<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.     

Antitumor Activity of the Methanol Extract of Hypericum hookerianum Stem Against Ehrlich Ascites Carcinoma in Swiss Albino Mice

A large number of plants belonging to the Hypericum family are known to possess strong antitumor properties. The methanol extract of H. hookerianum Wight and Arnott stem (MEHH) exhibited potent in vitro cytotoxic activity against various cancerous cell lines. In the present study, the high performance liquid chromatography (HPLC) standardized MEHH was tested for in vivo antitumor properties against Ehrlich ascites carcinoma (EAC) tumor bearing mice at 100, 200, and 400 mg/kg body weight doses given orally once daily for 14 days. The results indicate that administration of the extract not only increased the survival of animals with ascites tumor, decreased the body weight induced by the tumor burden, and reduced packed cell volume and viable tissue cell count, but also altered many hematological parameters changed during tumor progression, indicating the potent antitumor nature of the extract. Among the three doses tested, the 200 mg/kg body weight dose was found to be the most potent.     

In vivo antitumor effects of bitter principles from the antlered form of fruiting bodies of Ganoderma lucidum

Two triterpene fractions and a single ganoderma alcohol obtained from an antlered form of the fruiting bodies of Ganoderma lucidum were examined for their antitumor effects on the growth of inoculated mouse Lewis lung carcinoma in mice by intraperitoneal administration. The ganoderma alcohol fraction significantly suppressed the tumor growth at doses of 50 and 100 mg/kg in the treatment period, and even after the administration, showing antitumor activity with a T/C value of 70.6% at a dose of 100 mg/kg. On the other hand, no obvious activity was shown at each dose in the ganoderma-acid-fraction-treated groups. Furthermore, ganoderiol F, which exhibited the strongest cytotoxicity against four tumor cell lines among five ganoderma alcohols examined, remarkably inhibited the tumor growth, accounting for 63.7% and 78.7% of control group at a dose of 5 mg/kg, 54.1% and 63.0% at a dose of 10 mg/kg, and 47.7% and 53.9% at a dose of 20 mg/kg in and after the administration period, respectively, in a dose-dependent manner. These results suggest that the antitumor effects of bitter principles in G. lucidum are mainly due to ganoderma alcohols.     

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.     

Studies on the relationship between therapeutic schedule and antitumor effect of etoposide and cytosine arabinoside in murine L1210 leukemia

The sequence dependency of the antitumor effect of etoposide and ara-C was investigated against the L1210 ascites tumor in BDF1 mice. Etoposide (7.5 mg/kg or 15 mg/kg) and ara-C (25 mg/kg or 500 mg/kg) were administered intraperitoneally on days 1, 4 and 7 after inoculation of L1210 with or without time interval of 3 or 6 h. Antitumor effect was decided for cure rate and post inoculation survival time of the mice died of tumor. Six hours pretreatment with 15 mg/kg of etoposide followed by 500 mg/kg of ara-C yielded 100% of cure rate, but only 20% of cure rate was obtained with the reverse sequence. Simultaneous administration of etoposide and ara-C produced 70% of cure rate. At every dosage examined, pretreatment with etoposide given 6 hr before ara-C was the most effective antitumor schedule in L1210 leukemia.     

Plumbagin,A Plant Naphthoquinone with Antitumor and Radiomodifying Properties

The tumor inhibitory and radiomodifying effects of plumbagin (Pl), a naphthoquinone isolated from Plumbago rosea, on mouse Ehrlich ascites carcinoma was studied. Tumor response was assessed by increase in life span (% ILS) and animal survival at 120 days. The acute LD 50 of plumbagin in normal mice was 9.4 mg/kg body weight. Single doses from 2 to 6 mg/kg Pl, given intraperitoneally (i.p.), produced inhibition of exponentially growing tumors. However, increases in dose above 3 mg/kg did not increase 120 day survival significantly over that produced by 3 mg/kg. Multiple dose treatment, starting from 24 h after tumor cell inoculation, showed that a total dose of 9 mg/kg, administered in three fractions of 3 mg/kg, once daily, gave the maximum %ILS and tumor free survival. Combination of radiation (RT, 7.5 Gy to the abdomen) after the first Pl dose (1-3mg/kg/fraction) synergistically increased mouse survival at 120 days. The tumor inhibitory effect was less pronounced when treatment was started at more advanced tumor stages, but combination of low dose fractions (2.5 or 3 mg/kg/fraction) with RT enhanced the %ILS and animal survival. Higher dose fractions in combination with radiation were not tolerated by the mice. DNA appears to be the likely target of Pl cytotoxicity; the mechanism of interaction of Pl + RT in enhancing tumor response is not clear.     

Evaluation of combretastatin A-4 prodrug in a non-Hodgkin's lymphoma xenograft model: preclinical efficacy

Combretastatin A-4 prodrug (CA4P) is a new antitubulin agent currently in phase I/II clinical trials against solid tumors. We have previously reported on the in vitro activity of CA4P against a panel of malignant human B-lymphoid cell lines. In this study, we investigated the antitumor and the antiangiogenic activity of CA4P in our diffuse large cell lymphoma WSU-DLCL2-SCID mouse model. WSU-DLCL2 cells (10(7)) were injected s.c. into 5-week-old female ICR-SCID mice. Tumor-bearing mice were treated at the CA4P maximum tolerated dose (MTD) of 800 mg/kg in different dose/schedules. CA4P showed significant antitumor activity against this lymphoma model. Best results were seen when MTD was given in two and four divided doses (400 and 200 mg/kg, respectively). CA4P given in four divided doses (4 x 200 mg/kg) showed a log10 kill of 1.01, T/C of 11.7% and T-C of 12 days. Immunohistochemical staining using anti-CD31 antibody after 6, 24, 48 and 120 h treatment revealed a significant decrease in the number of tumor blood vessels after 24 h (about 80%). Only the periphery of treated tumors revealed the presence of blood vessels. Morphological examination of the tumors after tetrachrome staining showed a necrotic center in tumors of CA4P-treated animals. New blood vessel formation was noted to emerge in tumor tissues as early as 48 h following a single dose of CA4P. The G2/M arrest observed in vitro was not detected in vivo indicating predominance of the antiangiogenic effects with regard to antitumor efficacy in vivo. We conclude that CA4P has antiangiogenic activity in this lymphoma model and the use of this agent should be explored clinically in the treatment of non-Hodgkin's lymphoma.     

Antitumor activity of spergualin, a novel antitumor antibiotic

Spergualin (SGL), a novel antitumor antibiotic, exhibited strong antitumor activity against transplantable leukemias in mice: L1210, L1210(IMC), P388, P815, C1498, EL-4 and RL male 1. It also exhibited antitumor activity against M5076 fibrosarcoma, AH66 and AH66F rat hepatomas, but not against Meth-A fibrosarcoma, B16 melanoma, Lewis lung carcinoma (LL) and C26 colon adenocarcinoma. The antitumor activity of SGL was administration-schedule dependent. The strongest activity against L1210 was obtained by ip continuous infusion for 7 days or daily ip administration for 9 days. Single ip injection of SGL at 100 mg/kg to mice caused convulsion and death within 15 minutes after injection. Such acute toxicity was not observed by continuous infusion. SGL showed its strongest activity at subtoxic dose against sensitive tumors except for L1210(IMC). Mice implanted ip with L1210(IMC) were cured by treatment with SGL at 3.13 mg/kg/day for 9 days, but died from the tumor at 50 mg/kg/day X 9. The cured mice rejected a second inoculation of up to 10(6) tumor cells. The tumor cells isolated from mice after treatment with the high dose showed resistance to SGL in vivo. Mice implanted sc with L1210(IMC) were also cured by 9 daily ip administrations of SGL at 12.5 mg/kg/day, but solid tumor was observed at the implantation site until 3 days after the final injection of SGL in some cured mice. These results suggest that the therapeutic effect of SGL has a relatively high specificity for leukemias and that the immunological effect is involved in the antitumor activity.     

An enediyne-energized single-domain antibody-containing fusion protein shows potent antitumor activity

Single-domain antibodies are attractive as tumor-targeting vehicles because of their much smaller size than intact antibody molecules. Lidamycin is a macromolecular antitumor antibiotic, which consists of a labile enediyne chromophore (AE) and a noncovalently bound apoprotein (LDP). An enediyne-energized fusion protein VH-LDP-AE composed of single-domain antibody directed against type IV collagenase and lidamycin was prepared by a novel two-step method including DNA recombination and molecular reconstitution. VH-LDP-AE demonstrated extremely potent cytotoxicity to cancer cells and marked antiangiogenic activity in vitro. In the mouse hepatoma 22 model, drugs were administered intravenously as a single dose on day 1 with maximal tolerated doses. VH-LDP-AE (0.25 mg/kg) suppressed the tumor growth by 95.9%, whereas lidamycin (0.05 mg/kg) and mitomycin (1 mg/kg) by 79.6 and 51.1%, respectively. In the HT-1080 xenograft model in nude mice, drugs were given intravenously as a single dose on day 4 after tumor implantation. VH-LDP-AE at 0.25 mg/kg suppressed tumor growth by 76% (P<0.05) compared with that of lidamycin at 0.05 mg/kg (53%) on day 18. No obvious toxic effects were observed in all groups during treatments. The results showed that energized fusion protein VH-LDP-AE was more effective than lidamycin and mitomycin. These properties, together with its much smaller size than conventional antibody-based agents, suggested that VH-LDP-AE would be a promising candidate for cancer-targeting therapy. In addition, the two-step approach could serve as a new technology platform for making a series of highly potent engineered antibody-based drugs for a variety of cancers.     

Antitumor effects of royal jelly (RJ)

Antitumor effects of Royal Jelly (RJ) were investigated employing the transplantable tumors of mouse advance leukemia L1210 and P388 strains and Ehrlich, Sarcoma-180 ascites and solid tumor strains. RJ was administered orally in a prophylactic-therapeutic (30 days before and 30 days after the transplantations of tumor cells) or a therapeutic (30 days after the transplantations of tumor cells) manner. Tumor cells were transplanted i.p. (ascites tumor) or s.c. (solid tumor). The daily dose of RJ was 0 (control), 10, 100, or 1000 mg/kg. In the case of the therapeutic experiments employing advance leukemia L1210 and P388 strains, which gave quite a short survival period of 8 approximately 9 days, RJ did not show any antitumor effect. In the case of the therapeutic RJ application employing the Sarcoma-180 ascites tumor, which gave a moderate survival period of 16 days, the increased life span was 9.3 approximately 19.3%; and with the Ehrlich ascites tumor (survival period of 22.1 days), the increased life span was 20.4% (RJ 10 mg/kg . day) and 17.6% (RJ 1,000 mg/kg . day), but no antitumor effect was observed at the dose of 100 mg/kg . day. In the case of the therapeutic experiment employing Ehrlich solid tumor, tumor growth inhibition was 25.3 approximately 54.8%, where as the use of the prophylactic-therapeutic regimen gave a tumor growth inhibition of 38.3 approximately 45.7%. In the case of the therapeutic RJ application employing Sarcoma-180 solid tumor, tumor growth inhibition was 45.1 approximately 59.7%, where as the prophylactic-therapeutic regimen gave a tumor growth inhibition of 49.1 approximately 56.1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

复方紫草油的研制及临床应用

瑞行狼毒水提物抑制小鼠移植肿瘤Ｓ－１８０生长，５－２０ｇ／ｋｇ（相当生药）ｉｐ１０ｄ，抑制率为１６．２－４７．８％，ＳｃＬ对体外培养的Ｓ－１８０细胞生长、集落开矿和ＭＴＴ甲膳化合物生成有显著抑制作用，并和剂量呈正相关。表明ＳｃＬ的抗肿瘤作用是其直接作用于肿瘤细胞所产生。     

In vivo toxicity and antitumor activity of mangosteen extract

Mangosteen (Garcinia mangostana) has been widely used in the traditional medicine of Thailand to treat various ailments, especially diseases of the digestive system and infections. Many reports show antiproliferation of crude extracts and active constituents from mangosteen against many cancer cell lines. Therefore, the current study is proposed to demonstrate in vivo evidence on the antitumor activity of mangosteen. Crude methanolic extract (CME) from mangosteen pericarp including 25.19 % α-mangostin as an active xanthone was used in this study. The inhibition on tumor cell proliferation of CME was preliminarily evaluated against the murine colon cancer cell line NL-17 with an IC₅₀ value of 17 and 84 μg/ml based on WST-1 and LDH assays, respectively. The safety dose for animal application was assessed by in vivo toxicity studies using female BALB/c mice. Acute toxicity showed an LD₅₀ value and approximate lethal dose at 1,000 mg/kg, whereas the suitable dose for short-term study should be ≤200 mg/kg. The effective dose for antitumor activity of CME was found to be between 100 and 200 mg/kg, with a tumor size reduction of 50–70 %. Histological staining clearly illustrated a decrease of tumor cell density in the footpad in a dose-dependent manner. The median survival time and life span significantly increased in tumor-bearing mice with CME treatment. This study suggests that CME possesses a powerful antitumor activity. Therefore, it is worth undertaking further investigation to identify active compounds and obtain a deeper understanding of their mechanism, in order to acquire novel effective anticancer drugs.     

Aegle marmelos (L.) Correa inhibits the proliferation of transplanted Ehrlich ascites carcinoma in mice

The anticancer effect of hydroalcoholic extract of Aegle marmelos (AME) was studied in the Ehrlich ascites carcinoma bearing Swiss albino mice. The spatial effect of various AME administration schedules showed that six-day administration increased the survival of tumor bearing mice. The best antineoplastic action of AME was obtained when AME administered through intraperitoneal route than the oral route at equimolar dose. Administration of AME once daily for six consecutive days to the tumor bearing mice caused a dose dependent remission of the tumor at 400 mg/kg body weight, where the greatest antitumor effect was observed and the higher doses showed toxic manifestations. A 24-d lengthening in life span was observed in EAC animals treated with 400 mg/kg AME. This dose of 400 mg/kg was considered as the best dose, where the animals survived up to 43 d post-tumor-cell inoculation as against no survivors in the saline treated control group. The antitumor activity when tested for different schedules for triple administrations, the best effect was observed for 1-2-3, followed by 1-3-5 and 1-5-9 days, respectively. Stage specific evaluation of AME inhibited the increase in body weight gain in animals due to tumor development during early stages only. The AME treatment resulted in a dose dependent elevation in the median survival time (MST) and average survival time (AST) up to 400 mg/kg AME and decline thereafter. The effective dose of 400 mg of AME is 1/6th of the LD50 dose, which increased the MST and AST up to 29 and 27 d, respectively. The acute toxicity study of AME showed that the drug was non-toxic up to a dose of 1750 mg/kg b. wt. The LD10 and LD50 was found to be 2000 and 2250 mg/kg.     

瑞香狼毒抗肿瘤作用

甲硝唑致严重龟头溃烂１例刘安祥（侯马解放军第２８９医院侯马０４３０１４）患者张某某，男，３２岁，因患牙周炎在门诊治疗。应用甲硝唑（武汉制药厂，批号９４１１０７）０．４ｇ／次，牙周宁１２０ｍｇ／次，ｔｉｄ，ｐｏ。首次服用约１ｈ自感口唇麻木，全身不适，随...     

Design,synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives as potential antitumor candidate

A novel class of tetrahydroisoquinoline derivatives was designed and synthesized as antitumor agents and evaluated for their in vitro and in vivo biological activities. The antiproliferative activities of all the target compounds on HUVEC, MCF‐7, and HT‐29 were evaluated. Compared with colchicine (1.04 × 10^?2 μm ), 17d and 17e exhibited outstanding activity on MCF‐7 with IC₅₀ values 0.26 × 10^?2 μm and 0.89 × 10^?3μm in cell cytotoxicity assay. The tubulin polymerization assay demonstrated that 17d and 17e exhibited better inhibition rate. In the MCF‐7‐xenograft mouse model that was treated with 17d and 17e by intraperitoneal injection, the tumor weight was decreased at same rate with tamoxifen, and relative tumor proliferation rates were 59.48% and 41.33%, while tamoxifen was 45.08% with a daily dose of 20 mg/kg, which were demonstrated potent in vivo efficacy.     

螺旋藻多糖硫酸酯化修饰前后抗肿瘤及免疫活性的研究

比较螺旋藻多糖硫酸酯化修饰前后体内外抗肿瘤及免疫活性.采用MTT比色法研究药物在体外对人肿瘤细胞株的抑制作用,促进正常小鼠脾淋巴细胞的增殖活性以及对荷瘤小鼠NK和CTL细胞活性的影响.采用移植性肿瘤实验方法考察了药物对小鼠S180肉瘤的抑制作用.结果显示,螺旋藻多糖（NPSP）对肿瘤细胞株几乎无细胞毒作用,硫酸酯化螺旋藻多糖（SNPSP）对肿瘤细胞株具有显著的细胞毒作用,其中对SMMC-7721人肝癌细胞株抑制率最高达50%.NPSP50 mg/kg对小鼠S180肉瘤无抑制,相同剂量的SNPSP对小鼠S180肉瘤的抑制率达35.42%.NPSP具有促进脾淋巴细胞增殖作用,但对ConA和LPS诱导的脾淋巴细胞增殖反应无促进作用,SNPSP促进脾淋巴细胞增殖作用较NPSP增强,同时对ConA和LPS诱导的脾淋巴细胞增殖反应也具有明显的促进作用.NPSP和SNPSP均能促进荷瘤小鼠NK细胞和CTL细胞活性,其中SNPSP促进CTL细胞活性较NPSP增强.     

Adriamycin analogues. rationale, synthesis, and preliminary antitumor evaluation of highly active DNA-nonbinding N-(trifluoroacetyl)adriamycin 14-O-hemiester derivatives

N-(Trifluoroacetyl)adriamycin 14-valerate (AD 32), a novel DNA nonbinding analogue of adriamycin with superior experimental antitumor activity, has undergone extensive clinical trial, with documentation of antitumor activity and low toxicity in human subjects. However, poor water solubility necessitates that the drug be administered to patients by continuous intravenous infusion at high dilution in a surfactant-containing formulation, with steroid prophylaxis to protect against a chest pain syndrome associated with the vehicle. On the basis of pharmacologic considerations, the title compounds have been prepared as second-generation analogues of N-(trifluoroacetyl)adriamycin 14-valerate with improved aqueous solubility; use is made of the available carboxylic acid function to solubilize the products in dilute aqueous alkaline medium. Target compounds were made by treating N-(trifluoroacetyl)-14-halodaunorubicin (bromo or iodo) with monosodium salts of dibasic acids (malonic, succinic, glutaric, adipic, pimelic, azelaic, sebacic) in aqueous acetone. All of the products showed significant in vivo antitumor activity against the murine P388 leukemia (ip tumor, ip treatment once daily on days 1, 2, 3, and 4); most compounds were superior to the +181% increase in life span afforded by adriamycin (optimal dose 3.0 mg/kg per day), one of two drugs used as positive controls for the assays. Several of the test compounds showed highly curative activity in this system, similar to N-(trifluoroacetyl)adriamycin 14-valerate, the other positive control agent. The hemiadipate product exhibited the most desirable properties of high antitumor efficacy (86% cure rate all P388 tumor-bearing animals through four levels of a 40-70 mg/kg dose-response range), aqueous solubility (60 mg/mL in pH 7.4 phosphate buffer), and solution stability (no decomposition at 4 degrees C, 0.5% hydrolysis at 27 degrees C, over 24 h at pH 7.4).     

Isolation of isoguanosine fromCroton tiglium and its antitumor activity

This paper describes the isolation of isoguanosine from Croton tiglium L. and its cytotoxic effect against several tumor cell lines in culture and newly reports that isoguanosine has an antitumor activity against implanted S-180 ascitic tumor mice. Isoguanosine is effective at the dose of 24 mg/kg/day x 5, with T/C value of 168%. Isoguanosine inhibits the growth of S-180 and Ehrlich solid tumor in mice at the optimal doses of 96 mg/kg/day x 12 and 48 mg/kg/day x 12, with 1-T/C values of 65% and 60%, respectively.     

Antitumor effect of culinary-medicinal oyster mushroom, Pleurotus ostreatus (Jacq.: Fr.) P. Kumm., derived protein fraction on tumor-bearing mice models

Previously, we reported the in vitro anticancer and immunomodulatory effect of a protein fraction designated as Cibacron blue affinity purified protein (CBAEP) obtained from the culinary-medicinal oyster mushroom, Pleurotus ostreatus. In the present study, we investigated the in vivo antitumor potential of CBAEP in different tumor-bearing mice models and studied the detailed mechanism of tumor regression in Dalton lymphoma (DL)-bearing mice. The lethal dose (LD50) of CBAEP was found to be 55 mg/kg body weight and sublethal doses (5 mg/kg and 10 mg/kg body weight) showed a prolonged tumor survival time in DL, Sarcoma-180, and B16F0 melanoma tumor-bearing mice. Further, CBAEP reduced about 35.68 and 51.43% DL cell growth in 5 and 10 mg/kg body weight, respectively. The in vivo CBAEP treatment showed an apoptotic feature as demonstrated in morphological study and sub-G0/G1 population in cell cycle and Western blot of DL cells. CBAEP also activated immunosuppression condition in DL tumor-bearing host. It also stimulated immune cells in the presence of nonspecific immunostunulator (LPS and ConA) ex vivo as well as enhanced Th1 response with production of TNF-α, IFN-γ, and IL-2. Moreover, it activated tumor-associated macrophages and NK cells. The present findings revealed the potent antitumor property of CBAEP, which might help in developing a new anticancer drug.     

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.