Response of brain specific microenvironment to P-glycoprotein inhibitor: an important factor determining therapeutic effect of P-glycoprotein inhibitor on brain metastatic tumors

P-glycoprotein (P-gp), a factor responsible for the multidrug resistance of tumors, is specifically expressed in brain microenvironment. To test its roles in brain metastatic tumor chemoresistance, we implanted the paclitaxel-sensitive melanoma cell line, K1735, into the skin or brain of mice and examined its paclitaxel resistances. When implanted into the skin, paclitaxel inhibited tumor growth, however, it had no inhibitory effect on cells implanted into the brain. The paclitaxel resistance of the brain K1735 tumors was eliminated by combined treatment with a P-gp inhibitor, HM30181A, and paclitaxel. Previously we found that there is a defined therapeutic window for combined treatment of brain tumors with HM30181A and paclitaxel. To determine whether it is due to responses of the brain microenvironment we measured changes in P-gp expression and function of brain endothelial cells in response to HM30181A treatment in vitro and in vivo. They were significantly increased by high-dose HM30181A treatment and it was related with the therapeutic effect loss of high-dose HM30181A treatment. Therefore, P-gp in the brain microenvironment has crucial roles in the brain metastatic tumor chemoresistance and brain microenvironment responses to P-gp inhibitor treatment should be considered in the development of brain endothelial cell-targeted chemotherapy using P-gp inhibitor.     

HM30181A,a potent P-glycoprotein inhibitor,potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model

Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-β-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05).Conclusions:In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.     

Phase I/II Study of Weekly Oraxol for the Second‐Line Treatment of Patients With Metastatic or Recurrent Gastric Cancer

Lessons Learned

• Oraxol, a novel oral formulation of paclitaxel, displayed modest efficacy as second-line chemotherapy for gastric cancer.
• Considering its favorable toxicity profiles, further studies are warranted in various solid tumors including gastric cancer.

Background.

Oraxol consists of paclitaxel and HM30181A, a P-glycoprotein inhibitor, to increase the oral bioavailability of paclitaxel. This phase I/II study (HM-OXL-201) was conducted to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of Oraxol. In addition, we investigated the efficacy and safety of Oraxol as second-line chemotherapy for metastatic or recurrent gastric cancer (GC).

Methods.

In the phase I component, paclitaxel was orally administered at escalating doses (90, 120, or 150 mg/m² per day) with a fixed dose (15 mg/day) of HM30181A. Oraxol was administrated 6 times per cycle (days 1, 2, 8, 9, 15, and 16) every 4 weeks. In the phase II component, the efficacy and safety of Oraxol were evaluated.

Results.

In the phase I component, the MTD could not be determined. Based on toxicity and pharmacokinetic data, the RP2D of oral paclitaxel was determined to be 150 mg/m². In the phase II component, 4 of 43 patients (9.3%) achieved partial responses. Median progression-free survival and overall survival were 2.6 and 10.7 months, respectively. Toxicity profiles were favorable, and the most common drug-related adverse events (grade ≥3) were neutropenia and diarrhea.

Conclusion.

Oraxol exhibited modest efficacy and favorable toxicity profiles as second-line chemotherapy for GC.     

A pharmacokinetic and safety study of a novel polymeric paclitaxel formulation for oral application

Purpose: To investigate the pharmacokinetics, safety, and tolerability of a new oral formulation of paclitaxel containing the polymer polyvinyl acetate phthalate in patients with advanced solid tumors. Patients and methods: A total of six patients received oral paclitaxel as single agent given as a single dose of 100 mg on day 1, oral paclitaxel 100 mg in combination with cyclosporin A (CsA) 10 mg/kg both given as a single dose on day 8, and i.v. paclitaxel (Taxol®) 100 mg as a 3-h infusion on day 15. Results: The AUC (mean ± standard deviation) values of paclitaxel after oral administration without CsA and with CsA were 476 ± 254 and 967 ± 779 ng/ml h, respectively. T _max was 4.0 ± 0.9 h after oral paclitaxel without CsA, and 6.0 ± 3.1 h after oral paclitaxel with CsA. The mean AUC after oral administration as single agent was 13% of the AUC after i.v. administration of paclitaxel, and increased to 26% after co-administration with CsA. No haematological toxicities were observed, and only mild (CTC-grade 1 and 2) non-hematological toxicities occurred after oral intake of paclitaxel with or without CsA. Conclusion: The AUC of the new polymeric paclitaxel formulation increased a factor 2 in combination with CsA, which confirms that CsA co-administration can also improve exposure to paclitaxel after oral administration of a polymeric formulation. Because of the delayed release of paclitaxel from this formulation, we hypothesize that a split-dose regimen of CsA where it is administered before and after paclitaxel administration will further increase the systemic exposure to paclitaxel up to therapeutic levels. The formulation was well tolerated at the dose of 100 mg without induction of severe toxicities.     

Acute transient encephalopathy after weekly paclitaxel infusion

Paclitaxel is highly active against a variety of solid tumors including breast lung, ovarian and head and neck cancer. Although peripheral neurotoxicity is well-known side effect, central nervous system (CNS) toxicity-related standard dose of paclitaxel is extremely uncommon, because paclitaxel dose not cross the blood–brain barrier and is not detectable in the cerebrospinal fluid. We present a patient with advanced stage breast carcinoma who developed acute and spontaneous resolving encephalopathy after weekly dose of paclitaxel. The patient did not have brain metastasis, or prior whole-brain irradiation, or any type of neurosurgery. Radiological imaging studies showed no abnormalities. CNS toxicity of paclitaxel should be kept in mind in patients without a previous history of brain metastasis or brain irradiation and even with low weekly doses.     

Probenecid is a chemosensitizer in cancer cell lines

Resistance and toxicity are the major barriers to successful cancer chemotherapies. Developing molecules that reduce drug resistance and improve antineoplastic effects is of great interest for cancer research; ideally, these substances should not affect the pharmacodynamics of the chemotherapeutic agent while providing a synergistic antineoplastic effect. In this study, we tested in vitro co-administration of the antineoplastic agents cisplatin or paclitaxel with probenecid, an anion channel inhibitor, in a panel of cancer cell lines to determine the cytotoxicity and synergistic effects of these drug combinations. In addition, we measured the clonogenicity and apoptotic index in these cells. We observed a synergistic interaction between probenecid and the chemotherapeutic agents, and increasing doses of probenecid resulted in a significant decrease in the effective doses of the chemotherapeutic agents. For the antineoplastic agent and probenecid combinations, we found increased cell death, reduced colony formation, and a higher number of apoptotic cells, compared with treatment of cisplatin or paclitaxel alone. Further research is necessary to elucidate the molecular mechanisms by which the synergistic effect occurs. If these synergistic effects can be reproduced in vivo, the co-administration of probenecid with different chemotherapeutic agents may provide a valid treatment in patients with chemotherapy resistance.     

Synergistic effect and condition of pegylated interferon alpha with paclitaxel on glioblastoma

Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon alpha (IFN-alpha) as a single agent or combined with standard chemo-therapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-alpha (PEG-IFN-alpha) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-alpha administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-alpha for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-alpha determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-alpha/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-alpha and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.     

A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC)

Purpose To evaluate the toxicity profile and pharmacological properties of oral CP-547,632 alone and in combination with paclitaxel and carboplatin administered every 3 weeks, and to assess efficacy as measured by the objective response and progressive disease rates of oral CP-547,632 administered in combination with paclitaxel and carboplatin. Patients and methods Patients with stage IIIB/IV or recurrent non-small cell lung cancer receiving first-line chemotherapy were treated with oral daily CP-547,632 in combination with paclitaxel 225 mg/m² and carboplatin AUC = 6 every 3 weeks. Pharmacokinetics parameters for CP-547,632 and paclitaxel were determined independently and during co-administration. Results Seventy patients were enrolled and 68 patients were treated, 37 in phase 1 and 31 in phase 2 (14 with the combination and 17 with chemotherapy alone). Dose-limiting toxicity of CP-547,632 250 mg by mouth daily in combination with paclitaxel and carboplatin was grade 3 rash and grade 3 diarrhea despite medical intervention. CP-547,632 did not significantly affect the pharmacologic profiles of paclitaxel and carboplatin. No subject had CR. In phase I, seven subjects (22.6%) had a confirmed partial response. In phase II, four subjects (28.6%) receiving CP-547,632 plus chemotherapy had a confirmed partial response. In the phase II chemotherapy alone group, four subjects (25%) had a confirmed partial response. Conclusion The combination of CP-547,632 and paclitaxel and carboplatin was well-tolerated at doses up to 200 mg by mouth daily. Dose-limiting toxicity of CP-547,632 at 250 mg consisted of diarrhea and rash. CP-547,632 did not increase the objective response rate to chemotherapy alone in patients with advanced non-small cell lung cancer.     

Preclinical oral antitumor activity of BMS-185660, a paclitaxel derivative

Purpose: A water soluble paclitaxel derivative, BMS-185660, identified previously as having parenteral activity comparable with that of the parent drug, was evaluated for antitumor activity when given orally. Methods: Staged subcutaneous (s.c.) tumor models of both murine and human origin were used for this purpose. Results: BMS-185660 achieved levels of activity following oral administration which were comparable with those maximum effects obtained using intravenous (i.v.) paclitaxel. Consecutive daily oral administrations of BMS-185660 resulted in maximum gross log cell kill (LCK) values of 1.7–2.0 in two experiments involving the s.c. Madison 109 murine lung tumor model, which were comparable with the best effects of the derivative injected intravenously, and 0.3 to 0.9 LCK greater than the maximum effects obtained with i.v. paclitaxel; paclitaxel given orally was inactive. Against a human ovarian tumor model with developed resistance to cisplatin (A2780/cDDP), oral BMS-185660 achieved a maximum LCK of 1.8 compared with i.v. paclitaxel, which produced a maximum 2.4 LCK. Also, in the human HCT-116 colon carcinoma model, oral BMS-185660 cured a maximum of seven of eight mice compared with six of seven mice cured with i.v. paclitaxel. The loss in potency between comparably effective intravenously and orally administered doses of BMS-185660 was about four- to five-fold, but since no drug-associated lethality was ever observed following the oral administration of the highest doses of BMS-185660, further dose escalation may have been tolerated. The intermediate metabolite between BMS-185660 and paclitaxel is BMS-181681. This compound was also evaluated orally and found not to be active versus s.c. M109, despite demonstrating good activity by the i.v. route. Conclusion: The comparable activities of both intravenously and orally administered BMS-185660 to intravenously administered paclitaxel, combined with the attribute of improved water solubility, provides a good basis for further derivative development. Received: 10 September 1999 / Accepted: 16 March 2000     

Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.

Oral paclitaxel is not inherently bioavailable because of the overexpression of P-glycoprotein by intestinal cells and the significant first-pass extraction by cytochrome P450-dependent processes. This study sought to simulate the toxicological and pharmacological profile of a clinically relevant schedule of paclitaxel administered on clinically relevant i.v. dosing schedules in patients with advanced solid malignancies using oral paclitaxel administered with cyclosporin A, an inhibitor of both P-glycoprotein and P450 CYP3A. Nine patients were treated with a single course of oral paclitaxel in its parenteral formulation at a paclitaxel dose level of 180, 360, or 540 mg. Cyclosporin A was administered at a dose of 5 mg/kg p.o. 1 h before and concurrently with oral paclitaxel. Blood sampling was performed to evaluate the pharmacokinetics of paclitaxel, 6-alpha-hydroxypaclitaxel, 3-p-hydroxypaclitaxel, and cyclosporin A. The pharmacokinetic behavior of paclitaxel was characterized using both compartmental and noncompartmental methods. Model-estimated parameters were used to simulate paclitaxel concentrations after once daily and twice daily oral administration of paclitaxel and cyclosporin A. Aside from an unpleasant taste, the oral regimen was well tolerated, and there were no grade 3 or 4 drug-related toxicities. The systemic exposure to paclitaxel, as assessed by maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) values, did not increase as the dose of paclitaxel was increased from 180 to 540 mg, and there was substantial interindividual variability (4-6-fold) at each dose level. Mean paclitaxel Cmax values approached plasma concentrations achieved with clinically relevant parenteral dose schedules, averaging 268+/-164 ng/ml. AUC values averaged 3306+/-1977 ng x h/ ml, which was significantly lower than AUC values achieved with clinically relevant i.v. paclitaxel dose schedules. However, computer simulations using pharmacokinetic parameters derived from the present study demonstrated that pharmacodynamically relevant steady-state plasma paclitaxel concentrations of at least 0.06 microM would be achieved after protracted once daily and twice daily dosing with oral paclitaxel and cyclosporin A. Paclitaxel metabolites were detectable in three patients, and the 6-alpha-hydroxypaclitaxel: paclitaxel and 3-p-hydroxypaclitaxel:paclitaxel AUC ratios averaged 0.63 and 0.86, respectively; these values were substantially higher than values reported in patients treated with i.v. paclitaxel. Oral paclitaxel was bioavailable in humans when administered in combination with oral cyclosporin A 5 mg/kg 1 h before and concurrently with paclitaxel treatment, and plasma paclitaxel concentrations achieved with this schedule were biologically relevant and approached concentrations attained with clinically relevant parenteral dose schedules. However, treatment of patients with oral paclitaxel using a single oral dose administration schedule failed to achieve sufficiently high systemic drug exposure and pharmacodynamic effects. In contrast, computer simulations demonstrated that clinically relevant pharmacodynamic effects are likely to be achieved with multiple once daily and twice daily oral paclitaxel-cyclosporin A dosing schedules.     

Weekly oral paclitaxel as first-line treatment in patients with advanced gastric cancer.

BACKGROUND: Pharmacokinetic study has shown that co-administration of cyclosporin A (CsA), which acts as a P-glycoprotein (P-gp) and CYP-3A blocker, resulted in an 8-fold increase in the systemic exposure of oral paclitaxel. Two doses of oral paclitaxel on 1 day in combination with CsA resulted in higher systemic exposure than single dose administration. PATIENTS AND METHODS: In this phase II study, chemona?ve patients with advanced gastric cancer received oral paclitaxel weekly in two doses of 90 mg/m(2) on the same day; CsA (10 mg/kg) was given 30 min before each dose of oral paclitaxel. RESULTS: In 25 patients, the main toxicities were: nausea CTC grade 2/3, 10 patients (40%); vomiting grade 2/3, 4 patients (20%); diarrhea grade 2/3, 6 patients (24%); neutropenia grade 3/4, 5 patients (20%). In the 24 evaluable patients, eight partial responses were observed, resulting in an overall response rate (ORR) of 33% [95% confidence interval (CI) 18% to 52%]. Eleven patients had stable disease (46%) and 5 patients showed progressive disease (21%). The ORR in the total population was 32% (95% CI 17% to 50%). The median time to progression was 16 weeks (95% CI 9-22). Pharmacokinetic analyses revealed that the mean area under the plasma concentration-time curve (AUC) of orally administered paclitaxel (+/- standard deviation) was 3757.6 +/- 939.4 ng.h/ml in week 1 and 3928.4 +/- 1281 ng.h/ml in week 2. The intrapatient variability in the AUC was 12%. CONCLUSIONS: Oral paclitaxel in combination with CsA is both active and safe in chemona?ve patients with advanced gastric cancer. Toxicities were mainly gastrointestinal.     

A phase I study of oral uracil-ftorafur plus folinic acid in combination with weekly paclitaxel in patients with solid tumors.

INTRODUCTION: Ftorafur is an orally available prodrug of 5-fluorouracil (5-FU). Its combination with uracil in a molar ratio of 1:4 (UFT) increases the 5-FU concentration in tumor cells compared with ftorafur alone. Paclitaxel has a broad spectrum of activity against solid tumors and synergic effects with UFT have been demonstrated in vitro. A phase I study was performed to determine the maximum tolerated dose of the combination of UFT and paclitaxel in patients with advanced solid tumors. STUDY DESIGN: UFT and folinic acid were applied at 300 mg/m2/day and 90 mg/day, respectively, on days 1-28, repeated on day 36. Paclitaxel was applied on days 1, 8, 15 and 22 of each cycle. The starting dose of paclitaxel was 50 mg/m2 and escalation in 10 mg/m2 steps was performed up to 100 mg/m2 weekly. RESULTS: Forty-seven consecutive patients with various solid tumors have been included in six different dose levels. One hundred and thirty cycles have been applied. The treatment was well tolerated overall. Most frequently encountered adverse effects were gastrointestinal and hematological toxicity (diarrhea CTC 3/4 in 6% of patients, anemia in 11%, leukocytopenia in 9%, polyneuropathy in 9%, fatigue in 11%, other in 6%). Partial remissions were observed in 28% of patients. CONCLUSION: Owing to the lack of overlapping toxicities, UFT/folinic acid plus paclitaxel can be combined at doses of proven single agent activity. Side effects are mainly attributable to the gastrointestinal toxicity of UFT and to the neuro- and hematotoxicity of paclitaxel. The recommended doses for phase II studies are 300 mg/m2 of UFT plus 90 mg of folinic acid on days 1-28, and 90 mg/m2 of paclitaxel weekly.     

Phase I and pharmacokinetic study of oral paclitaxel.

PURPOSE: To investigate dose escalation of oral paclitaxel in combination with dose increment and scheduling of cyclosporine (CsA) to improve the systemic exposure to paclitaxel and to explore the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT). PATIENTS AND METHODS: A total of 53 patients received, on one occasion, oral paclitaxel in combination with CsA, coadministered to enhance the absorption of paclitaxel, and, on another occasion, intravenous paclitaxel at a dose of 175 mg/m(2) as a 3-hour infusion. RESULTS: The main toxicities observed after oral intake of paclitaxel were acute nausea and vomiting, which reached DLT at the dose level of 360 mg/m(2). Dose escalation of oral paclitaxel from 60 to 300 mg/m(2) resulted in significant but less than proportional increases in the plasma area under the concentration-time curve (AUC) of paclitaxel. The mean AUC values +/- SD after 60, 180, and 300 mg/m(2) of oral paclitaxel were 1.65 +/- 0.93, 3.33 +/- 2.39, and 3.46 +/- 1.37 micromol/L.h, respectively. Dose increment and scheduling of CsA did not result in a further increase in the AUC of paclitaxel. The AUC of intravenous paclitaxel was 15.39 +/- 3.26 micromol/L.h. CONCLUSION: The MTD of oral paclitaxel was 300 mg/m(2). However, because the pharmacokinetic data of oral paclitaxel, in particular at the highest doses applied, revealed nonlinear pharmacokinetics with only a moderate further increase of the AUC with doses up to 300 mg/m(2), the oral paclitaxel dose of 180 mg/m(2) in combination with 15 mg/kg oral CsA is considered most appropriate for further investigation. The safety of the oral combination at this dose level was good.     

Tumor targeting by covalent conjugation of a natural fatty acid to paclitaxel.

Certain natural fatty acids are taken up avidly by tumors for use as biochemical precursors and energy sources. We tested in mice the hypothesis that the conjugation of docosahexaenoic acid (DHA), a natural fatty acid, and an anticancer drug would create a new chemical entity that would target tumors and reduce toxicity to normal tissues. We synthesized DHA-paclitaxel, a 2'-O-acyl conjugate of the natural fatty acid DHA and paclitaxel. The data show that the conjugate possesses increased antitumor activity in mice when compared with paclitaxel. For example, paclitaxel at its optimum dose (20 mg/kg) caused neither complete nor partial regressions in any of 10 mice in a Madison 109 (M109) s.c. lung tumor model, whereas DHA-paclitaxel caused complete regressions that were sustained for 60 days in 4 of 10 mice at 60 mg/kg, 9 of 10 mice at 90 mg/kg, and 10 of 10 mice at the optimum dose of 120 mg/kg. The drug seems to be inactive as a cytotoxic agent until metabolized by cells to an active form. The conjugate is less toxic than paclitaxel, so that 4.4-fold higher molar doses can be delivered to mice. DHA-paclitaxel in rats has a 74-fold lower volume of distribution and a 94-fold lower clearance rate than paclitaxel, suggesting that the drug is primarily confined to the plasma compartment. DHA-paclitaxel is stable in plasma, and high concentrations are maintained in mouse plasma for long times. Tumor targeting of the conjugate was demonstrated by pharmacokinetic studies in M109 tumor-bearing mice, indicating an area under the drug concentration-time curve of DHA-paclitaxel in tumors that is 8-fold higher than paclitaxel at equimolar doses and 57-fold higher at equitoxic doses. At equimolar doses, the tumor area under the drug concentration-time curve of paclitaxel derived from i.v. DHA-paclitaxel is 6-fold higher than for paclitaxel derived from i.v. paclitaxel. Even at 2 weeks after treatment, 700 nM paclitaxel remains in the tumors after DHA-paclitaxel treatment. Low concentrations of DHA-paclitaxel or paclitaxel derived from DHA-paclitaxel accumulate in gastrocnemius muscle; which may be related to the finding that paclitaxel at 20 mg/kg caused hind limb paralysis in nude mice, whereas DHA-paclitaxel caused none, even at doses of 90 or 120 mg/kg. The dose-limiting toxicity in rats is myelosuppression, and, as in the mouse, little DHA-paclitaxel is converted to paclitaxel in plasma. Because DHA-paclitaxel remains in tumors for long times at high concentrations and is slowly converted to cytotoxic paclitaxel, DHA-paclitaxel may kill those slowly cycling or residual tumor cells that eventually come into cycle.     

Synergistic interaction between cyclophosphamide or paclitaxel and the bioreductive compound NLCPQ-1, in vivo

The antitumor effect of cyclophosphamide (CPM) and paclitaxel was investigated in BALB/c mice bearing EMT6 tumors, in combination with the bioreductive compound NLCPQ-1 by using the in vivo/in vitro assay as the endpoint. An optimum administration schedule for a synergistic interaction between NLCPQ-1 and CPM/paclitaxel was determined and dose modification factors (DMF) were calculated for antitumor effect and bone marrow toxicity. All drugs were given by IP injection; NLCPQ-1 at 15 mg/kg, which is much less than its maximally tolerated dose (MTD greater than 50 mg/kg), paclitaxel up to 25 mg/kg, and CPM up to 200 mg/kg. Bone marrow toxicity studies were performed in parallel by using a modified CFU-GM assay. A schedule-dependent synergistic interaction was observed for both chemotherapeutic agents combined with NLCPQ-1 but with entirely different patterns, as has been previously seen with the analog NLCQ-1. The optimal degree of potentiation, P (percentage of tumor cells that were killed due to clear potentiation), was 31 and 33 when NLCPQ-1 was administered 2 h before CPM and 3-3.5 h after paclitaxel, respectively. At the above time schedules, NLCPQ-1 modified the dose of CPM and paclitaxel, for 60% tumor cell killing, by a factor of 1.8 and 2.1, respectively. Bone marrow toxicity was not enhanced by combining either chemotherapeutic agent with NLCPQ-1. Comparison with results from previous similar studies with NLCQ-1 revealed that, on a molar basis, NLCPQ-1 was a less potent chemosensitizer than NLCQ-1. However, the results still suggest a potential clinical use of NLCPQ-1 as an adjuvant to CPM or paclitaxel therapy against solid tumors.     

Dual kinin B1 and B2 receptor activation provides enhanced blood–brain barrier permeability and anticancer drug delivery into brain tumors

The low permeability of the BBB is largely responsible for the lack of effective systemic chemotherapy against primary and metastatic brain tumors. Kinin B1R and B2R have been shown to mediate reversible tumor-selective BBB disruption in preclinical animal models. We investigated whether co-administration of two novel potent kinin B1R and B2R agonists offers an advantage over administering each agonist alone for enhancing BBB permeability and tumor targeting of drugs in the malignant F98 glioma rat model. A new covalent kinin heterodimer that equally stimulates B1R and B2R was also constructed for the purpose of our study. We found that co-administration of B1R and B2R agonists, or alternatively administration of the kinin heterodimer more effectively delivered the MRI contrast agent Gd-DTPA and the anticancer drug carboplatin to brain tumors and surrounding tissues than the agonists alone (determined by MRI and ICP-MS methods). Importantly, the efficient delivery of carboplatin by the dual kinin receptor targeting on the BBB translated into increased survival of glioma-bearing rats. Thus, this report describes a potential strategy for maximizing the brain bioavailability and therapeutic efficacy of chemotherapeutic drugs.     

A phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel

PURPOSE: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m(2) paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. RESULTS: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. CONCLUSIONS: The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m(2) paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.     

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (P < .01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both P < .0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.     

Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer.

PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS: The combination of TNP-470 administered at 60 mg/m(2) three times per week and paclitaxel 225 mg/m(2) administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.     

Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model

To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41%, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94%, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.