Pharmacokinetics of mitomycin-c lipidic prodrug entrapped in liposomes and clinical correlations in metastatic colorectal cancer patients.

Background Pegylated liposomal (PL) mitomycin-c lipidic prodrug MLP) may be a useful agent in patients with metastatic colo-rectal carcinoma (CRC). We report here on the pharmacokinetics and clinical observations in a phase 1A/B study with PL-MLP. Methods Plasma levels of MLP were examined in 53 CRC patients, who received PL-MLP either as single agent or in combination with capecitabine and/or bevacizumab. MLP was determined by an HPLC-UV assay, and its pharmacokinetics was analyzed by noncompartmental methods. The correlation between clinical and pharmacokinetic parameters was statistically analyzed. Results PL-MLP was well tolerated with a good safety profile as previously reported. Stable Disease was reported in 15/36 (42%) of efficacy-evaluable patients. Median survival of stable disease patients (14.4 months) was significantly longer than of progressive disease patients (6.5 months) and non-evaluable patients (2.3 months). MLP pharmacokinetics was stealth-like with long T½ (~1 day), slow clearance, and small volume of distribution (Vd). The addition of capecitabine and/or bevacizumab did not have any apparent effect on the pharmacokinetics of MLP and clinical outcome. High baseline neutrophil count and CEA level were correlated with faster clearance, and larger Vd. Stable disease patients had longer T½ and slower clearance than other patients. T½ and clearance were significantly correlated with survival. Conclusions PL-MLP treatment results in a substantial rate of disease stabilization in metastatic CRC, and prolonged survival in patients achieving stable disease. The correlation of neutrophil count and CEA level with pharmacokinetic parameters of MLP is an unexpected finding that needs further investigation. The association of long T½ of MLP with stable disease and longer survival is consistent with an improved probability of disease control resulting from enhanced tumor localization of long-circulating liposomes and underscores the relevance of personalized pharmacokinetic evaluation in the use of nanomedicines.

Development of a high-precision bladder hyperthermic intracavitary chemotherapy device for bladder cancer and pharmacokinetic study.

BACKGROUND: Bladder hyperthermic intracavitary chemotherapy (HIVEC) has good effectiveness for bladder cancer, but conventional HIVEC systems lack precision and convenient application. To test the safety of a new HIVEC device (BR-TRG-II-type) in pigs and to perform a preliminary clinical trial in patients with bladder cancer. METHODS: This device was tested on six pigs to optimize the temperature and time parameters. Then, 165 patients (HIVEC after transurethral resection (TUR), n = 128; or HIVEC, n = 37) treated between December 2006 and December 2016 were recruited. Mitomycin C (MMC) was the chemotherapeutic agent. A serum pharmacokinetic study was performed. The primary endpoints were tumor recurrence, disease-free survival (DFS), and cumulative incidence rate (CIR) during follow-up. The adverse effects were graded. RESULTS: The animal experiment showed that 45 °C for 1 h was optimal. HIVEC was successful, with the infusion tube temperature stably controlled at about 45 °C, and outlet tube temperature of about 43 °C in all patients, for three sessions. Serum MMC levels gradually increased during HIVEC and decreased thereafter. The mean DFS was 39 ± 3.21 months (ranging from 8 to 78 months), and the DFS rate was 89.1% during follow-up. No adverse events occurred. CONCLUSION: The use of the BR-TRG-II-type HIVEC device is feasible for the treatment of bladder cancer. Future clinical trials in patients with different stages of bladder cancer will further confirm the clinical usefulness of this device. TRIAL REGISTRATION: chictr.org.cn: ChiCTR1900022099 (registered on Mar. 252,019). Retrospectively registered.

Systemic Absorption of Mitomycin-C When Used in Pterygium Surgery.

PURPOSE: To determine whether scleral topical application of mitomycin-C (MMC) results in measurable plasma levels of systemic absorption. METHODS: The study comprised 27 patients who were treated with MMC 0.2 mg/mL (0.02%) for 60 seconds during pterygium surgery. Blood samples were taken 30 minutes after surgery and evaluated by the human plasma liquid chromatography tandem-mass spectrometry method to determine the presence of MMC. RESULTS: The amount of MMC in 27 samples tested was determined as below 0.25 ppb (ng/mL). CONCLUSIONS: In this study of 27 patients treated with topical application of MMC for pterygium surgery, there was no measurable evidence of systemic drug absorption. Although systemic absorption has been found with the use of larger quantities of MMC, there is an extremely low likelihood of systemic absorption or toxicity of MMC after pterygium surgery.

Targeting of pegylated liposomal mitomycin-C prodrug to the folate receptor of cancer cells: Intracellular activation and enhanced cytotoxicity.

Mitomycin C (MMC) is a powerful anti-bacterial, anti-fungal and anti-tumor antibiotic, often active against multidrug resistant cells. Despite a broad spectrum of antitumor activity, MMC clinical use is relatively limited due to its fast clearance and dose-limiting toxicity. To exploit the potential antitumor activity of MMC and reduce its toxicity we have previously developed a formulation of pegylated liposomes with a lipophilic prodrug of MMC (PL-MLP), activated by endogenous reducing agents which are abundant in the tumor cell environment in the form of different thiols. PL-MLP has minimal in vitro cytotoxicity unless reducing agents are added to the cell culture to activate the prodrug. In the present study, we hypothesized that targeting PL-MLP via folate receptors will facilitate intracellular activation of prodrug and enhance cytotoxic activity without added reducing agents. We grafted a lipophilic folate conjugate (folate-PEG(5000)-DSPE) to formulate folate targeted liposomes (FT-PL-MLP) and examined in vitro cell uptake and cytotoxic activity in cancer cell lines with high folate receptors (HiFR). 3H-cholesterol-hexadecyl ether (3H-Chol)-radiolabeled liposomes were prepared to study liposome-cell binding in parallel to cellular uptake of prodrug MLP. 3H-Chol and MLP cell uptake levels were 4-fold and 9-fold greater in KB HiFR cells when FT-PL-MLP is compared to non-targeted PL-MLP liposomes. The cytotoxic activity of FT-PL-MLP liposomes was significantly increased up to ~5-fold compared with PL-MLP liposomes in all tested HiFR expressing cell lines. The enhanced uptake and intracytoplasmic liposome delivery was confirmed by confocal fluorescence studies with Rhodamine-labeled liposomes. In vivo, no significant differences in pharmacokinetics and biodistribution were observed when PL-MLP was compared to FT-PL-MLP by the intravenous route. However, when liposomes were directly injected into the peritoneal cavity of mice with malignant ascites of J6456 HiFR lymphoma cells, the tumor cell levels of MLP were significantly greater with the folate-targeted liposomes. Thus, folate targeting enhances liposome uptake by tumor cells enabling intracellular activation of prodrug in the absence of exogenous reducing agents, and leading to increased cytotoxicity. These results may be particularly relevant to the application of folate-targeted PL-MLP in intracavitary or intravesical treatment of cancer.

Systemic absorption and pharmacokinetics of single-dose early intravesical mitomycin C after transurethral resection of non-muscle-invasive bladder cancer.

OBJECTIVE: To study the systemic absorption and pharmacokinetics of a single dose of intravesical mitomycin C (MMC) given immediately after transurethral resection of bladder tumor (TURBT). METHODS: Fourteen patients with primary or recurrent non-muscle-invasive bladder cancer were eligible for a single early intravesical instillation of MMC (40 mg in 50 mL distilled water) administered immediately after TURBT. Blood samples were obtained at baseline and at 20, 40, 60 (time of voiding), 90, 120, and 150 minutes after instillation. Concentrations of the drug were determined by validated high-performance liquid chromatography assay. During TURBT, we counted the number of excursions of the resecting loop required to completely eradicate the tumor, including a portion of the underlying muscular wall. TURBTs were categorized as small and large, defined as requiring ≤6 or >6 full excursions of the resecting loop, respectively. RESULTS: Maximal MMC plasma concentrations were reached 40 minutes after instillation. At 150 minutes, only minimal drug plasma levels were detectable in 4 patients. The highest plasma peak was 49.25 ng/mL. In the first samples, at 20 minutes after instillation, the plasma concentration of MMC was significantly correlated with the extent of TURBT (P = .026). Four patients (28.6%) complained of G1 side effects, 3 after a large TURBT and 1 after a small TURBT, and 1 patient had G2 dysuria after a large TURBT. CONCLUSION: Low peak blood levels of MMC are observed after a single-dose intravesical instillation immediately after TURBT, with low systemic and local toxicity. The early absorption rate depends on TURBT extension.

A phase I trial of thermal sensitization using induced oxidative stress in the context of HIPEC.

BACKGROUND: Inducing oxidative stress under hyperthermic conditions significantly decreases tumor cell growth in a murine model of human colon cancer carcinomatosis. This phase I study examines the safety and pharmacokinetics of induced oxidative stress by the addition of hydrogen peroxide (H2O2) to the perfusate in patients undergoing cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced abdominal-only malignancies. METHODS: Patients with advanced colon or appendiceal malignancies underwent maximal cytoreduction followed by HIPEC with mitomycin C (MMC). In addition, H2O2 was added to the perfusate at three concentrations (n = 3/level, 0.05, 0.075, 0.1 %). A control group consisted of patients perfused with MMC alone (n = 3). Perfusate, serum MMC, and H2O2 levels were measured, as were tissue levels of MMC. RESULTS: Twelve patients were enrolled onto this trial. The median (range) peritoneal carcinomatosis index was 13 (3-20) requiring a median operative time of 6.3 (4-8.5) h. The median postoperative length of stay was 9 (5-34) days, with six patients requiring readmission within 30 days. Similar complications were observed at all three H2O2 levels, as well as in the control group. One patient required reexploration for a colon perforation (control group), and three patients developed enterocutaneous fistulas (0.075 % H2O2, 0.1 % H2O2 and control group). There were no operative mortalities. CONCLUSIONS: Hyperthermic intraperitoneal chemotherapy with induced oxidative stress after maximal cytoreduction is well tolerated. On the basis of the encouraging toxicity profile after cytoreduction and HIPEC with induced oxidative stress, a phase II trial to verify activity is indicated.

[Determination of mitomycin C in rabbit plasma by ultra-high performance liquid chromatography-tandem mass spectrometry].

An ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the determination of mitomycin C (MMC) in rabbit plasma was established. The blank rabbit plasma sample solutions added with mitomycin C and triamcinolone acetonide (internal standard, IS) were prepared. The solutions containing MMC and IS were extracted from the plasma with ethyl acetate using liquid-liquid extraction method. A Hypersil Gold C18 column (50 mm x 2.1 mm, 1.9 microm) was employed and the column temperature was set at 35 degrees C. The isocratic elution of methanol and 0.1% (v/v) formic acid aqueous solution as mobile phase was performed at a flow rate of 0.2 mL/min, and a rapid separation was completed within 3 min. The electrospray was operated in the positive ionization mode and the MMC and IS were identified in selected reaction monitoring (SRM) mode. The monitoring ions of MMC and IS were m/z 335. 2 --> 242.2 and m/z 435.2 --> 397. 3/415.2, respectively, which were used to qualify and quantify the targets by the method of matrix-matched standard solution. The calibration curve showed good linearity within the mass concentrations of 1 to 1 000 microg/L (r = 0.997 8, weighting: 1/x2). The limit of detection (S/N = 3) was 0.2 microg/L. The recoveries were from 85% to 115% at the spiked levels of 1, 5, 100 and 800 microg/L, and the relative standard deviations (RSDs) of intra- and inter-day were both less than 15%. The method can meet the determination requirements of biological samples, and can be used for the determination of mitomycin C in rabbit plasma after the administration of mitomycin C. The method is selective, sensitive, convenient, rapid and reproducible in the determination of mitomycin C, and also can be used for the pharmacokinetics research of mitomycin C in plasma.

Risk factors for the leakage of chemotherapeutic agents into systemic circulation after transcatheter arterial chemoembolization of hepatocellular carcinoma.

This prospective study was to investigate the possible risk factors for the leakage of chemotherapeutic agent into the systemic circulation after transcatheter arterial chemoembolization (TACE) of hepatocellular carcinoma (HCC). Peripheral plasma concentrations of chemotherapeutic agents were determined at 1 hour and 72 hours after TACE by high-performance liquid chromatography in 53 patients. HCC were divided into three types namely single nodule (<5cm), multiple nodules (all <5cm), and main nodule measuring 5cm or more. Forty-four patients (83%) showed detectable chemotherapeutic concentrations within 72 hours after TACE. Patients with single nodular-type HCC had lower incidence of detectable plasma chemotherapeutic agents after TACE than the other two groups (all p<0.05). The injected doses of lipiodol, epirubicin, and mitomycin C were lower in patients without detection than in patients with detectable chemotherapeutic agents (all p<0.05). Multivariate logistic regression showed that tumor type and injected dose of lipiodol were two independent risk factors for the leakage of mitomycin C at 1 hour after TACE (all p<0.05), and the injected dose of mitomycin C was the risk factor for the leakage of epirubicin at 1 hour after TACE (p<0.05). In conclusion, multiple nodular type and large nodule measuring 5cm or more have a risk of leakage of mitomycin C after TACE. Injected dose of lipiodol and mitomycin C as risk factor for the leakage of mitomycin C and epirubicin respectively may be because of competition of their injected volume within the limited space of target.

Changes induced by surgical and clinical factors in the pharmacology of intraperitoneal mitomycin C in 145 patients with peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are a combined treatment modality considered for selected patients with peritoneal carcinomatosis from colorectal and appendiceal cancer. Mitomycin C is a drug often used in this clinical setting. The surgical and clinical factors that may influence the pharmacokinetics of hyperthermic intraperitoneal chemotherapy should be further elucidated. MATERIALS AND METHODS: The patients included were 145 who had colorectal or appendiceal carcinomatosis resected using cytoreductive surgery prior to treatment with hyperthermic intraperitoneal chemotherapy with mitomycin C as part of a multidrug regimen. The effect of clinical and surgical factors on drug distribution after single intraperitoneal bolus administration with mitomycin C was determined. RESULTS: The pharmacokinetics of 145 patients treated with intraperitoneal mitomycin C showed a 27 times greater exposure to peritoneal surfaces when compared to plasma. At 90 min, 29% of the drug remained in the chemotherapy solution, 62% was retained in the body, and 9% was excreted in the urine. The extent of peritonectomy increased the clearance of mitomycin C from the peritoneal space (p = 0.051). A major resection of visceral peritoneal surface and a contracted peritoneal space reduced drug clearance. A contracted peritoneal space significantly reduced (p = 0.0001) drug concentrations in the plasma. CONCLUSIONS: Surgical and clinical factors may require modifications of drug dose or timing of chemotherapy administration. A large visceral resection and a contracted peritoneal space caused a reduced mitomycin C clearance. Total diffusion surface is an important determinant of mitomycin C pharmacokinetics.

Phase I clinical trial and pharmacokinetics of intravesical mitomycin C in dogs with localized transitional cell carcinoma of the urinary bladder.

BACKGROUND: Transitional cell carcinoma (TCC) is the most common cancer of the urinary tract in dogs. The most frequent cause of death is urinary obstruction from the primary tumor. Standard medical therapy for TCC is only partially effective. HYPOTHESIS/OBJECTIVES: Intravesical administration of mitomycin C (MMC) in dogs with invasive TCC will result in antitumor activity against the primary tumor and minimal systemic drug absorption. ANIMALS: Thirteen privately owned dogs with naturally occurring, histopathologically diagnosed TCC of the urinary bladder. METHODS: A prospective phase I trial was performed. MMC was given intravesically (600 µg/mL initial concentration) for 1 h/d for 2 consecutive days each month. The MMC concentration was escalated to a maximum of 800 µg/mL in groups of 3 dogs until the maximum tolerated dose (MTD) was determined. Serum assays for MMC were performed to determine the extent of systemic absorption of the MMC. RESULTS: The MTD of MMC based on local toxicoses was 700 µg/mL (1-h dwell time, 2 consecutive days). In addition, 2 dogs had severe myelosuppression and appeared to have systemic absorption of MMC. Five dogs had partial remission, and 7 dogs had stable disease. CONCLUSIONS: Intravesical MMC has antitumor activity in dogs with invasive TCC. Further study is needed to determine the cause of the myelosuppression associated with MMC administration, and to develop strategies to minimize this risk.

[Determination of magnetic mitomycin C-polybutylcyanoacrylate nanoparticles in mouse plasma].

OBJECTIVE: To establish a method by high-performance liquid chromatography (HPLC) for determining the concentration of magnetic mitomycin C-polybutylcyanoacrylate nanoparticles in mouse plasma. METHODS: Chromatography was performed on a LiChroCART C18 (250 mm x 4 mm, 5 microm) column with the mobile phase consisting of acetonitrile-NaAC (15:85), the flow rate of 1.0 ml/min, and the detection wavelength of 365 nm. Sample extraction was carried out with ethylacetate. RESULTS: The linear range of mouse plasma mitomycin C concentration was 0.04-1.00 microg/ml, and the linear equation of Y=16 388X-17.17 (r=0.999 8) was derived. CONCLUSION: This method is very easy to operate and suits the need of perclinical pharmacokinetic studies of mitomycin-magnetic nanoparticles and yields accurate and precise results.

Balloon catheter hypoxic abdominal and pelvic perfusion with tumour necrosis factor-alpha, Melphalan and Mitomycin C: a pharmacokinetic study in pigs.

BACKGROUND: Addition of tumour necrosis factor-alpha (TNF) to hypoxic abdominal perfusion (HAP) and hypoxic pelvic perfusion (HPP) with chemotherapeutic agents for treatment of un-resectable malignancies may lead to similar enhanced anti-tumour effects as are observed when TNF is added to isolated limb perfusions (ILP) with Melphalan. Here, we validate the methodology of HAP and HPP using balloon catheter techniques, and investigate the distribution of TNF, Melphalan and Mitomycin C (MMC) over the regional and systemic blood compartments when applying these techniques. MATERIALS AND METHODS: Twelve pigs underwent HAP or HPP with TNF, Melphalan and MMC for 20 min. Throughout and after the procedures blood samples were obtained from hepatic, portal and systemic blood compartments and plasma concentrations of perfused agents were determined. RESULTS: We demonstrated that HAP and HPP result in temporary loco-regional concentration advantages of all perfused agents, although from start of perfusion significant systemic leakage occurred. CONCLUSION: On basis of these results it seems that the advantage in terms of regional plasma concentration of TNF may be insufficient for TNF-mediated effects to occur, making future addition of this cytokine to these procedures in the clinical setting questionable. The observed regional concentration advantages of MMC and Melphalan, however, warrant further studies on clinical application of these agents in both settings.

Lipid transfer protein transports compounds from lipid nanoparticles to plasma lipoproteins.

Nanometer-sized lipid emulsion particles with a diameter of 25-50 nm, called Lipid Nano-Sphere (LNS), are expected as a promising drug carrier to show prolonged plasma half-life of an incorporating drug. In terms of successful drug delivery using LNS, a drug should be incorporated into the lipid particles and remain within the particle, not only in the formulation in vitro but also after administration into the systemic blood circulation. In this study, we showed that phospholipids and some water-insoluble molecules also moved from lipid particles to plasma lipoproteins or albumin in serum and plasma half-lives of these compounds did not reflect that of the drug carriers. It was suggested that phospholipid or its derivative were transferred from LNS particles to plasma lipoproteins by lipid transfer proteins (LTP) in the circulation. These phenomena leaded to unsuccessful delivery of the drug with lipid-particulate drug carriers. On the other hand, lipophilic derivatives with cholesterol pro-moiety tested in this study were not released from LNS particles and showed prolonged plasma half-lives. Lipophilicity is known to be an important parameter for incorporating drugs into lipid particles but substrate specificity for LTP seems to be another key to success promising drug design using lipid emulsion particulate delivery system.

Extent of parietal peritonectomy does not change intraperitoneal chemotherapy pharmacokinetics.

PURPOSE: To measure the clearance intraperitoneal mitomycin C and doxorubicin in patients having peritonectomy and analyze the impact of the extent of peritoneal resection on pharmacokinetics. METHODS: A group of 15 patients with peritoneal carcinomatosis were submitted to cytoreductive surgery and heated intraperitoneal chemotherapy. Ten patients received mitomycin C and five, doxorubicin. Six patients underwent total parietal peritonectomy and nine had less-extensive peritonectomy. Pharmacokinetics were determined by sampling peritoneal fluid and blood. Drug concentrations over time, area under the curve ratios and the amount of drug recovered from the peritoneal cavity were calculated and compared between the groups. RESULTS: The concentrations of mitomycin C over time in the peritoneal fluid and plasma were similar in five patients with total parietal peritonectomy as compared to five patients with less-extensive peritonectomy ( P=0.5350 and 0.6991; Mann-Whitney test). Mitomycin C area under the curve ratio in total peritonectomy patients was 20.5 and 25.7 in patients with less-extensive peritonectomy. The difference in total amount of drug recovered from the peritoneal cavity was not significant (30.6+/-6.188% versus 22.6+/-3.84%, P=0.095). In the studies with doxorubicin, one patient underwent total parietal peritonectomy with similar pharmacokinetics to four patients submitted to partial peritonectomy. CONCLUSIONS: The extent of parietal peritoneal resection did not affect the pharmacokinetics of intraoperative intraperitoneal chemotherapy. The pharmacological barrier between the abdominopelvic cavity and plasma is not directly related to an intact peritoneum.

Pharmacokinetics of intra-arterial mitomycin C in the chemoembolization treatment of liver metastases with polyvinylalcohol or degradable starch microspheres.

OBJECTIVES: In cancer treatment, arterial blood flow reduction by embolization combined with intra-arterial chemotherapy may be advantageous by achieving high and prolonged drug concentrations in the tumor, and lower systemic drug exposure. The pharmacokinetics of intra-arterial mitomycin C (MMC) was investigated in patients with liver metastases undergoing chemoembolization treatment. METHODS: The chemoembolization treatment consisted of the use of polyvinylalcohol microspheres (ITC-Contour, diameter 150-250 micro m, irreversible vessel occlusion, 20 mg MMC, 15 patients) followed by sealing of the supplying artery with Ethibloc. Alternatively, starch microspheres (Spherex, diameter 45 micro m, biologically degradable, 10 ml of suspension containing 60 mg starch/ml, 20 mg MMC in 7 patients, 15 mg/m2 body surface in 3 patients) were used. MMC was infused over 6 min into the artery supplying the tumor. Serum MMC concentrations were determined from peripheral venous blood samples [protein precipitation with acetonitrile, reverse-phase HPLC with ultraviolet detection (C18 column, elution with 0.01 M, pH 6.5 phosphate buffer/methanol, v/v 70:30, 365 nm)]. The pharmacokinetic parameters were computed assuming an open two-compartment model and linear kinetics. RESULTS: The disposition parameters for MMC in patients treated with polyvinylalcohol microspheres were comparable to data from the literature (C(max)=913+/-98 ng/ml, T(max)=7.7+/-0.3 min, V(c)=0.27+/-0.03 l/kg, V(ss)=0.59+/-0.07 l/kg, Cl=757+/-67 ml/min, T(1/2 alpha)=5.8+/-0.8 min, T(1/2 beta)=50.4+/-4.1 min). There was no significant difference in the disposition parameters for MMC between patients treated with polyvinylalcohol microspheres and those treated with starch microspheres ( P>0.05). In particular, there was no significant difference in the standardized AUC between the groups; this implies that the systemic toxicity of MMC is comparable when polyvinylalcohol microspheres and ethibloc (AUC 1472+/-123 microg min/l per 1 mg MMC) or starch microspheres (AUC: 1448+/-172 microg min/l per 1 mg MMC) are used. CONCLUSION: The AUC values found in this study do not indicate a reduction in the systemic toxicity of MMC if applied intra-arterially in combination with embolizing microspheres, when compared to the AUC values in the literature for intra-arterial application without embolization, or intravenous MMC application. The amount of starch microspheres may have been too small to cause marked effects. On the other hand, there is a very wide range of AUC values reported in the literature for different application modes, and the use of such historical controls is not adequate for detecting more subtle advantages of the chemoembolization procedure, which may, however, exist.

Effect of local hyperthermia of the bladder on mitomycin C pharmacokinetics during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma.

AIMS: To assess the effect of local hyperthermia on the systemic absorption of mitomycin C (MMC) during intravesical chemotherapy for the treatment of superficial transitional cell carcinoma of the bladder, and to establish the likely safety of this procedure. METHODS: Group 1 (n = 12) received 20 mg intravesical MMC plus local hyperthermia, group 2 (n = 13) 20 mg MMC alone, group 3 (n = 16) 40 mg MMC plus local hyperthermia and group 4 (n = 10) 40 mg MMC alone. Patients in groups 1, 2, and 4 underwent post-tumour resection adjuvant treatment, whereas those in group 3 still had tumour present and were treated to eradicate it. Intravesical instillation lasted 60 min, with the solution (50 ml) being replaced after the first 30 min. Blood samples were taken before, and every 15 min during instillation. MMC concentrations in plasma and in urine were determined by h.p.l.c. RESULTS: The highest MMC plasma concentration (67.9 ng ml(-1)) occurred in a patient in group 3. This value was well below the threshold concentration (400 ng ml-1) for myelosuppression. Local hyperthermia associated with the intravesical chemotherapy enhanced plasma MMC concentrations at 30, 45 and 60 min compared with chemotherapy alone (Group 1 vs 2, P < or = 0.008). Systemic exposure to MMC was not significantly increased by doubling the intravesical dose when intravesical chemotherapy alone was administered. Patients in group 3 displayed the highest degree of MMC absorption and the greatest variability in pharmacokinetics between patients. CONCLUSIONS: Local hyperthermia enhances the systemic absorption of MMC during intravesical chemotherapy for bladder cancer. In the doses used, plasma MMC concentrations were always more than six times lower than those shown to cause toxicity.

Theoretical considerations and in vitro concentration response studies with two human colorectal carcinoma cell lines. The rational experimental base for clinical studies in regional chemotherapy.

The theoretical advantage of regional vs. systemic chemotherapy was calculated, based on pharmacokinetic considerations. The relevance of exposure time and high local concentrations of chemotherapeutic drugs for regional chemotherapy was elucidated in time dependent concentration response curves with two human cell lines. The theoretical pharmacological advantage of regional vs. systemic chemotherapy was defined by the formula Rd = (AUCi. a. 1 + AUCi. a. 2)/(AUCi. v.) and in hepatic artery infusion is for adriamycin (ADM) 5.8-.6, cis-platinum (CDDP) 8, epirubicine (EPI) 6.3, 5-fluorouracil (5-FU) 22-58, mitomycin C (MMC) 4.6, mitoxantrone (NOV) 6.3. All drugs but 5-FUDR exerted concentration response behaviour in the cell line-experiments. In the cell lines cytotoxicity depended on exposure time so that concentration chi time products at (IC50), (c chi t (IC50)), were calculated to determine an optimal in vitro exposure time. Based on these results and clinical considerations, optimal clinical exposure times could be defined for regional chemotherapy. The results may be of high relevance for e.g. hepatic artery infusion at the lower and chemoembolization or intraperitoneal instillation at the higher test concentration, respectively.

Pharmacokinetic of intraarterial mitomycin C with extra corporeal detoxification in humans.

PURPOSE: A study has been performed in 15 patients with liver metastases from colorectal cancer to evaluate the pharmacokinetic of mitomycin C and the effectiveness of drug removal techniques during high-dose locoregional chemotherapy. PATIENTS AND METHODS: Haemofiltration and/or haemodialysis of post-hepatic venous blood were performed during 22 intra-arterial infusions of mitomycin C by the use of a double lumen catheter surgically introduced in the inferior vena cava. Mitomycin C levels were measured by high performance liquid chromatography in the extracorporeal circuit blood, in the peripheral venous blood and ultrafiltrate. RESULTS: The mean reduction of mitomycin C bioavailability in the extracorporeal circuit blood was 42.3 per cent using haemofiltration, 58.9 per cent using haemofiltration plus haemodialysis and 59.3 per cent with haemodialysis alone. The resulting mean mitomycin C plasmatic half-life was 40.2 minutes using haemofiltration, 24.9 minutes using haemofiltration plus haemodialysis and 24.1 minutes using haemodialysis alone. CONCLUSIONS: The detoxification of posthepatic venous blood during intra-arterial hepatic chemotherapy is an effective method to increase mitomycin C concentrations and oncological response and limit extra hepatic toxicity.

Pharmacological determinants of the antitumour activity of mitomycin C.

Recent investigations into bioreductive anticancer drugs have focused on profiling reductase enzymes and relating their expression to therapeutic activity in an approach referred to as enzyme directed drug development. However, few studies have attempted to validate this approach in vivo and even less is known about how the expression of reductases relates quantitatively and qualitatively to metabolic activation. In the present study, the antitumour activity, pharmacokinetics and metabolism of mitomycin C (MMC) has been determined in vivo in two murine adenocarcinomas of the colon, MAC 16 (high DT-diaphorase activity) and MAC 26 (low DT-diaphorase activity) after intra-tumoural injection of drug. Over a broad range of drug concentrations (50-250 microg), MAC 16 proved to be consistently the more sensitive tumour (e.g. 75 microg of MMC, T/C 11% for MAC 16 and 31% for MAC 26). Higher levels of parent drug (peak concentration 103 microg/tumour compared to 58 microg/tumour) were maintained over 45 min in MAC 16 after which time clearance was rapid from both tumours. Four metabolites were detected in both tumours characteristic of different pathways of metabolism. However, by far the major metabolite was 2,7-diaminomitosene (2,7-DM), an accurate indicator of metabolic activation of MMC. Despite higher reductase levels and greater sensitivity to the drug, there was 4-fold less production of 2,7-DM in MAC 16. These results indicate a lack of a simple relationship in vivo between reductase expression and metabolic activation and suggest factors other than pharmacological determinants being responsible for the chemosensitivity of the MAC tumours to MMC.

Pharmacokinetics of mitomycin C in pelvic stopflow infusion and hypoxic pelvic perfusion with and without hemofiltration: a pilot study of patients with recurrent unresectable rectal cancer.

This pilot study was conducted to evaluate the advantage in drug delivery for regional chemotherapy in patients with unresectable recurrent rectal carcinoma by different methods. For this research, the pharmacokinetic advantages of mitomycin C delivery by four different methods were compared: intraaortic infusion with aortic stopflow; intraaortic infusion with inferior vena cava stopflow; intraaortic infusion with aortic and inferior caval vein stopflow (hypoxic pelvic perfusion); and hypoxic pelvic perfusion with hemofiltration. The results of this study indicate that pelvic stopflow infusion followed by hypoxic pelvic perfusion significantly increases mitomycin C concentrations in the blood coming from the tumor site. Also, use of hemofiltration reduces mitomycin C levels in peripheral blood after high-dose regional chemotherapy. Further investigations involving more patients should be carried out in the future to validate these results.