Intracarotid VP-16 in malignant brain tumors

Twenty-eight patients with malignant brain tumors (16 with primary brain tumors and 12 with brain metastases) progressing after cranial irradiation with or without chemotherapy received varying doses of intracarotid VP-16. Courses of therapy were repeated every 4 weeks along with computerized axial tomography scan and neurologic examination. Of 15 evaluable patients with primary malignant brain tumors, 1 responded to therapy and 5 had no immediate tumor progression for 2–10 months. None of 12 evaluable patients with brain metastases responded to intracarotid VP-16 although 5 had no immediate tumor progression from 1–4 months. Side effects of treatment were uncommon. Using this route of administration, intracarotid VP-16 does not appear to increase response rates in patients with primary malignant brain tumors, compared with results reported for intravenous VP-16.     

Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors

VP-16 100 mg/m2 was given intravenously to 10 patients undergoing surgical resection of intracerebral tumors, and the drug was assayed in resected tumor using high pressure liquid chromatography. VP-16 concentrations varied from undetectable (less than .1 microgram/g) to 5.9 micrograms/g (mean, 1.4 microgram/g). VP-16 concentrations in tumors were lower than concurrent plasma concentrations. In addition, intracerebral tumors had a lower concentration of VP-16 than did extracerebral tumors (mean VP-16 concentration, 3.9 micrograms/g) from 7 patients receiving VP-16 50-100 mg/m2 intravenously. Plasma pharmacokinetics of VP-16 were different in our patients with intracerebral tumors than in previously studied patients with extracerebral tumors and it is unclear what role this may played in variability of tumor VP-16 concentrations. VP-16 concentrations were similar in glioblastomas and brain metastases. Specimens from patients with small cell undifferentiated carcinoma of the lung had the highest VP-16 concentrations. A patient who had both viable and necrotic tumor resected during an occipital lobectomy had a higher drug concentration in the necrotic than in the viable area of tumor. In addition, VP-16 concentration decreased as a function of distance into brain from the tumor. Based on our data, VP-16 might be expected to have less activity against intracerebral than against extracerebral human tumors.     

VP-16, vincristine and procarbazine with radiation therapy for treatment of malignant brain tumors

Summary Twelve patients aged 34 to 65 with malignant gliomas were treated with VP-16, Procarbazine, Vincristine and concurrent radiation therapy. There were 9 patients with glioblastoma multiforme and 3 with anaplastic astrocytoma. All patients had a subtotal resection or biopsy as the initial procedure.Six patients (1 anaplastic astrocytoma) have developed progressive disease. Mean time to tumor progression was 46 weeks. This combined modality treatment program was associated with reversible hematologic toxicity which was severe in 2 patients. These data compare favorably to data obtained from similiar patients treated with radiation therapy and BCNU.     

Dose-dependent brain penetration of SDZ PSC 833, a novel multidrug resistance-reversing cyclosporin,in rats

 This study quantitatively assessed the brain penetration of a potent P-glycoprotein inhibitor, SDZ PSC 833, and its effect on the blood-brain barrier (BBB) permeability (PS) of an anticancer agent, vincristine. At lower doses of SDZ PSC 833 the brain penetration, defined as the brain-to-blood partition coefficient (Kp), was very low in spite of the high lipophilicity of this compound. At higher doses, however, the brain penetration of SDZ PSC 833 was markedly increased. Since the blood pharmacokinetics of SDZ PSC 833 proved to be linear in the dose range studied, these results demonstrated a dose-dependent brain passage of SDZ PSC 833. The brain passage of cyclosporin A was also found to be dose-dependent. However, the potency of SDZ PSC 833 in inhibiting the efflux mechanism at the BBB was higher than that of cyclosporin A since 10 times higher doses of cyclosporin A were required to obtain the same Kp values recorded for SDZ PSC 833. Moreover, the coadministration of SDZ PSC 833 increased the brain penetration of cyclosporin A, whereas the latter did not modify that of SDZ PSC 833. The increase in SDZ PSC 833 and vincristine PS values observed at high blood levels of SDZ PSC 833 are consistent with the hypothesis of a saturation of the P-glycoprotein pump present at the BBB. The involvement of P-glycoprotein in the brain passage of SDZ PSC 833 could be of great significance for clinical application of the drug in the treatment of brain cancers when it is given in combination with anticancer agents. Received: 8 October 1995/Accepted: 25 January 1996     

Clinical trial of CPT-11 and VM-26/VP-16 for patients with recurrent malignant brain tumors

CPT-11 is a potent inhibitor of topoisomerase I and has shown antitumor activity in brain xenografts and in clinical trials in recurrent/progressive malignant glioma. VM-26 and VP-16 are topoisomerase II inhibitors and have also shown activity in phase II trials. We performed a phase II trial of intravenous CPT-11 (125 mg/m²) followed 24 h later by VM-26 (125 mg/m²). VP-16 (125 mg/m²) was later substituted for VM-26 due to drug shortage. For patients on anticonvulsants, the starting dose for all drugs was 150 mg/m². Drugs were given weekly for 3 weeks followed by 1-week rest. Twenty-five patients were entered into the study. Three patients (12%) had improvement in CAT/MRI brain scans (95% confidence interval 3–31%). Fatigue and myelosuppression, mainly leukopenia, were the main toxicities. This combination of the topoisomerase I inhibitor CPT-11 followed by the topoisomerase II inhibitor, VM-26 or VP-16, has shown modest antitumor activity comparable to that reported for each drug singly. Myelosuppression is the main toxicity when topoisomerase I and II inhibitors are combined together.     

Comparative activity of idarubicin and idarubicinol in combination with cyclosporin A in multidrug-resistant leukemia cells

 4-Demethoxydaunorubicin (idarubicin, IDA) is an anthracycline that has shown good cytotoxic activity in vitro against tumor cell lines displaying the multidrug-resistant (MDR) phenotype. IDA is converted in the liver into idarubicinol (2HIDA) and, in this form, seems to exert its antitumoral activity in vivo. Recent studies have shown that 2HIDA has tumoricidal activity similar to that of the parent drug when tested in vitro in sensitive neoplastic cells. In this work we compared in vitro the effects of IDA and 2HIDA used alone and in combination with 2 μM cyclosporin A (CyA) in the MDR leukemic cell lines FLCR and K562R and in their sensitive parent cell lines FLC and K562. IDA and 2HIDA showed the same cytotoxic activity in sensitive cells. After 1 h of exposure of cells to each anthracycline, we observed that the cellular uptake of IDA and 2HIDA was also similar. In resistant cells, 2HIDA was 3–4 times less active than IDA. We observed that the intracellular uptake of 2HIDA was lower than that of IDA, and this may be correlated with a greater ability of P-glycoprotein to expel 2HIDA as opposed to IDA. Indeed, when MDR cells were exposed to IDA and 2HIDA in combination with 2 μM CyA, the cytotoxic effect of these anthracyclines was the same, and it was similar to that observed in sensitive cells. These data confirm the utility of the combination of IDA and an MDR-reversing agent in hematological malignancies displaying the MDR phenotype. Received 7 April 1995/Accepted 13 May 1996     

An Early Phase II Study of Etoposide (VP-16) in Advanced Gastric Cancer

An early phase II study was conducted to evaluate the anti-tumoreffects and toxicity of etoposide in patients with unresectableor relapsed advanced gastric cancer. From April 1991 to December1992, 13 patients were enrolled into this study; one was subsequentlyconsidered ineligible. Before enrollment, all the patients hadbeen treated with chemotherapy which did not include etoposide.Etoposide (100 mg/m²/day) was administered as an intravenousinfusion over 120 min for five consecutive days and was repeatedevery four weeks. Seven patients received one course of thistherapy and the remaining five received two. No patient showeda complete or a partial response. No change and progressivedisease were observed in three and nine patients, respectively.The clinical toxicities (grade 3–4; WHO) of leukocytopenia,anemia and alopecia occurred in 50, 42, and 42% of the patients,respectively. We conclude that this dose of etoposide administeredaccording to the present schedule is ineffective in previouslytreated patients with advanced gastric cancer.     

Enhancement of Reversing Effect of Cyclosporin A on Vincristine Resistance by Anti-P-glycoprotein Monoclonal Antibody MRK-16

The synergistic effect of MRK-16, a monoclonal antibody against P-glycoprotein, and cyclosporin A (CsA) on the modulation of vincristine resistance was studied by isobologram analysis in three different, highly multidrug-rcsistant tumor cells. In all cell lines, the synergistic effect was demonstrated at various concentrations of MRK-16 and CsA. While MRK-16 alone did not enhance the sensitivity of the moderately resistant KB-8–5 cells to vincristine, it increased two-fold the reversing effect of cyclosporin A at 1 μM , an achievable blood concentration. Since MRK-16 alone showed therapeutic effects against multidrug-resistant tumors, the combined use of MRK-16, CsA and antitumor agents should provide therapeutic benefits for the treatment of resistant tumors.     

Combination chemotherapy involving orally administered etoposide and JM-216 in murine tumor models

Purpose: Orally administered VP-16 (etoposide) was evaluated in combination with an orally administered platinum analog, JM-216 [ammine/cyclohexylamine diacetatodichloride Pt(IV)], in mice bearing murine tumors, for therapeutic synergy. Methods: The treatment schedules used involved two courses of therapy, each course consisting of administration every day for 5 days beginning on either day 4 or day 5 posttumor implantation, and again on day 11 or day 12 postimplantation. Result: The amounts of each drug tolerated in the combination treatment setting were much less than their individual maximum tolerated doses (MTDs). Thus, to be used safely, each drug's dose had to be greatly reduced from the amount tolerated when the drugs were given individually. Multiple experiments using a staged P388 leukemia model implanted intravenously yielded confirmatory data supporting the existence of a therapeutic synergy for the drug combination. Identical regimens applied in the staged M5076 sarcoma model implanted subcutaneously, however, were not considered to have yielded data indicative of therapeutic synergy. Conclusions: A clinical phase I study using this combination chemotherapy can be recommended on the basis of the results obtained in the leukemia model. Received: 25 May 1996 / Accepted: 29 October 1996     

EFFICACY OF IFOSFAMIDE AND VP-16 （ETOPOSIDE） IN PATIENTS WITH SMALL CELL LUNG CANCER AND THE CORRELATION BETWEEN MICROVESSEL COUNT ON CHEMOSENSITIVITY

Objective： To evaluate the efficacy of ifosfamide and etoposide （VP-16） in patients with small cell lung cancer （SCLC）, and investigate the correlation between microvessel count （MVC） in tumor and chemotherapeutic sensitivity. Methods： Forty-one consecutive cases of SCLC received chemotherapy of ifosfamide plus VP-16, and underwent investigation retrospectively. Immunohistochemistry using anti-human blood type H monoclonal antibody was conducted and MVC was recorded under light microscope. Results： There were 27 limited-disease and 14 extensive-disease patients. The overall response rate was 92.7% （38/41） with 28 cases （68.3%） of complete response （CR）, 10 （24.4%） with partial response （PR）, 3 （7.3%） with progressive disease （PD）. The 1-, 2-, 3-, and 5-year survival rates were 68.3% （28/41）, 48.3% （20/41）, 23.7% （9/38） and 11.1% （3/27）, respectively, with the median survival of 26.8 months. The principal toxicities were grade 3-4 neutropenia in 8 cases （19.5%）, grade 3-4 thrombocytopenia in 6 cases （14.6%）, mild liver toxicity in 7 cases （17.0%） and mild renal function damage in 4 cases （9.8%）. The mesenchymal vasculature was clearly visualized, with the mean value of 34.7 under each high microscopic power field. Of SCLC with more MVC （n=26）, CR accounted for 84.6%; while in cancers with less MVC （n=l 5）, CR took up 40.0%, with significant difference （P〈0.05）. Conclusion： Administrating ifosfamide and VP-16 is in accordance with the biological features of SCLC and results in beneficial results as well as acceptable side effects. The MVC is positively correlated with the chemotherapeutic sensitivity, and serves as a vital factor contributing to chemosensitivity.     

Amelioration of methotrexate-induced malabsorption by vitamin A

 Methotrexate (MTX) induces damage to the small intestine, resulting in malabsorption and diarrhea. We found that the coadministration of vitamin A (VA) with MTX protected the small intestine from MTX-induced damage. In this study, the permeability of D-glucose, D-xylose and L-leucine through the small intestine of rats treated with MTX and/or VA was studied using everted segments of small intestine. MTX treatment decreased permeability and VA coadministration prevented the decrease. The transport of D-glucose in the small intestine of MTX plus VA- and VA-treated rats and of control rats followed Michaelis-Menten kinetics, in contrast to the transport kinetics in MTX-treated rats. The pharmacokinetics of orally administered [¹⁴C]-D-glucose in control rats and MTX- and/or VA-treated rats was also studied. The bioavailability of D-glucose in MTX-treated rats was lower than in the other three groups. VA coadministration improved the bioavailability of D-glucose. Thus, it seems likely that VA ameliorates MTX-induced malabsorption. Received: 13 September 1995 / Accepted: 18 May 1996     

Digitonin enhances the efficacy of carboplatin in liver tumour after intra-arterial administration

 Platinum-containing drugs enter the cell slowly and have a poor tissue penetration. Increasing the permeability of the cell membrane might increase the intracellular drug concentration. Digitonin, a detergent that increases cell permeability by binding to cholesterol molecules in the cell membrane, can increase cisplatin accumulation and reduce tumour growth in vitro. The aim of this study was to determine whether digitonin could increase the efficacy of carboplatin (CBDCA) in vivo. In LH rats, a hepatoma was implanted in the liver. At 7 days after implantation, digitonin (or saline in the control group) was infused via the hepatic artery and, 10 min later, CBDCA was injected. Biopsies from the tumour and liver parenchyma were obtained after 1 h. The concentration of platinum measured in the liver tumours was higher in the digitonin group than in the control groups. In the liver parenchyma the concentrations were of the same magnitude. Measured with the ¹³³Xe-clearance technique, digitonin did not alter the tumour blood flow. Digitonin enhanced the tumour-growth-retarding effect of CBDCA given intra-aterially at 5 mg/kg but not at 25 mg/kg. No increase in toxicity was observed for digitonin given together with CBDCA at 5 mg/kg. Systemic administration of CBDCA was not influenced by digitonin. These findings demonstrate that pretreatment with digitonin increases the tumour uptake of CBDCA and potentiates the cytotoxic effect of CBDCA. Received: 21 September 1996 / Accepted: 17 March 1997     

Intracellular Levels of Two Cyclosporin Derivatives Valspodar (PSC 833) and Cyclosporin A Closely Associated with Multidrug Resistance-modulating Activity in Sublines of Human Colorectal Adenocarcinoma HCT-15

P-Glycoprotein, which mediates multidrug resistance (MDR) in cancer chemotherapy, is a principal target of Cyclosporin A and [3'-keto-Bmt¹]-[Val²]-cyclosporin (valspodar; PSC 833). To clarify mechanisms contributing to the different MDR-modulating activities of valspodar and Cyclosporin A, we investigated the relation of the intracellular levels of the two Cyclosporin derivatives to their modulating effect on MDR in different P-glycoprotein-expressing human colorectal carcinoma HCT-15 cells (parental HCT-15 and adriamycin-resistant sublines). In this study, valspodar was found to be much more potent than Cyclosporin A in both sensitizing resistant cells to MDR-related anticancer drugs (e.g., adriamycin, vincristine and paclitaxel (taxol)) and increasing 2-[6-amino-3-imino-3H-xanthen-9-yl]benzoic acid methyl ester (rhodamine 123) retention and [G-³H]vincristine sulfate ([³H]vincristine) accumulation in these cells. Furthermore, a good correlation was detected between P-glycoprotein levels and the MDR-reversing effect of valspodar. In contrast, the effects of Cyclosporin A could not be linked to P-glycoprotein levels in the MDR cells. In addition, the intracellular accumulation of valspodar was found to be 3–6 fold higher than that of Cyclosporin A in four sublines and verapamil, an inhibitor of P-glycoprotein-mediated transport, enhanced the accumulation of Cyclosporin A, but not valspodar. These results suggested that valspodar accumulation is not actively regulated by the P-glycoprotein-mediated efflux system     

Effect of P-glycoprotein modulation with cyclosporin A on cerebrospinal fluid penetration of doxorubicin in non-human primates

Purpose: P-glycoprotein (Pgp) is a transmembrane drug efflux pump that is expressed in multidrug-resistant cancer cells and in a variety of normal tissues, including brain capillary endothelial cells which comprise the blood-brain barrier. We studied the effects of the Pgp inhibitor, cyclosporin A (CsA), on the cerebrospinal fluid (CSF) penetration of the Pgp substrate, doxorubicin, in non-human primates. Methods: The animals received doxorubicin alone (2.0 mg/kg i.v. over 60 min) or doxorubicin (1 mg/kg i.v. over 60 min) and CsA (loading dose 4.0 mg/kg i.v. over 2 h, followed by continuous infusion of 12 mg/kg per day over 48 h). Plasma and CSF were collected over 48 h and the doxorubicin concentration was measured by reverse-phase high-pressure liquid chromatography (HPLC) with fluorescence detection (detection limit 5 nM). A two-compartment model was fitted to the plasma concentration-time data. Results: Pgp was demonstrated to be present in the epithelium of the choroid plexus by immunohistochemical methods, indicating that CSF drug penetration could be used as a surrogate for blood-brain barrier penetration. Steady state whole blood CsA concentrations, which were measured with a fluorescence-polarization immunoassay (TDX) that detects both CsA and its metabolites, ranged from 551–1315 μg/l at 24 h. The clearance of doxorubicin in four animals was reduced by 34%, 38%, 45% and 49% when given with CsA. The doxorubicin concentration in the CSF was <5 nM in all animals, both after doxorubicin alone and doxorubicin with CsA. Conclusions: The Pgp inhibitor, CsA, at a concentration that alters systemic clearance of doxorubicin, does not appear to significantly increase the CSF penetration of doxorubicin. Received: 18 May 1999 / Accepted: 3 September 1999     

Molecular characterization of the in vivo alkylating agent resistant murine EMT-6 mammary carcinoma tumors

 The expression of several early-response genes and genes associated with malignant disease was assessed in the EMT-6/parent tumor and the EMT-6/CTX and EMT-6/CDDP in vivo resistant tumor lines growing as tumors or as monolayers in culture. In the absence of treatment the levels of mRNA for the genes c-jun, c-fos, c-myc, Ha-ras and p53 were increased in the EMT-6/CTX and EMT-6/CDDP as compared with the EMT-6/parent tumor, whereas the expression of erb-2 was similar in all three tumors. Although the cells from each of the three tumors show increased expression of early response genes after exposure to cisplatin (CDDP; 100 μM, 2 h) or 4-Hydroxyperoxycyclophosphamide (4-HC; 100 μM, 2 h) in culture, in mRNA extracted from tumor tissue these changes are absent or very small. Both C-jun and erb-2 were detectable in liver. There was increased expression of both of these genes in the livers of tumor-bearing animals as compared with non-tumor-bearing animals. The highest expression of both c-jun and erb-2 occurred in the livers of animals bearing the EMT-6/CDDP tumor. Treatment of the animals with CDDP or cyclophosphamide, in general, resulted in increased expression of both genes at 6 h post treatment. The increased expression of these genes may impart metabolic changes in the tumors and/or hosts that contribute to the resistance of these tumors to specific antitumor alkylating agents. Received: 17 January 1994/Accepted: 15 July 1994     

Pharmacokinetics and toxicity of 120-hour continuous-infusion hydroxyurea in patients with advanced solid tumors

 A group of 18 patients with advanced cancer were entered on a phase I study of a 120-h continuous intravenous infusion of hydroxyurea. The dose of hydroxyurea was escalated in cohorts of patients from 1 to 2 to 3.2 g/m² per day. The primary dose-limiting toxicity was neutropenia, often accompanied by leukopenia, thrombocytopenia and generalized skin rash. Prophylactic treatment of patients with dexamethasone and diphenhydramine hydrochloride prevented the skin rash, but not the hematopoietic toxicities. The pharmacokinetics of hydroxyurea were studied in all patients. The steady-state concentrations of hydroxyurea were linearly correlated with the dose (R ² = 0.71, n = 18, P<0.0001). The mean±SE concentrations were 93±16, 230±6 and 302±27 μM at 1, 2 and 3.2 g/m² per day, respectively. The mean±SE renal and nonrenal clearances of hydroxyurea were 2.14±0.18 and 3.39±0.28 l/h per m² (n = 16), neither of which correlated with the dose. The concentration of hydroxyurea in plasma decayed monoexponentially with a mean±SE half-life of 3.25±0.18 h (n = 17). The steady-state concentration of hydroxyurea was >200 μM in all nine patients treated at 2 g/m² per day, a dose which was well tolerated for 5 days. We recommend this dose for phase II trials in combination with other antineoplastic agents. Received: 28 November 1995 / Accepted: 18 May 1996     

环孢素A逆转白血病多药耐药的临床探讨

目的探讨环孢素A(CsA)逆转复发难治性急性白血病(AL)多药耐药(MDR)的临床疗效.方法对45例复发难治性急性白血病患者进行P-170检测,并对其中30例P-170阳性患者随机分为治疗组(CsA 化疗)和对照组(单用化疗)进行逆转MDR的研究.结果 P-170在复发难治性急性白血病中有高表达(66.7%),治疗组总有效率(60.0%)明显高于对照组(26.7%),差异有显著性(P＜0.05).结论 CsA能够逆转难治性白血病耐药性,在治疗复发难治性急性白血病方面具有良好的临床应用价值.     

Modulation of Adriamycin cytotoxicity and transport in drug-sensitive and multidrug-resistant Chinese hamster ovary cells by hyperthermia and cyclosporin A

Purpose: Chemosensitizers such as cyclosporin A can increase intracellular accumulation of chemotherapeutic agents such as Adriamycin in certain multidrug-resistant (MDR) cell lines with overexpression of P-glycoprotein. It is likely that, when combined with cyclosporin A, hyperthermia could increase membrane permeability to Adriamycin and enhance its cytotoxic effects. The ability of both hyperthermia and cyclosporin A to modulate the cytotoxicity, transport and subcellular distribution pattern of Adriamycin was studied in a pleiotropic MDR Chinese hamster ovary cell line (CH^RC5) and in the drug-sensitive parent line (AuxB1). Methods: Adriamycin cytotoxicity was evaluated by clonogenic cell survival, drug transport using [¹⁴C]-labeled Adriamycin and intracellular drug distribution by fluorescence microscopy. Results: Adriamycin cytotoxicity was increased in both drug-sensitive and MDR cells by cyclosporin A (5 μM) alone, and by hyperthermia alone (41–43 °C) only in sensitive cells. However, when cyclosporin A and 42 °C hyperthermia were used in combination, a large increase in drug cytotoxicity occurred in both cell lines. This effect increased with time and was temperature-dependent. The increase in Adriamycin cytotoxicity caused by cyclosporin A and hyperthermia was accompanied by alterations in membrane permeability to the drug. Cyclosporin A increased [¹⁴C]Adriamycin uptake, while drug efflux decreased, for both AuxB1 and CH^RC5 cells and nuclei. For AuxB1 cells only, drug distribution studies showed that cyclosporin A promoted an increase in both nuclear and cytoplasmic drug accumulation. Hyperthermia, combined with cyclosporin A, increased [¹⁴C]Adriamycin uptake. This effect was seen as an increase in intensity of nuclear and cytosolic drug fluorescence in both cell lines. Cyclosporin A alone diminished drug efflux and caused Adriamycin to remain firmly bound in the nucleus of AuxB1 cells, while it remained primarily in the cytoplasm of CH^RC5 cells. Conclusions: Hyperthermia alone had little effect on Adriamycin cytotoxicity and transport in MDR cells, in contrast to drug-sensitive cells. This suggests that P-glycoprotein is fully functional in these MDR cells. Our findings suggest that cyclosporin A and hyperthermia could be beneficial by increasing intracellular drug accumulation, thus improving the effectiveness of Adriamycin against both drug-sensitive and MDR cells within a localized target region. Received: 17 February 1999 / Accepted: 26 August 1999     

Antitumor activity of prolonged as compared with bolus administration of 2′,2′-difluorodeoxycytidine in vivo against murine colon tumors

2′,2′-Difluorodeoxycytidine (gemcitabine) is a cytidine analogue with established antitumor activity against several experimental tumor types and against human ovarian and non-small-cell lung cancer. Both preclinical studies and most clinical trials involving patients with solid tumors have focused on short-term administration schedules; however, mechanistic studies indicate that a continuous-infusion schedule may be more effective. We determined the maximal tolerated dose (MTD) of gemcitabine in mice using various schedules. At these MTDs we observed considerably better antitumor activity of gemcitabine in two of three murine colon carcinoma lines using a prolonged administration as compared with a standard bolus protocol (i.p. 120?mg/kg q3d×4). On the latter schedule, Colon 26–10 grown in BALB/c mice was the most sensitive tumor line, showing a growth-delay factor (GDF, number of doubling times gained by the treatment) of 6.7, whereas Colon 38 (grown in C57/B16 mice) was the least sensitive tumor, displaying a GDF of 0.9. Prolonged treatment (q3d×6) of Colon 26–10 at a lower dose (100?mg/kg) enhanced the antitumor activity (GDF 9.6) while producing similar toxicity. A similar weight loss was found following the continuous infusion (c.i.) of gemcitabine using Alzet osmotic pumps s.c. for 3 or 7 days (2?mg/kg), but the GDF increased to 2.4 in Colon 38 (C57/B16) as compared with that provided by the bolus injections. Continuous infusion of gemcitabine at 15?mg/kg per 24?h q7d×2 i.v. via the tail vein was more effective than bolus injection against Colon 26–10, with the GDF being >17.7 and 73% of the tumors regressing completely. However, against Colon 38 tumors this schedule was not effective (GDF 0.4), even with a 25% higher dose. The plasma pharmacokinetics of gemcitabine was determined after one bolus dose (120?mg/kg). The peak concentration of gemcitabine was 225?μM and that of the deaminated catabolite 2′,2′-difluorodeoxyuridine (dFdU) was 79?μM. The elimination of gemcitabine was much faster than that of dFdU, with the t _1/2ß values being 15?min and 8?h, respectively. For the c.i. schedules, plasma concentrations were below the detection limit of the assay (<0.5?μM). Our results suggest that prolonged infusion of gemcitabine can give a better antitumor activity than bolus injections and shows promise of being active in clinical trials.     

Lack of in vivo crossresistance with gemcitabine against drug-resistant murine P388 leukemias

 Gemcitabine, a novel pyrimidine nucleoside antimetabolite, has shown clinical antitumor activity against several tumors (breast, small-cell and non-small-cell lung, bladder, pancreatic, and ovarian). We have developed a drug-resistance profile for gemcitabine using eight drug-resistant P388 leukemias in order to identify potentially useful guides for patient selection for further clinical trials of gemcitabine and possible noncrossresistant drug combinations with gemcitabine. Multidrug-resistant P388 leukemias (leukemias resistant to doxorubicin or etoposide) exhibited no crossresistance to gemcitabine. Leukemias resistant to vincristine (not multidrug resistant), cyclophosphamide, melphalan, cisplatin, and methotrexate were also not crossresistant to gemcitabine. Only the leukemia resistant to 1-β-D-arabinofuranosylcytosine was crossresistant to gemcitabine. The results suggest that (1) it may be important to exclude or to monitor with extra care patients who have previously been treated with 1-β-D-arabinofuranosylcytosine and (2) the lack of crossresistance seen with gemcitabine may contribute to therapeutic synergism when gemcitabine is combined with other agents. Received: 14 October 1994/Accepted: 9 October 1995