AIMTo investigate the tissue distribution and pharmacokinetics of hydroxycamptothecin (HCPT) after aerosol inhalation in rabbits.

METHODSRP-HPLC was used to determine the concentration of HCPT in different tissues and plasma of rabbits. The tissue distribution of HCPT after aerosol inhalation or iv administration was compared. The plasma concentrations at different time after aerosol inhalation were compared with iv injection.

RESULTSThe HCPT concentrations in lung after aerosol inhalation at 0.5, 1 and 2 h were 13.52, 27.81 and 20.82 times higher than that of iv administration group, respectively. At the same time, concentrations in other tissues were decreased obviously. The absolute bioavailability of HCPT after aerosol inhalation was 7.38%.

CONCLUSIONAfter aerosol inhalation, HCPT is retained mostly in lung. So this administration route can raise the therapeutic index and reduce adverse effects.

Administration, Inhalation ; Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; blood ; pharmacokinetics ; Biological Availability ; Camptothecin ; administration & dosage ; analogs & derivatives ; blood ; pharmacokinetics ; Female ; Injections, Intravenous ; Lung ; metabolism ; Male ; Rabbits ; Tissue Distribution

OBJECTIVETo develop HCPT liposome with small diameter and to study the tissue distribution of the HCPT liposome in rats.

METHODModified solvent-injection method was used to prepare HCPT liposome. The entrapment efficiency, morphology, size and zeta potential were also investigated. The transformation temperature and the ratio of cholesterol to phospholipids were determined by fluorescence spectrophotometry. HCPT liposome and HCPT injection (5 mg x kg(-1)) were injected by tail vein in mice, respectively. The tissue concentrations of HCPT were determined by LC-MS/MS.

RESULTUnder selected process conditions, the HCPT liposomes were spherical and integrated with the mean entrapment efficiency of (96.83 +/- 2.32)%, the size of (180.5 +/- 4.5) nm and the zeta potential of--(32.1 +/- 1.3) mV. It showed that the optimum proportion of cholesterol to phospholipids was 1.5: 10, the optimum transformation temperature was 32.5 degrees C; HCPT liposome at a dose of 5 mg x kg(-1) led to higher concentration and longer duration of action compared with HCPT injection on market.

CONCLUSIONHCPT liposome prepared by solvent-injection method was characteristic of small mean diameter, high encapsulation efficiency and long circulation in vivo.

Animals ; Camptothecin ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Female ; Liposomes ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Tissue Distribution

OBJECTIVETo study the pharmacokinetic of 10-Hydroxycamptothecin HCPT by intraperitoneal administration.

METHODSix dogs were given HCPT by intraperitoneal perfusion: HCPT 2 mg x kg(-1), dissolved in 300 mL NS. During the course of experiments, peritoneal fluids and blood were sampled using a standardized protocol. The concentration of HCPT in all samples was determined by high performance liquid chromatography (HPLC).

RESULTThe area under the curve (AUC) of peritoneal fluids was significantly highly as compared to the AUC of femoral vein and portal vein (P < 0.001).

CONCLUSIONThese experiments demonstrate that intraperitoneal chemotherapy has significant effect on the pharmacokinetics of IP route of HCPT administration. This method should be a more reasonable chemotherapy for the prevention of recurrence and liver metastasis of gastric cancer, colon cancer and ovary cancer after radical resection.

Animals ; Antineoplastic Agents, Phytogenic ; administration & dosage ; pharmacokinetics ; Area Under Curve ; Ascitic Fluid ; metabolism ; Camptothecin ; administration & dosage ; analogs & derivatives ; pharmacokinetics ; Dogs ; Infusions, Parenteral ; Male

Methoxypolyethylene glycol-poly lactic acid (PELA) was synthesized by ring-opening copolymerization of lactide in the presence of mPEG and its structure was characterized by 1H NMR. The novel hypomicrons were prepared by solution-casting method using PELA block copolymer as a matrix and 7-ethyl-10-hydroxycamptothecin (SN-38) as an antitumor agent. The morphology, size and size distribution, drug loading, entrapment efficiency, and release characteristics in vitro of the SN-38 loaded hypomicrons were studied. The results showed that the obtained hypomicrons showed spherical shape with the core-shell structure, the sizes are in the range of 157-238 nm, and the drug loading content varied from 1.35%-3.58% depending on the copolymer composition and the SN-38 fed amount. The in vitro release behavior in phosphate-buffered saline, pH 7.4, exhibited a sustaining release manner and was affected by the copolymer composition. The drug-loaded amount and entrapment efficiency decreased with increasing the molecular weight of the copolymer. With the increasing of the SN-38 fed amount, the drug-loaded amount and the size of hypomicrons increased, the entrapment efficiency decreased. The SN-38 hypomicrons increased the solubility of SN-38 in water and were valuable for the development of the novel dosage form of SN-38.
Antineoplastic Agents, Phytogenic ; administration & dosage ; Camptothecin ; administration & dosage ; analogs & derivatives ; Drug Carriers ; Lactic Acid ; chemistry ; Microspheres ; Particle Size ; Polyesters ; Polyethylene Glycols ; chemistry ; Polymers ; chemistry ; Solubility ; Technology, Pharmaceutical

OBJECTIVETo evaluate the safety and preliminary efficacy of dose-modified regimen of 5-fluorouracil plus oxaliplatin and irinotecan (mFOLFOXIRI) for patients with advanced colorectal cancer (CRC).

METHODSData of 312 CRC patients confirmed by pathology receiving triplet drug alone or combined with target therapy between October 2012 and December 2016 at the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. CRC patients who had previously completed adjuvant therapy (or neoadjuvant therapy) within 6 months or palliative chemotherapy were excluded, meanwhile those with poor general condition (ECOG score > 2) or grade 2 neuropathy and allergy to oxaliplatin were excluded as well. Regimen of mFOLFOXIRI: oxaliplatin 85 mg/m² dissolved in 5% glucose solution 500 ml by intravenous infusion for 2 h; irinotecan 150 to 165 mg/m² dissolved in 0.9% sodium chloride 250 ml by intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 h, day 1; 5-FU 2800 mg/m², 48-h continuous intravenous infusion; once every 2 weeks. Therapy could be combined with a targeted drug, bevacizumab 5 mg/kg every two weeks; cetuximab 500 mg/m² every two weeks. Side effect was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.0.3). The objective response rate was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) after administering at least four cycles of chemotherapy.

RESULTSThe median age was 52 years (range 16-73) in the whole group; 113 patients (36.2%) had locally advanced CRC, and 199 (63.8%) had metastatic CRC. Most patients (274/312, 87.8%) did not receive any treatment earlier. There were a total of 1651 chemotherapy cycles in the whole group, with a median of 6(1-19) cycles. Of these 1651 cycles, 124 cycles of chemotherapy(7.5%) were dose-adjusted; 176 cycles of chemotherapy(10.7%) were delayed for median 5(3-13) days; 124 cycles(7.5%) required dose decrease. The overall relative dose intensity was >90%; the specific drug dose intensity was 93.6%(2620 mg×m⁻²×d⁻¹) for fluorouracil, 97.8%(83 mg×m⁻²×d⁻¹) for oxaliplatin, and 94.2%(155 mg×m⁻²×d⁻¹) for irinotecan. Twenty-three patients (7 of intestinal perforation, 7 of intestinal obstruction, 1 of grade 4 hematologic toxicity, and 8 of grade 3 fatigue) refused subsequent chemotherapy due to intolerable toxicity. Main grade 3 or 4 adverse events in patients were neutropenia in 69 cases (22.1%), fatigue in 35 cases (11.2%), and anemia in 28 cases (8.9%). Twenty serious adverse events (6.4%) occurred, including 13 patients of febrile neutropenia (4.2%), 7 patients of intestinal perforation (2.2%, 4 patients in upper rectum, 2 in sigmoid colon, and 1 in transverse colon cancer), and 9 of them had subsequent sepsis (2.9%). All the patients with intestinal perforation underwent emergency operation. No treatment-related deaths occurred. In 199 patients with metastatic CRC, because 22 patients did not receive image evaluation, the preliminary efficacy of 177 patients was actually evaluated. A total of 113 objective response events were observed. The overall response rate was 63.8%(113/177), partial response rate was 61.6%(109/177), clinically complete response rate was 2.3%(4/177), stable disease was 29.9% (53/177), progressive disease was 6.2%(11/177), and the disease control rate was 93.8%(166/177). In 127 patients receiving triplet drug, objective response rate was 40.9% for those with less than four cycles and 81.1% for those with more than four cycles (P<0.001).

CONCLUSIONThe mFOLFOXIRI regimen with reduced dose can be safely used in advanced CRC and has achieved promising results in terms of short-term efficacy.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Camptothecin ; administration & dosage ; analogs & derivatives ; Colorectal Neoplasms ; drug therapy ; Fluorouracil ; administration & dosage ; Humans ; Leucovorin ; administration & dosage ; Middle Aged ; Organoplatinum Compounds ; administration & dosage ; Retrospective Studies ; Treatment Outcome ; Young Adult

BACKGROUND: Irinotecan, in combination with 5-fluorouracil (5-FU) and a high dose of leucovorin (LV), known as FOLFIRI regimen, has shown activity in recurrent or metastatic colorectal cancer. Therefore, we evaluated the efficacy and safety of irinotecan, 5-FU and a low dose of LV (modified FOLFIRI) as a first line of therapy for patients with relapsed or metastatic colorectal cancer. METHODS: Between January 2002 and October 2004, 44 patients with histologically confirmed recurrent or metastatic colorectal cancer were enrolled. The chemotherapy regimen schedule consisted of 180 mg/m2 of irinotecan being administered intravenously (i.v) on Day 1, 400 mg/m2 of 5-FU via i.v bolus with 600 mg/m2 of continuous infusion for 22 hrs on both Day 1 and 2, and 20 mg/m2 of leucovorin on both Day 1 and 2, repeated every two weeks. RESULTS: The overall response rate was 47.8%. Of the 40 evaluated patients, one had CR (2.3%) and 20 had PR (46.5%). Toxicities were mild and easily manageable. Three patients experienced 23 episodes of Grade 3/4 leukopenia., Only one patient developed Grade 3/4 diarrhea. None experienced Grade 3/4 thrombocytopenia. CONCLUSION: Modified FOLFIRI with a low dose of LV is an effective and tolerable regimen for patients with recurrent or metastatic colorectal cancer.
Neoplasm Recurrence, Local/*drug therapy ; Neoplasm Metastasis/*drug therapy ; Middle Aged ; Male ; Leucovorin/administration & dosage ; Humans ; Fluorouracil/administration & dosage ; Female ; Disease Progression ; Colorectal Neoplasms/*drug therapy/pathology ; Camptothecin/administration & dosage/analogs & derivatives ; Antineoplastic Combined Chemotherapy Protocols/*administration & dosage ; Aged ; Adult

This study plans to prepare lipid bilayer-coated mesoporous silica nanoparticles (LMSNs) which are pH sensitive with core-shell structure to improve the tumor cell lethality of antitumor drug. The lipid coated mesoporous silica nanoparticles loaded with irinotecan (CPT-11) (CPT-11-LMSNs) were prepared by hot water-film hydration method, and the characterized its morphology, particle size and release in vitro. Meanwhile, the intracellular uptake and cell toxicity of CPT-11-LMSNs and intracellular accumulation of CPT-11 were evaluated on human breast carcinoma cell line (MCF-7). The results indicated that the mean diameter of the spherical LMSNs was (120.27 +/- 5.91) nm. The slow release in simulated normal physiological conditions and a rapid release under simulated intracellular condition demonstrated the pH sensitivity of CPT-11-MSNs in vitro. Moreover, the CPT-11-LMSN could improve the intracellular CPT-11 cumulant 2.1 times and reduce half maximal inhibitory concentration (IC50) values of CPT-11 1.4 times compared with CPT-11-MSNs, demonstrating a stronger cell lethality.
Antineoplastic Agents, Phytogenic ; administration & dosage ; pharmacology ; Camptothecin ; administration & dosage ; analogs & derivatives ; pharmacology ; Cell Proliferation ; drug effects ; Drug Carriers ; Humans ; Hydrogen-Ion Concentration ; Lipid Bilayers ; administration & dosage ; chemistry ; MCF-7 Cells ; Nanoparticles ; Particle Size ; Porosity ; Silicon Dioxide ; administration & dosage ; chemistry

OBJECTIVETo explore efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) regimen by dose attenuation in locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer(MPC).

METHODSBetween April 2014 and October 2015, 35 patients with LAPC (n=18) or MPC (n=17) were treated with mFOLFIRINOX regimen (irinotecan 135 mg/m(2), oxaliplatin 68 mg/m(2), 5-FU 2 400 mg/m(2), no bolus of 5-FU, leucovorin 400 mg/m(2)) in the Second Affiliated Hospital of Zhejiang University School of Medicine. The primary end point was progression free survival. The second end points were overall survival, objective response rate, adverse effects, surgical resection rate for LAPC.

RESULTSAmong 35 patients, 6 patients (17.1%) who dropped out and received less than 2 cycles were excluded for response analysis. Among the other 29 patients, 9 patients had grade 3 or 4 adverse effects. No patients ceased treatment due to adverse effects. The 29 patients received 5 (2-13) cycles were evaluated by efficacy and found partial remission in 16 cases, stable disease in 10 cases, progression disease in 3 cases. Response rate was 55.2%. Nine patients with LAPC accomplished surgery after neoadjuvant treatment without perioperative complication and death, and 6 patients accepted R0 resection.

CONCLUSIONSThe mFOLFIRINOX regimen used in the study is well-tolerated in Chinese population with high treatment efficacy on patients with LAPC and MPC. Further investigation of efficacy and adverse effects on more advanced pancreatic cancer patients is necessary.

Antineoplastic Combined Chemotherapy Protocols ; Camptothecin ; administration & dosage ; analogs & derivatives ; Disease Progression ; Disease-Free Survival ; Fluorouracil ; administration & dosage ; Humans ; Leucovorin ; administration & dosage ; Neoadjuvant Therapy ; Organoplatinum Compounds ; administration & dosage ; Pancreatic Neoplasms ; drug therapy ; Tertiary Care Centers ; Treatment Outcome

OBJECTIVETo explore how arylamine N-acetyltransferases (NATs) is related to cell apoptosis.

METHODSNAT activity in apoptotic HepG2 cells was measured using high performance liquid chromatography (HPLC); the apoptosis rate of HepG2 cells acted upon by an NAT inhibitor was measured using flow cytometry.

RESULTSNAT activity was lowered in apoptotic HepG2 cells; apoptosis rate induced by camptothecin (CAM) increased after inhibition of NAT activity in HepG2 cells.

CONCLUSIONNAT can inhibit apoptosis in HepG2 cells.

Apoptosis ; drug effects ; Arylamine N-Acetyltransferase ; antagonists & inhibitors ; metabolism ; Camptothecin ; administration & dosage ; Cells, Cultured ; Dose-Response Relationship, Drug ; Hepatocytes ; cytology ; drug effects ; enzymology ; Humans

OBJECTIVETo evaluate the efficacy and adverse effects of weekly irinotecan combined with capecitabine as a second-line chemotherapy for treatment of advanced gastric cancer.

METHODSTwenty-one patients with advanced gastric cancer who had failed first-line therapy received irinotecan on days 1 and 8 plus capecitabine on days 1-14 for a 21-day cycle. Each patient was treated for at least two cycles and evaluated 4 weeks later for the responses.

RESULTSOf the 21 patients, none showed complete remission (CR), 5 (23.8%) showed partial remission (PR), 6 (28.6%) showed stable disease (SD) and 10 (47.6%) showed progressive disease (PD). The overall response rate was 23.8%, and 11 patients (52.4%) benefited (CR+PR+SD) from the clinical therapy, with a mean time to tumor progression of 3.61±0.97 months. The main adverse effects of this regimen included myelosuppression, nausea, vomiting and diarrhea.

CONCLUSIONThe regimen of weekly irinotecan plus capecitabine has a definite effect for treatment of advanced gastric cancer with tolerable toxicity.

Adenocarcinoma ; drug therapy ; pathology ; Adult ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Camptothecin ; administration & dosage ; analogs & derivatives ; Capecitabine ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; Female ; Fluorouracil ; administration & dosage ; analogs & derivatives ; Humans ; Male ; Middle Aged ; Stomach Neoplasms ; drug therapy ; pathology ; Treatment Outcome