these cells with oxaliplatin abolished the increase in PARP cleavage induced by irinotecan (29%). In HCT-8 cells, a very little PARP cleavage was observed whatever the drug treatment. The persistence of platinum-DNA adducts in the presence of irinotecan could be due to a direct impact of irinotecan on NER gene expression or to an indirect effect on topoisomerase I activity. Complementary studies are required to determine if the cellular parameters identified in this study could be translated at the clinical level to predict clinical response after combined treatment with oxaliplatin and irinotecan in humans.

Animals↗

PubMed2001

[Oxaliplatin tolerance in the treatment of metastatic colorectal cancers].

Oxaliplatin is a new platinum compound with a 1,2-diaminocyclohexane (DACH) carrier ligand. It has recently been developed in metastatic colorectal cancer treatment, where it is generally combined with 5FU and leucovorin. Safety data in this indication concern over 1,700 patients, who received 12,500 cycles during clinical trials. Oxaliplatin appears to be relatively well tolerated and easy to handle, even on an outpatient basis. Gastrointestinal toxicity is common, but controllable and rarely severe or long-lasting. Haematological and mucosal tolerance is satisfactory, and oxaliplatin does not seem to have renal toxicity. Neurological side effects are the drug's limiting toxicity and can present as acute neurotoxicity (dysesthesiae), which is rapidly reversible, or sometimes as a longer-lasting effect, correlated in this case with the cumulative dose and leading to functional impairment in 10 to 20% of patients after 6 cycles or more. Neurological symptoms improve in the vast majority of cases after treatment is stopped. In this situation, it is even possible to restart oxaliplatin treatment. Good patient information and dose adjustments should allow us to manage the majority of neurological toxicity associated with oxaliplatin administration.

Antineoplastic Agents↗

PubMed2001

Schedule-dependent activity of topotecan in OVCAR-3 ovarian carcinoma xenograft: pharmacokinetic and pharmacodynamic evaluation.

Topotecan is a topoisomerase (Topo) I inhibitor used in ovarian carcinoma chemotherapy. Topo I inhibitors are thought to be more cytotoxic using protracted schedules of administration. We tested this hypothesis on a preclinical model: human ovarian carcinoma OVCAR-3 implanted i.p. Nude mice were treated i.p. with a total dose of topotecan of 12.5 mg/kg delivered in 1, 5, 10, 20, 40, or 80 daily injections. The toxicity was maximal when the total dose was delivered within 5 and 10 days of treatment. However, the efficacy was the greatest (all of the mice cured) in the 20-day schedule using 0.625 mg/kg/day, hence, making this latter schedule the most efficient without any major toxicity. A pharmacokinetic study was conducted to identify parameters related to the efficacy and toxicity of topotecan in our model. The use of a population pharmacokinetic approach allowed us to define a therapeutic window: maintaining plasma concentrations above 0.2 microM for >10 h was necessary for an optimal antitumor effect and avoiding plasma concentrations >0.7 microM allowed a manageable toxicity. Finally, Topo I activity was monitored in ascites from animals treated with different topotecan administration schedules. The optimal schedule defined above allowed for sustained inhibition of Topo I activity associated with a greater antitumor activity. These in vivo data constitute a rationale for clinical studies testing this type of administration.

Animals↗

PubMed2001

[Cost-effectiveness in diagnosis and treatment of carcinomas of unknown primary origin].

The aim was to compare, in terms of cost-effectiveness, two diagnostic strategies for finding out the primary site of tumors revealed by metastasis, adopting the hospital's perspective. The observed strategy reflected the usual practices of doctors at the Regional Cancer Center in Toulouse (France), and was based on a sample of 202 patients of this Center. The standardized strategy, which reflected limited diagnostic investigation, was simulated using the same sample of patients to whom we applied the recommendations of local experts. In the low assumption regarding the effectiveness of the standardized strategy, the observed strategy compared to the standardized one raised the life expectancy from 407 to 418 days at an incremental cost of $US 1,236 per patient (1996 values). In this case, one day of additional life induced a cost of $US 112 per patient. In the high assumption, the incremental effectiveness was null and the incremental cost was $US 1,236 per patient. In conclusion, the effectiveness of the observed strategy as compared to the standardized strategy was highly questionable, given that the patients' quality of life was not taken into account.

Adult↗

PubMed2000

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.51 per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of -2+/-17%, and + 5+/-20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Aged↗

PubMed2000

Dihydropyrimidine dehydrogenase activity in normal, inflammatory and tumour tissues of colon and liver in humans.

BACKGROUND/PURPOSE: Dihydropyridmidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). Although this catabolism is likely to occur in the liver in humans, there may be a local inactivation in tumours, modifying the efficacy of 5FU. The aim of this study was to examine the DPD activity in normal, inflammatory and malignant tissues from both the colon and the liver to assess the modifications of DPD activity in the process of tumourigenesis. METHODS: DPD activity was evaluated in 107 patients, corresponding to 194 samples (70 colorectal tumour and normal colon, nine metastases secondary to a colon cancer, ten inflammatory colon, 20 samples of normal liver, seven from primary liver cancer, and eight from inflammatory liver). DPD activity was determined using an enzymatic reaction followed by analysis of 5FU and its catabolite dihydro-5FU by high-performance liquid chromatograph. Results were expressed as pmol of 5FU catabolized/min x mg protein. RESULTS: DPD was highly variable in tumour and normal tissues, both from colon and liver. In colon, the correlation between DPD activity in tumour and normal mucosa was weak, even if it was statistically significant due to the higher number of samples. In inflammatory colon tissue (ulcerative colitis or Crohn's disease), DPD activity was significantly higher than in normal tissue (P = 0.006). In liver metastases from colon cancer, DPD activity was not significantly different from that observed in primary colon tumour (P = 0.32). In liver, DPD activity was significantly lower in primary liver tumour than in uninvolved liver specimens (P = 0.001). In inflammatory liver tissue (hepatitis), DPD activity ranged between normal and tumour tissues, and did not differ significantly either from normal tissue or primary liver cancer. CONCLUSIONS: DPD activity was modified in colon and in liver during a pathological process and the dysregulation of DPD increased from a benign to a malignant tissue.

Adolescent↗

PubMed2000

Prognostic factors for tumour response, progression-free survival and toxicity in metastatic colorectal cancer patients given irinotecan (CPT-11) as second-line chemotherapy after 5FU failure. CPT-11 F205, F220, F221 and V222 study groups.

Our purpose was to determine, in patients with metastatic colorectal carcinoma treated with irinotecan single-agent after 5-FU failure, the most significant predictive parameters for tumour response, progression-free survival and toxicity. Between October 1992 and April 1995, 455 patients with 5-FU resistant metastatic colorectal carcinoma entered four consecutive phase II trials. The first two studies assessed tumour response, the other two were randomized studies which assessed the efficacy of racecadotril to prevent irinotecan-induced diarrhoea. Due to homogeneous main eligibility criterias, data from those studies could be pooled for statistical analysis. Potential clinical and biological predictive factors (PF) for toxicity, tumour growth control, e.g. response or stabilization and progression-free survival (PFS), were studied in multivariate analysis. 363 patients were evaluable for response, 432 were evaluable for PFS, 368 for neutropenia and 416 for delayed diarrhoea, respectively. Normal baseline haemoglobin level (Hb), time since diagnosis of colorectal carcinoma, grade 3 or 4 neutropenia or diarrhoea at first cycle and a low number of organs involved were the most PF for tumour growth control (P<0.05). Significant prognostic variables for PFS were WHO Performance Status, liver and lymph-node involvement, time since diagnosis, age and CEA value (P < or =0.02). Six groups of patients based on the number of unfavourable prognostic factors are presented. Baseline bilirubin, haemoglobin level, number of organs involved and time from diagnosis were PF for neutropenia; PS, serum creatinine, leukocyte count, time from 5-FU progression and prior abdominopelvic irradiation were PF for delayed diarrhoea (P< or =0.05). These PF should help clinicians to anticipate for a given patient the probability to observe a response/stabilization or a toxicity. These results should also be prospectively confirmed in ongoing or future trials using irinotecan, both as a single agent and in combination with other drugs.

Adult↗

PubMed2000

Dose and time dependencies of 5-fluorouracil pharmacokinetics.

OBJECTIVES: The purpose of this study was to examine the interpatient and intrapatient variability of the Michaelis-Menten plasma parameters of 5-fluorouracil administered according to a schedule combining a bolus of 400 mg/m2 followed by 22-hour infusion of 600 mg/m2 for 2 consecutive days. PATIENTS: A pharmacokinetic population approach was used to analyze the data from 21 patients with colorectal cancer. RESULTS: The 5-fluorouracil plasma concentrations versus time were best described by a two-compartment model with nonlinear elimination from the central compartment. The relationships between the pharmacokinetic parameters and patient characteristics were tested. On day 1 the mean values (with interindividual variability as expressed by the coefficient of variation) were 1390 mg x h(-1) (20%), and 5.57 mg x L(-1) (22%) for the maximum rate of elimination, and the half-saturating plasma concentration. The maximum rate of elimination was positively correlated to the body surface area and the percentage of liver involvement by metastatic disease determined by tomodensitometric examination. The model was successfully tested with independent data sets corresponding to other schedules. The analysis of this intrapatient variability showed that the half-saturating plasma concentration increased from day 1 to day 2, especially in the patients with low lymphocyte cell dihydropyrimidine dehydrogenase activity. CONCLUSION: The pharmacokinetic parameters obtained in this study would be useful to predict the 5-fluorouracil plasma concentrations following other schedules of administration of 5-fluorouracil and to study the possible pharmacokinetic interactions between 5-fluorouracil and other drugs.

Adult↗

PubMed2000

Characterization of CPT-11 converting carboxylesterase activity in colon tumor and normal tissues: comparison with p-nitro-phenylacetate converting carboxylesterase activity.

Irinotecan (CPT-11) is a topoisomerase I inhibitor commonly used in the treatment of colorectal tumors. It is a prodrug, converted to an active metabolite, SN-38, by carboxylesterases (CEs). CEs are ubiquitary enzymes that react with numerous substrates. A specific CPT-11 converting enzyme was isolated from rat serum, with different kinetic properties than other CEs. We determined kinetic properties of specific CPT-11 CE activity (CPT-CE) in human normal liver and colon tumors. Km were very similar (3.4 microM in liver and 3.8 microM in colon tumors), but Vmax was higher in liver (2.7 pmol/min/mg protein) than in colon tumor (1.7 pmol/min/mg protein). CPT-CE and total CE (using p-nitro-phenylacetate as substrate) were weakly correlated in colon tumors. The large interpatient variability observed in liver CPT-CE activity could play a potential role in the pharmacokinetic variability observed with irinotecan.

Animals↗

PubMed2000

[Pharmacokinetics and individual dose adjustment of carboplatin].

Carboplatin differs from cisplatin by its pharmacokinetics and toxicity profile. Carboplatin is mainly eliminated by the kidneys and its dose-limiting toxicity is the bone marrow suppression. Myelosuppression of carboplatin is more closely correlated with the area under the curve (AUC) of ultrafiltrable plasma concentration versus time to which a patient is exposed, than it is with the administered dose. Similar relationships have been shown between AUC and antitumour effect, although they are in a smaller number and less close. Several methods of dosage individualisation a priori (before carboplatin administration) have been proposed. Since carboplatin is often prescribed to patients with altered renal functions, this dose optimisation is particularly justified. Dose individualisation is based on both equations allowing to predict the patient carboplatin clearance and the choice of target AUC. The different equations proposed are based on direct measurement of the renal filtration glomerular rate or on patient demographic and biological characteristics such as weight and serum creatinine. The respective advantages and limits of these equations are now well known. However, the values of optimal AUC that depend on cytotoxic drugs combined to carboplatin and the patient hematopoietic status, are not precisely determined for each protocol of chemotherapy. When carboplatin is given by reiterated administrations within each course, it is possible to adjust the last doses according to a limited number of blood samples following the first infusion and a Bayesian analysis of the observed plasma concentrations. These methodologies are more complex, but they may be useful for the intensification protocols. Carboplatin is still the only cytotoxic drug for which dose is individualised not according to the body surface area but according to pharmacokinetic parameters.

Age Factors↗

PubMed1999

CPT-11 converting carboxylesterase and topoisomerase activities in tumour and normal colon and liver tissues.

CPT-11 is a prodrug activated by carboxylesterases to the active metabolite SN-38 which is a potent inhibitor of topoisomerase I. CPT-11 is of clinical interest in the treatment of colorectal cancer. We evaluated the activities of CPT-11 converting carboxylesterase (CPT-CE) and topoisomerase I (topo I) in 53 colorectal tumours, in eight liver metastases and in normal tissue adjacent to the tumours. Both CPT-CE and topo I activities were widely variable in the malignant and the normal tissue of patients with colorectal carcinomas. CPT-CE was only two to threefold lower in primary tumours compared to normal liver, suggesting that a local conversion to SN-38 might occur in tumour cells. CPT-CE was similar in liver and in normal colon tissues. Levels of topo I in tumour ranged from 580 to 84 900 U mg protein(-1) and was above 40 000 U mg protein(-1) in 11 of 53 patients. Similarly, a very high ratio (> 5) between tumour and normal tissues were observed in 12 of 53 patients. An inverse correlation was observed between the topo I activity and the clinical stage of disease. Clinical studies are in progress in our institution to explore a possible relationship between CPT-CE and topo I activities in tumour cells and the response to CPT-11-based chemotherapy in patients with colorectal cancer.

Adult↗

PubMed1999

[Compassionate use of gemcitabine in advanced pancreatic cancer: a French multicentric study].

Advanced-stage surgically unresectable adenocarcinoma of the pancreas is highly lethal. Attempts to improve this survival with chemotherapy were dismal, until gemcitabin was shown to be clinically beneficial and to modestly improve survival. We started an open multicentric compassionate study of gemcitabine in advanced adenocarcinoma of the pancreas to assess those benefits. Of 74 patients who were enrolled, 46 were assessable for tumoral response (2 partial response, 18 stable disease, 24 progressing disease). A clinical benefit was obtained in 48% of assessable patients. Myelotoxicity, nausea and vomiting were the major side effect. The median event-free and overall survivals from study inclusion were 2. 5 and 5 months respectively. This study confirms that gemcitabine can be effective even in patients with pretreated advanced adenocarcinoma of the pancreas.

Adult↗

PubMed1998

Cellular interactions of 5-fluorouracil and the camptothecin analogue CPT-11 (irinotecan) in a human colorectal carcinoma cell line.

CPT-11 (irinotecan) is a DNA topoisomerase I inhibitor active against metastatic colorectal carcinoma. We investigated, in a human colon carcinoma cell line, HT-29, the effects of CPT-11 and 5-fluorouracil (5FU) combinations. A strong synergism between CPT-11 and 5FU was observed after sequential exposure and only additivity or antagonism after simultaneous exposure. When cells were first exposed to 5FU, the product of cellular CPT-11 concentrations versus time (CxT) was 6895 +/- 1020 pmol x hr/10(6) cells, while it was 3875 +/- 121 pmol x hr/10(6) cells with CPT-11 alone (p < 0.01). The same phenomenon was observed with SN-38: 148.2 +/- 49.5 versus 83.4 +/- 23.6 pmol x hr/10(6) cells (p < 0.05). Consequently, the formation of protein-DNA complexes was 1.4 times greater with 5FU pretreatment than with CPT-11 alone (p = 0.03). Moreover, the incorporation of 5FU derivatives into DNA was multiplied by a factor of 1.5 24 hr after CPT-11 exposure. When cells were first incubated with CPT-11, the decrease in thymidylate synthase (TS) activity was identical to that obtained after 5FU exposure (1.09 to 0.023 pmol/min/mg protein), but this decrease persisted for 24 hr (0.014 pmol/min/mg protein) (p = 0.035). At the same time, a 1.8-fold increase in the incorporation of 5FU derivatives into DNA and a 2-fold increase in DNA-protein complex formation were evidenced. With the two sequential associations, we observed a persistent S-phase arrest, as compared with CPT-11 alone. These results suggest that CPT-11 and 5FU combinations are of clinical interest, and mechanisms of interaction between the two drugs seem to be multifactorial.

Antimetabolites, Antineoplastic↗

PubMed1998

Population pharmacokinetics of total and unbound etoposide.

A population pharmacokinetics study using the NONMEM program was undertaken to determine the effects of different covariates on the pharmacokinetic parameters of etoposide. A total of 1,044 plasma etoposide concentrations were determined by high-performance liquid chromatography (HPLC) in 100 patients (pts; 75 men and 25 women aged 25-85 years) treated for various tumor types with i.v. (57 pts) or oral (43 pts) etoposide. For 67 pts, etoposide plasma protein binding was determined by equilibrium dialysis; the unbound fraction ranged from 4% to 24%. A linear two-compartment model with first-order absorption (for oral dosing) accurately described the concentration versus time data. The central and peripheral volumes of distribution were significantly correlated with the body surface area [Vc (L) = 5.5 x BSA (m2) and Vp = 4.1 x BSA], but even after BSA had been taken into account, the interindividual variability of the two volumes remained high (34% and 57%, respectively). The clearance (CL) was not correlated with the following covariates: age, BSA, sex, height, and levels of serum bilirubin and liver enzymes. The final regression model for CL was CL (ml/min) = 49.8 x (1 - 0.009 x PRO) x WT/Scr + 33.8 x (1 - 0.29 x META) x (1 - 0.012 x ALB), where ALB, PRO, WT, and Scr, respectively, were albuminemia, proteinemia (g/l), weight (kg), and serum creatinine (microM) and META = 1 if the patient had liver metastases (otherwise, META = 0). The interindividual variability in CL (mean value 30 ml/min) decreased only from 32% to 26% when these covariates were taken into account. The mean oral bioavailability was 66%, showing an interindividual variability of 37%. The plasma clearance of the unbound fraction was strongly and negatively correlated with Scr but was not dependent on either PRO or ALB. These data show that modifications in PRO levels do not directly affect plasma exposure to unbound etoposide. This analysis makes possible the rational consideration of modifications of covariates such as Scr in etoposide dosing. This population data base will constitute the prerequisite for adaptative control with feedback dosing for continuous oral administration of etoposide.

Administration, Oral↗

PubMed1998

Comparison of the pharmacokinetics and efficacy of irinotecan after administration by the intravenous versus intraperitoneal route in mice.

Irinotecan (CPT-11) is a new drug active in colorectal cancer. A comparison was made of the efficacy and pharmacokinetics of CPT-11 after i.p. versus i.v. administration to mice. We found that i.p. administration of CPT-11 to mice bearing C26 colon cancer was more efficient and less toxic than i.v. administration; a 100-mg i.p. dose induced an increase in life span equivalent to that produced by a 300-mg i.v. dose, and toxic deaths appeared after doses of 400 mg/kg given i.v. and 800 mg/kg given i.p. Pharmacokinetic parameters of CPT-11 and SN-38 were compared after i.v. or i.p. administration in mice bearing P388 leukemia ascites. Peritoneal CPT-11 and SN-38 AUC values were higher after i.p. administration than after i.v. injection. Plasmatic AUC values remained equivalent. Moreover, peritoneal CPT-11 clearance was 10-fold lower after i.p. versus i.v. administration. If the survival and pharmacologic advantage of i.p. CPT-11 in the murine model considered can be translated to a safe and practical mode of therapy in patients and if local toxicity does not prove to be a major adverse effect, then a potentially useful agent could be added to the drugs known to be active when given by the i.p. route for adjuvant therapy in colon cancer.

Animals↗

PubMed1998

A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer.

BACKGROUND: Most patients with advanced ovarian cancer will relapse following platinum-based combination chemotherapy and be considered for second-line treatment. Gemcitabine, a nucleoside analogue, is active against a range of solid tumors. This phase II study investigated the activity of single-agent gemcitabine in patients with recurrent ovarian cancer. PATIENTS AND METHODS: Thirty-eight patients with FIGO stage III (34%) or IV (64%) ovarian cancer who were previously treated with platinum-containing regimens were enrolled. Patients received 1200 mg/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle. RESULTS: Patients completed an average of 3.6 cycles. Two complete and three partial responses were seen in 36 evaluable patients, for an overall response rate of 13.9% (95% CI: 4.7%-29.5%). The median survival time was 6.7 months. Toxicities were generally mild. The most common were grade 3-4 neutropenia and grade 3 leukopenia reported in 23.7% and 10.5% of patients, respectively. One patient had grade 4 pulmonary toxicity. CONCLUSION: Single-agent gemcitabine is active and well tolerated in patients with recurrent ovarian cancer.

Adult↗

PubMed1998

Cytotoxic effect of interferon-alpha2a in combination with all-trans retinoic acid or cisplatin in human ovarian carcinoma cell lines.

Ovarian cancer has a poor prognosis due to the frequent appearance of a drug-resistant state. An alternative therapeutic approach may lie in combinations of conventional chemotherapeutic agents with new classes of drug, such as interferons (IFN) and differentiation-inducing agents. There is clinical evidence that both IFN-alpha2a-all-trans retinoic acid (ATRA) and IFN-alpha2a-cisplatin have significant activities on growth of malignant cells, cell differentiation or programmed cell death in solid tumors. In order to throw more light on the cellular basis of these findings and to optimize a schedule of such drug combinations, we examined the cytotoxic effects of various combinations on five human ovarian carcinoma cell lines. The experiments were based on a clonogenic assay on plastic. The different cell lines exhibited different sensitivities to the three drugs tested. Using the cell line most sensitive to these drugs, we then examined the effect of different sequences of two drug combinations. We observed a potentiation after pretreatment with ATRA followed by IFN-alpha2a and ATRA or after pretreatment with IFN-alpha2a followed by IFN-alpha2a and cisplatin. Using this schedule of administration, cytotoxic interactions between the two drugs were investigated by median effect analysis. Synergism or antagonism were observed depending on the intrinsic sensitivity of the cell line to the first drug and the concentrations used. The magnitude of these interactions was found to be influenced by the cellular sensitivity to the second drug. These results show that schedules of drug combinations are not easy to design and may help account for the various failures and the discrepant effects observed in clinical trials.

Cell Line↗