Metabolism and pharmacokinetics in rats of ganoderiol F,a highly cytotoxic and antitumor triterpene from <Emphasis Type="Italic">Ganoderma lucidum</Emphasis>

The metabolism of ganoderiol F (GF), a cytotoxic and antitumor triterpene from Ganoderma lucidum, by intestinal bacteria and its pharmacokinetics in rats were investigated by using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). GF was converted to ganodermatriol by anaerobic incubation with bacterial mixtures from rats and humans. This metabolite was detected in rat feces, but not in plasma and urine, after oral administration of GF. The fate of GF after oral (p.o.) and intravenous (i.v.) administration to rats was examined in pharmacokinetics studies. Plasma samples pretreated by solid-phase extraction were quantified by HPLC/MS/MS over a GF concentration range of 1.25–100 ng/ml (S/N = 5). The intra- and interday precision (CV%) was below 8% and accuracy was within the range of 95.9–103.6% for all samples. The range of recovery ratios was 89.2–98.2%. After the administration of GF at 0.5 mg/kg i.v., the plasma concentrations of GF quickly declined and the elimination half-life values (t _1/2α and t _1/2β) were about 2.4 and 34.8 min. On the other hand, the elimination half-life values (t _1/2α) after p.o. administration of GF at doses of 20 and 50 mg/kg were 14.4 and 143.3 min for the former, and 18.6 and 114.6 min for the latter. The AUC_0–t value was 11.17 (ng/ml) h at a GF dose of 0.5 mg/kg i.v., but 49.4 and 111.6 (ng/ml) h at GF doses of 20 and 50 mg/kg p.o., respectively, indicating that the AUC_0–t value is proportional to the administered oral doses. The estimated absolute bioavailability of GF in rats was F = 0.105.     

Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor

We developed a novel water-soluble camptothecin analogue, CKD602, and evaluated the inhibition of topoisomerase I and the antitumor activities against mammalian tumor cells and human tumor xenografts. CKD602 was a nanomolar inhibitor of the topoisomerase I enzyme in the cleavable complex assay. CKD602 was found to be 3 times and slightly more potent than topotecan and camptothecin as inhibitors of topoisomerase, respectively. In tumor cell cytotoxicity, CKD602 was more potent than topotecan in 14 out of 26 human cancer cell lines tested, while it was comparable to camptothecin. CKD602 was tested for thein vivo antitumor activity against the human tumor xenograft models. CKD602 was able to induce regression of established HT-29, WIDR and CX-1 colon tumors, LX-1 lung tumor, MX-1 breast tumor and SKOV-3 ovarian tumor as much as 80, 94, 76, 67, 87% and 88%, respectively, with comparable body weight changes to those of topotecan. Also the therapeutic margin (R/Emax: maximum tolerance dose/ED₅₈) of CKD602 was significantly higher than that of topotecan by 4 times. Efficacy was determined at the maximal tolerated dose levels using schedule dependent i.p. administration in mice bearing L1210 leukemia. On a Q4d×4 (every 4 day for 4 doses) schedule, the maximum tolerated dose (MTD) was 25 mg/kg per administration, which caused great weight loss and lethality in <5% tumor bearing mouse. This schedule brought significant increase in life span (ILS), 212%, with 33% of long-term survivals. The ex vivo antitumor activity of CKD602 was compared with that of topotecan and the mean antitumor index (ATI) values recorded for CKD602 were significantly higher than that noted for topotecan. From these results, CKD602 warrants further clinical investigations as a potent inhibitor of topoisomerase I.     

Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma

Summary The effect of leucovorin (LV) given in various doses and schedules on the in vivo antitumor activity and toxicity of 5-fluorouracil (5FU) was studied in two murine colon cancer lines, i.e., Colon 26 (relatively resistant to 5FU) and Colon 38 (5FU sensitive), maintained in Balb-c and C57B1/6 mice, respectively. Mice were treated weekly with 5FU at the maximum tolerated dose, alone and in combination with LV. In Colon 26, neither simultaneous administration of 5FU and LV nor 5FU combined with delayed administration of LV potentiated the antitumor activity of 5FU. LV given twice — 1 hr before (50 mg/kg) and then together (50 mg/kg) with 5FU (100 mg/kg) — gave significantly better delay of tumor growth of both tumor lines than 5FU did alone (100 mg/kg). No differences were found after a total LV dose of 100 or 200 mg/kg. Delayed administration of uridine (3500 mg/kg) allowed the use of higher 5FU doses, which improved the antitumor effect on Colon 26. Systemic toxicity led to moderate weight loss in treated mice, but was comparable for mice treated with 5FU alone or combined with LV. Hematological toxicity consisted of moderate leukopenia (nadir 40%), which was observed with the most active schedule and was less severe than with 5FU alone. This schedule did not cause thrombocytopenia, but after discontinuation the thrombocyte count showed an overshoot. Addition of uridine to this schedule reduced hematological toxicity only slightly. It is concluded that LV potentiated the antitumor activity of 5FU against two solid tumor lines, i.e., a relatively resistant and a sensitive murine colon carcinoma, and that toxicity was moderate.Abbreviations 5FU 5-fluorouracil - LV leucovorin (folinic acid, 5-formyl-tetrahydrofolate) - FdUMP 5-fluoro 2-deoxyuridine 5monophosphate - TS thymidylate synthase - CH2-THF 5-10 methylenetetrahydrofolate - UR uridine - GDF growth delay factor - TD tumor doubling time - MTD maximum tolerated dose - T/C mean tumor volume of treated mice divided by mean tumor volume of control mice     

Amelioration of thrombocytopenia with concomitant ornithine in sarcomabearing rats receiving high dose difluoromethylornithine

Summary The dose limiting toxicity of difluoromethylornithine (DFMO), when administered by continuous infusion, is thrombocytopenia. DFMO-induced antitumor activity and thrombocytopenia were time- and dosedependent up to 1700 mg/kg/d when administered continuously for 12 days. Concomitant ornithine administration (at selected molar ratios to DFMO) ameliorated thrombocytopenia induced by DFMO at a dose of 2000 mg/kg/day without adversely affecting its antitumor activity. The purpose of this study was to determine if ornithine could ameliorate the thrombocytopenia of higher DFMO doses and increase the efficacy of DFMO. Fischer 344 male rats with a transplantable sarcoma in the right flank were given 2000 and 3500 mg/kg/d DFMO alone or with ornithine at a molar ratio of 0.4 for 8 days by continuous infusion. Concomitant ornithine infusion overcame the thrombocytopenia that was induced by either dose of DFMO without reducing the antitumor activity against the sarcoma. The antitumor activity, tumor polyamine levels, and tumor S-adenosylmethionine decarboxylase activity did not consistently change with increasing doses of DFMO or with the addition of ornithine to the infusion regimen. These results demonstrate that the thrombocytopenia induced by doses of DFMO greater than 2000 mg/kg/d can be ameliorated without compromising the antitumor activity. Address for offrints: V.B. Grossie, Jr. Department of General Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX, 77030, USA     

In vivo antitumor efficacy of CW252053, a folate-based thymidylate synthase inhibitor

Previous studies have demonstrated that CW252053, a quinazoline antifolate, exhibits potent inhibitory activity against thymidylate synthase (TS) as well as cytotoxic activity against tumor cell lines in vitro. In this study, we evaluated the in vivo antitumor efficacy of CW252053 in the mouse tumor model. Female B6D2F1 mice were injected with LY3.7.2C TK-/- (thymidine kinase deficient mouse lymphoma) cells into the gastrocnemius muscle. Then, CW252053 was administered twice daily by intraperitoneal injection for 10 days, and tumor growth was monitored daily by leg diameter measurement. All animals in the vehicle, 5-FU, and low dose (30 mg/kg) CW252053 treated groups died between days 12 and 23 because of the tumor burden. In contrast, dosing with 60 mg/kg of CW252053 produced a cure rate against tumor growth of 37.5% and a survival rate of 50%. Even more significantly, a higher dose of CW252053 (120 mg/kg) elicited both a 100% cure rate and a 100% survival rate at the termination of the study, confirming that this compound has very potent in vivo antitumor activity against tumor growth. During the experimental period of this study no signs of toxicity were observed even at the high CW252053 dosage rate of 120 mg/kg.     

Antitumor efficacy of AG3340 associated with maintenance of minimum effective plasma concentrations and not total daily dose, exposure or peak plasma concentrations

Oral administration of AG3340, a novel metalloprotease (MMP) inhibitor, suppresses the growth of human colon adenocarcinoma (COLO-320DM) tumors in vivo (Proc Am Assoc Cancer Res 39: 2059, 1998). In this report, we tested the hypothesis that the growth inhibition of these tumors is associated with maintaining minimum effective plasma concentrations of AG3340. Nude mice were given a total oral daily dose of 25 or 200 mg/kg; 6.25 mg/kg was given four times per day (QID) (25 mg/kg/day), and 100 mg/kg was given in two daily doses (BID) (200 mg/kg/day). Peak plasma concentrations (C_max) of 83 ± 43 (mean ± SD) and 1998 ± 642 ng/ml were detected 30 min after a single dose with 6.25 mg/kg and 100 mg/kg AG3340, respectively. AUC_{(0-24 h)} values estimated from dosing with 25 and 200 mg/kg/day AG3340 were 672 and 10882 ng^*h/ml, respectively. Importantly, both regimen inhibited tumor growth equivalently (74 to 82%). Efficacy was also compared at a total daily dose of 25 mg/kg by giving AG3340: QID (6.25 mg/kg per dose), BID (12.5 mg/kg per dose), and once daily (25 mg/kg per dose). The C_max of these regimens was 83 ± 43, 287 ± 175 and 462 ± 495 ng/ml, respectively. AG3340 did not inhibit tumor growth with the latter two regimens. The efficacy of 6.25 mg/kg QID (25 mg/kg/day) was superior to the efficacy of 25 mg/kg BID (50 mg/kg/day), substantiating the independence of efficacy from the total daily dose and C_max. Expectedly, peak to trough fluctuations were significantly smaller with the QID regimen than with BID and QD dosing. After 24 h, the trough was greater than 1 ng/ml with QID dosing but was less than 1 ng/ml after QD and BID dosing. These results suggest that the antitumor efficacy of AG3340 was associated with maintaining minimum effective plasma concentrations of AG3340 and demonstrate that the antitumor efficacy of AG3340 was independent of the total daily dose, peak plasma concentration, and drug exposure in this tumor model.     

萘普替尼靶向表皮生长因子受体不同突变亚型的抗肿瘤作用研究

目的 研究萘普替尼对表皮生长因子受体（EGFR）不同突变亚型荷瘤小鼠肿瘤生长的影响。方法 建立野生型EGFR人表皮鳞癌A431、L858R/T790M双突变EGFR非小细胞肺癌H1975、Del19突变型EGFR非小细胞肺癌HCC827及HER2高表达的胃癌N87的裸鼠移植瘤模型,待肿瘤长至100 mm³左右将小鼠分组,A431荷瘤小鼠分组：对照组、阿法替尼12 mg/kg和萘普替尼3.50、1.75、0.87、0.29 mg/kg;H1975荷瘤小鼠分组：对照组、阿法替尼30 mg/kg和萘普替尼7.00、3.50、1.75 mg/kg;HCC827荷瘤小鼠分组：对照组、阿法替尼12 mg/kg和萘普替尼3.50、1.75、0.87、0.60、0.29 mg/kg;N87荷瘤小鼠分组：对照组、阿法替尼12 mg/kg和萘普替尼7.00、3.50、1.75、0.87、0.29 mg/kg,每组10只动物。分组后即开始ig给药,对照组给予同体积去离子水,A431、H1975、HCC827、N87荷瘤小鼠分别给药14、21、7、14 d。观察相对肿瘤体积（RTV）、肿瘤增殖率及对肿瘤质量的抑制率,在体考察萘普替尼的抗肿瘤作用。结果 A431荷瘤小鼠：与对照组比较,萘普替尼各剂量组RTV均显著减小（P<0.01）,肿瘤增殖率分别为26.6%、32.5%、34.8%、42.2%;瘤质量均显著降低（P<0.01）,抑瘤率范围在48.3%~73.9%;0.87 mg/kg为起效剂量,3.5 mg/kg剂量与阿法替尼12 mg/kg效果相当,3.5mg/kg组小鼠体质量显著降低（P<0.01）。H1975荷瘤小鼠：与对照组比较,萘普替尼各剂量组RTV均显著降低（P<0.05、0.01）,肿瘤增殖率分别为14.5%、38.2%、65.3%;3.5 mg/kg为起效剂量,与阿法替尼30 mg/kg作用相当;7.0、3.5 mg/kg组小鼠体质量显著降低（P<0.05、0.01）。HCC827荷瘤小鼠：与对照组比较,萘普替尼3.50、1.75、0.87、0.60 mg/kg组RTV降低极为显著（P<0.01）,肿瘤增殖率均小于40%;瘤质量呈不同程度地降低,抑瘤率范围52.9%~89.7%;0.6 mg/kg为起效剂量,1.75 mg/kg剂量与阿法替尼12 mg/kg作用相当,3.5、1.75 mg/kg组小鼠体质量显著降低（P<0.01）。N87荷瘤小鼠：萘普替尼7.00、3.50、1.75 mg/kg组RTV及瘤质量均显著低于对照组（P<0.05、0.01）,且肿瘤增殖率均小于40%,抑瘤率范围54.9%~95.00%;1.75 mg/kg为起效剂量,3.5 mg/kg与阿法替尼12 mg/kg作用相当;7.0、3.5 mg/kg组小鼠体质量显著降低（P<0.01）。结论 萘普替尼具有明显的抗肿瘤作用,其中对EGFR野生型或单突变型荷瘤抗肿瘤作用较好。关键词：萘普替尼;表皮生长因子受体;表皮生长因子受体酪氨酸激酶抑制剂;突变;非小细胞肺癌     

Preclinical efficacy and safety assessment of nano-oxaliplatin oral formulation prepared by novel Fat Employing Supercritical Nano System,the FESNS®

Background: It is expected that oral cancer drug will provide ease of administration with decreased unwanted events to the patients. The purpose of this study is to prepare oral formulation of nano-oxaliplatin and examine the anticancer efficacy and safety. Nano-oxaliplatin was prepared utilizing our proprietary technology, the Fat Employing Supercritical Nano System (FESNS^®).

Result: It showed regular nanoparticles with a mean diameter of around 212?nm. When nano-oxaliplatin was orally administered in rats, the relative bioavailability of nano-oxaliplatin oral formulations was about 25–31% compared to the Eloxatin^® administered intravenously (i.v.). For antitumor activity in xenograft model, nano-oxaliplatin oral formulation (20?mg/kg, once daily) presented superior inhibition of tumor growth against Eloxatin^® (5?mg/kg, i.v. once a week). In single-dose toxicity, dead animals were observed at or above 1000?mg/kg (LD₅₀: 888.38?mg/kg for male; 725.43?mg/kg for female rats). In repeated dose toxicity, there were hematological changes observed in rats, which is a common finding in the class of cancer drugs. It was thought that the expected dose level that has cytotoxic effect without death would be 30?mg/kg in rats, which is double the dose level of Eloxatin^®.

Conclusion: Nano-oxaliplatin oral formulation changed the pharmacokinetic behavior of crude oxaliplatin, thus increasing oral bioavailability as well as its anticancer activity. In addition, single and repeated dose toxicity studies indicated that oral nano-oxaliplatin is superior in toxicity at the pharmacologically active doses compared to Eloxatin^® in rats. Nano-oxaliplatin oral formulation has potential as a novel anticancer therapy.     

Biologic Activity of 5′-Deoxy-5-fluorouridine by Rectal Administration

5-Deoxy-5-fluorouridine (dFUR) is used orally to treat human malignancies. This study compared the antitumor activity and toxicity of rectally and orally administered dFUR. A 7-day treatment of dFUR (350 or 700 mg/kg/day) was infused rectally over 30 min or administered by oral gavage (500 mg/kg/day) to rats bearing transplanted dimethylhydrazine-induced colon tumors. The oral treatment was previously shown to produce a 82% cure of the tumor-bearing animals. The tumor weight after 7 day treatment was compared to that before treatment. The size of the tumor in the saline-treated control group (N = 6) increased by 55%. The maximum tumor size reductions by drug treatments were 40% for the 350-mg/kg rectal dose (N = 5), >99% for the 700-mg/kg rectal dose (N = 10), and 100% for the 500-mg/kg oral dose (N = 4). The 350-mg/kg rectal dose did not produce any cures, while the 700-mg/kg rectal dose produced 80% cures and the 500-mg/kg oral dose 100% cures. The cured animals remained tumor-free during the observation period of 163 to 243 days. The tumor-bearing rats were euthanized between 46 and 132 days when they appeared moribund or when the tumor began to ulcerate. The 700-mg/kg rectal and 500-mg/kg oral treatments produced greater weight loss than saline, suggesting a drug-induced intestinal toxicity. After rectal drug treatment, the animal weight returned to pretreatment level within 3 days, indicating a rapidly reversible intestinal toxicity. The oral group suffered a greater weight loss than the rectal group and took more than 10 days to recover. This suggests that the intestinal toxicity of the rectal treatment was less severe than the oral treatment. The leukocyte and thrombocyte counts after drug treatments were not significantly different from the pretreatment levels, which suggests an absence of myelosuppression. In summary, these results indicate that dFUR by rectal administration had antitumor activity with minimal host toxicity.     

<Emphasis Type="Italic">Pulsatilla</Emphasis> saponin D: The antitumor principle from<Emphasis Type="Italic">Pulsatilla koreana</Emphasis>

By bioassay-guided separation, an already known saponin, Pulsatilla saponin D was isolated from the root of Pulsatilla koreana Nakai as a antitumor component when evaluated by in vivo antitumor activity as well as in vitro cytotoxic activity test. It showed potent inhibition rate of tumor growth (IR, 82%) at the dose of 6.4 mg/kg on the BDF1 mice bearing LLC cells.     

VRCTC-310 — A novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Summary Two purified animal venom toxins, crotoxin and cardiotoxin, have been combined to produce a unique natural product (VRCTC-310) currently under investigation as an antitumor agent by the National Cancer Institute.In vitro, it has demonstrated cytotoxic disease specificity and a unique mechanism of action when submitted to COMPARE analysis.In vivo, tolerance was developed to the neurotoxic properties of crotoxin which allowed comparison of several schedules of fixed and escalating daily i.m. doses to mice bearing s.c. Lewis Lung carcinoma. An 83% inhibition of tumor growth was achieved using an escalating dose schedule starting at 1.8 mg/kg and reaching 6.3 mg/kg/day on day 20. Although some irritation around the sites of i.m. injection was noted, animal weight loss was negligible and there were no other signs of adverse toxicity. This natural product represents a new, membrane interactive anticancer agent which produces a unique spectrum of cytotoxicityin vitro and which has demonstrated interestingin vivo antitumor efficacy.     

抗癌新药-乙双吗啉(AT-1727)的药理研究

乙双吗啉(AT-1727)是我国合成的一种抗癌新药。它是一种双内酰亚胺化合物,实验证明,乙双吗啉对小鼠肉瘤S₃₇、S₁₈₀有显著抗肿瘤作用,对ECS,HCS,脑瘤B₂₂及L₆₁₅等移植性肿瘤亦有明显抗肿瘤作用。它对S₃₇的50%抑制剂量(ID₅₀)为1.88 mg/kg(ip)及6.61 mg/kg(po)。其抗肿瘤作用与给药方案有一定关系。乙双吗啉对小白鼠毒性LD₅₀为372.8±27.mg/kg(ip)及243.8±26.1 mg/kg(po)。因此,乙双吗啉腹腔注射及口服时,对S₃₇的化疗指数分别为47.5及36.9。给健康犬肌肉注射乙双吗啉25及50 mg/kg/天,连用10天,除出现食量减少,白细胞轻度下降外,对红细胞,血小板、肝、肾功能均无明显影响。乙双吗啉对以溶血素反应为指标的体液免疫有抑制作用;对以移植物抗宿主反应为指标的细胞免疫则无抑制作用。     

Pharmacokinetics and tissue distribution study of 16-dehydropregnenolone liposome in female mice after intravenous administration

Objective: 16-Dehydropregnenolone (16-DHP) is a potential antitumor compound with poor solubility. A liposome entrapped 16-DHP (16-DHP-LM) formulation was developed to surmount its solubility obstacle. The aim of this study is to investigate the pharmacokinetics of 16-DHP-LM and 16-DHP solution in female mice and tissue distribution of 16-DHP-LM in female tumor-bearing nude mice.

Methods: Rotary-evaporated film method was used to prepare 16-DHP-LM. The comparison of pharmacokinetics between 16-DHP-LM and 16-DHP solution in female mice was investigated after intravenous administration at a single dose of 15?mg/kg. The dose proportionality of 16-DHP-LM was also evaluated after intravenous administration of 16-DHP-LM at the doses of 7.5, 15.0 and 30.0?mg/kg. The tissue distribution of 16-DHP-LM in female tumor-bearing nude mice was evaluated after intravenous administration of 16-DHP-LM at a single dose of 30.0?mg/kg.

Results: The pharmacokinetic study indicated that the 16-DHP-LM group had higher area under the plasma concentration-time curve (AUC), lower apparent volume of distribution (Vz) and smaller systemic clearance (CL) than the 16-DHP solution group. For dose proportionality, good linearity of the pharmacokinetics of 16-DHP after intravenous administration of 16-DHP-LM was observed in the regression analysis of the AUC-dose plot (r?=?0.99) and the C_max-dose plot (r?=?0.98). The tissue distribution study showed that the main tissue depots for 16-DHP in tumor-bearing nude mice were plasma, liver, spleen and tumor, which was benefit to anti-tumor effect. All these results provided a significant basis for the design of clinical trial of 16-DHP-LM.     

In vitro cytotoxic activity of tri-<Emphasis Type="Italic">n</Emphasis>-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) and preliminary antitumor activity in vivo

Summary  The cytotoxicity in vitro and antitumor activity in vivo of the organotin compound tri-n-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) have been investigated. The IC50 values obtained in a panel of tumor cell lines were compared to those of the parental compound IST-FS 29 in the same cells. IST-FS 35 resulted significantly more active than IST-FS 29 with IC50 values in the range 0.16–1.8 μM. Toxicity studies in vivo, after intravenous administration of escalating concentrations of IST-FS 35, provided the identification of the maximal tolerated dose (3.5 mg/kg) which was employed as therapeutic dose in the antitumor activity experiments. Preliminary results, in transplanted murine tumor models, revealed that both the P388 myelomonocytic leukaemia and the B16-F10 melanoma, implanted subcutaneously in BDF1 mice, were inhibited about 96% in their tumor volume at day 11, following a single intravenous injection of the compound. Additional studies are mandatory to unravel the mechanism of action for the development of IST-FS 35 as potential antitumor drug.     

PEGylation alleviates the non-specific toxicities of Alpha-Momorcharin and preserves its antitumor efficacy in vivo

Alpha-Momorcharin (α-MMC) is a ribosome inactivating protein from Momordica charantia with anti-tumor activity. Previously, we had observed that modification of α-MMC with polyethylene glycol (PEG) could reduce toxicity, but it also reduces its anti-tumor activity in vitro. This study aims to investigate whether the metabolism-extended properties of α-MMC resulting from PEGylation could preserve its anti-tumor efficacy in vivo through pharmacokinetics and antitumor experiments. The pharmacokinetics experiments were conducted in rats using the TCA (Trichloroacetic Acid) method. Antitumor activity in vivo was investigated in murine mammary carcinoma (EMT-6) and human mammary carcinoma (MDA-MB-231) transplanted tumor mouse models. The results showed that PEGylation increased the plasma half-life of α-MMC in rats from 6.2–7.5?h to 52–87?h. When administered at 1?mg/kg, α-MMC-PEG and α-MMC showed similar anti-tumor activities in vivo, with a T/C% of 38.56% for α-MMC versus 35.43% for α-MMC-PEG in the EMT-6 tumor model and 36.30% for α-MMC versus 39.88% for α-MMC-PEG in the MDA-MB-231 tumor model (p?>?0.05). Importantly, at the dose of 3?mg/kg, all the animals treated with α-MMC died while the animals treated with α-MMC-PEG exhibited only moderate toxic reactions, and α-MMC-PEG exhibited improved anti-tumor efficacy with a T/C% (relative tumor growth rate) of 25.18% and 21.07% in the EMT-6 and MDA-MB-231 tumor models, respectively. The present study demonstrates that PEGylation extends the half-life of α-MMC and alleviates non-specific toxicity, thereby preserving its antitumor efficacy in vivo, and a higher lever of dosage can be used to achieve better therapeutic efficacy.     

灵芝多糖的急性毒性和抗肿瘤作用

目的：探讨灵芝多糖的急性毒性和抗肿瘤作用。方法：观察灵芝多糖的LD50及对S180小鼠肉瘤细胞的抑制作用。结果：灵芝多糖的LD50远大于国家标准15g/kg,属无毒级别。同时当灵芝多糖的剂量为250mg/kg时,对S180小鼠肉瘤细胞的抑瘤率为43.44%。结论：灵芝多糖有很好的抗肿瘤作用,同时无急性毒性,值得推广应用。     

Experimental antitumor activity of BMY-28175 a new fermentation derived antitumor agent

Summary BMY-28175 is a novel antitumor antibiotic produced in fermentation by Actinomadura verrucosospora. The cytotoxic effects of BMY-28175 were determined using murine and human tumor cell lines in vitro. Following 72 hour exposure, the drug had IC50 values 1.5 to 13.5 ng/ml in a microtiter assay. BMY-28175 was evaluated for antitumor activity against several experimental murine and human tumor models. The drug administered ip was active against ip implanted P388 leukemia, L1210 leukemia, B16 melanoma, M109 lung carcinoma, C26 colon carcinoma, M5076 sarcoma and Lewis lung carcinoma. In addition, BMY-28175 administered iv was active against iv implanted P388 and L1210 leukemias. BMY-28175 was active against sc implanted B16 melanoma (increased lifespan and/or inhibition of primary tumor growth) in about 60% of the tests. The growth of sc implanted M109 was inhibited by BMY-28175 in a single experiment. BMY-28175 was also active against the MX-1 human mammary xenograft implanted in the subrenal capsule of nude mice. The optimal dose for BMY-28175 in these various studies ranged from 0.16 g/kg per injection with consecutive daily (qd1-9) administration, to 51.2 g/kg with single dose administration. The results of these studies indicate that BMY-28175 is one of the most potent antitumor agents yet observed, with a broad spectrum of activity against tumors of murine and human origin and activity against tumors located distal to the site of drug administration.     

Pharmacokinetics of verproside after intravenous and oral administration in rats

Verproside, a catalpol derivative iridoid glucoside isolated from Pseudolysimachion longifolium, is a candidate for anti-asthmatic drug. The dose-dependency of the pharmacokinetics of verproside was evaluated in rats after intravenous and oral administration. After intravenous administration of verproside (2, 5 and 10 mg/kg doses), the systemic clearance (Cl) was significantly reduced and AUC was significantly increased at 10 mg/kg dose compared to 2 and 5 mg/kg doses. The volume of distribution at steady state (V _ss) remained unchanged as the dose was increased. The extent of urinary excretion was low for both intravenous (3.3–6.2%) and oral (0.01–0.04%) doses. Isovanilloylcatalpol was identified as a metabolite after intravenous administration of verproside and showed the significant decreases in AUC and C _max at 10 mg/kg verproside dose. The reduced systemic clearance of verproside at high doses appears to be due to the saturable metabolism. Upon oral administration of verproside (20, 50 and 100 mg/kg doses), C _max was nonlinearly increased. The extent of verproside recovered from the gastrointestinal tract at 24 h after oral administration was 0.01–0.72% for all three doses studied. The absolute oral bioavailability (F) was 0.3 and 0.5% for 50 and 100 mg/kg doses, respectively. Low F appears to be due to first-pass metabolism.     

Polysaccharides from Cymbopogon citratus with antitumor and immunomodulatory activity

Abstract

Context: Most of the present studies on the antitumor efficiency of Cymbopogon citratus (DC.) Stapf (Gramineae) are limited to its low-mass compounds, and little information about the antitumor activity of polysaccharides from this plant is available.

Objectives: This study focused on the potential antitumor and immunomodulatory activities of polysaccharides (CCPS) from C. citratus.

Materials and methods: CCPS was isolated using the water extraction-ethanol precipitation method. The sarcoma 180 (S180) cells-inoculated mice were intraperitoneally administrated with CCPS (30–200?mg/kg/d) for seven consecutive days. The effects of CCPS on tumor growth, thymus and spleen weights, splenocyte proliferation, and cytokine secretion in the tumor-bearing mice were measured. The cytotoxicity of CCPS (50–800?μg/mL) towards S180 cells was also studied.

Results: CCPS significantly inhibited the growth of the transplanted S180 tumors, with the inhibition rates ranging from 14.8 to 37.8%. Simultaneously, CCPS dose-dependently improved the immunity of the tumor-bearing mice. With the highest dose of 200?mg/kg/d, the thymus and spleen indices were increased by 21.9 and 91.9%, respectively; ConA- and LSP-induced splenocyte proliferations were increased by 32.7 and 35.3%, respectively. The secretions of interleukin 2 (IL-2), interleukin 6 (IL-6), interleukin 2 (IL-12), and tumor necrosis factor-α (TNF-α) were increased by 103.2, 40.2, 23.6, and 26.3%, respectively. Nevertheless, almost no toxicity of CCPS towards S180 cells was observed, with the maximal inhibition rate less than 15% at the CCPS concentration of 800?μg/mL.

Conclusion: CCPS exhibited antitumor activity in vivo, and this activity might be achieved by immunoenhancement rather than direct cytotoxicity.     

Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models

Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar levels of EGFR expression, the antitumor activity of erlotinib is robust both as monotherapy and in combination with chemotherapies.