Highest Nontoxic Dose Research Articles

Study of the Antiviral Activity and Toxicity of Dextrin - In Vitro Study

Objective: This study was to in vitro study of the antiviral effect of "Dextrin" on the replication of the EMCV virus in HeLa cells and toxicity of "Dextrin". Methods: For this purpose, the virus at a dose of 100 TCD50 is applied to a 24-hour monolayer of HeLa cells. The experiment is carried out under conditions of 5% CO2 saturation and 100% humidity. The virus dose used was expressed as a tissue cytopathic dose of 100 TCD50/ml. Cultivation of HeLa cells, to study toxicity, was performed on 96-well plates under conditions of 5% CO2 saturation and 100% humidity. The toxic effect of "Dextrin" on HeLa cells was studied by the degree of destruction of the monolayer and at the population level. Results: Peak levels of the virus reached after 48 hours of replication accompanied by complete destruction of the cell monolayer (7-8 cycles of replication). As follows from the graph, “Dextrin significantly” (significance is indicated by asterisks.) reduces the dose of the virus when introduced into the medium with HeLa cells to, or at the early stages of EMCV virus replication (-1,0 and 1 hour). Based on the data obtained, it was decided to use a dose of 1:100 (1%), which is the highest non-toxic dose. Conclusion: “The investigated Dextrin has an antiviral effect against the EMCV virus, when applied in the early stages of infection. This may open up the prospect of studying the antiviral spectrum of Dextrin in more future studies”.

Abstract 4039: Riluzole synergizes with paclitaxel to induce apoptosis and inhibit cell growth in triple negative breast cancer

Abstract Introduction: Systemic treatment for triple negative breast cancer (TNBC) includes paclitaxel, which works by inhibiting the breakdown of microtubules. We previously observed that riluzole, an FDA-approved drug for the treatment of amyotrophic lateral sclerosis, can inhibit TNBC proliferation, invasion, and colony formation. We now test whether riluzole can act synergistically with paclitaxel to inhibit TNBC growth and induce apoptosis in TNBC. Methods: After treatment of various TNBC cell lines with constant ratio concentrations of riluzole and paclitaxel we conducted cell proliferation transformation assays (MTT) to measure cell inhibition potential. Synergy or additivity was determined by the Chou-Talalay using Compusyn software. PARP cleavage normalized to GAPDH was also measured by Western blot to estimate apoptosis due to the riluzole-paclitaxel combination. In vivo synergy was studied using a xenograft study with MDA-MB-231, a human TNBC cell line sensitive to riluzole. Results: MTT results show that riluzole and paclitaxel work synergistically to inhibit cell proliferation in all TNBC cell lines tested, as determined by isobolograms and CI values <1. The strongest synergistic effect was observed in the cell lines SUM159, SUM149, and SUM229, where synergism occurred at Fa values as low as 0.5 (50% inhibition of cell proliferation). Measuring PARP cleavage, we demonstrated that the riluzole-paclitaxel drug combination induces greater apoptosis than does either drug alone. The significant impact of the drug combination was best demonstrated in cell lines SUM159, SUM149 and SUM229, but was observed in all cell lines tested. In the xenograft study, the highest non-toxic dose of paclitaxel (7.2 mg/kg) combined with riluzole resulted in 8/9 tumor-free mice, with a tumor growth inhibition ratio (T/C) of 0%, where <10% is considered highly therapeutic. This result was better than riluzole monotherapy (0/9 tumor-free and T/C = 99%) or paclitaxel monotherapy (4/8 tumor-free and T/C = 8%). Conclusions: Our results demonstrate that the addition of riluzole to paclitaxel results in at least additive and in many cases synergistic effects against TNBC. Our observations thus suggest that repurposing riluzole, which is an oral drug with an excellent safety profile, to add to paclitaxel to treat TNBC represents a potential strategy to improve the efficacy of adjuvant and neoadjuvant treatments for TNBC and/or reduce chemotherapy doses and toxicity in patients. Our data support the need to proceed to clinical trials to test this approach in patients. Citation Format: Miriam A. Bukhsh, Cecilia L. Speyer, Waris S. Jafry, Rachel E. Sexton, David Thomas, David Gorki. Riluzole synergizes with paclitaxel to induce apoptosis and inhibit cell growth in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4039. doi:10.1158/1538-7445.AM2017-4039

A novel lipid prodrug strategy for sustained delivery of hexadecyloxypropyl 9-[2-(phosphonomethoxy)ethyl]guanine (HDP-PMEG) on unwanted ocular proliferation

Proliferative vitreoretinopathy (PVR) is a blinding eye disease and there is no effective pharmacological measure to prevent PVR development. The difficulty comes from lack of potent antiproliferative agent and lack of sustained delivery to cover high-risk time window for PVR to develop. Lipid prodrug of PMEG, hexadecyloxypropyl 9-[(2-phosphonomethoxy)ethyl]guanine (HDP-PMEG), was prepared and was evaluated as a pharmacological adjuvant to surgical management of PVR. A dose-escalation study determined that the highest nontoxic dose for intravitreal use in pigmented rabbits was 3 µg per eye. The genotoxicity of HDP-PMEG was harnessed as a perioperative preventative measure against PVR in a rabbit eye model while the sustained intravitreal pharmacological effect was evaluated on a laser-induced fibrovascular model in rat eye. After intravitreal 3 µg, HDP-PMEG particles in the rabbit vitreous was visible for at least 6 weeks. A single 50-min intravitreal infusion of HDP-PMEG demonstrated significant inhibition of PVR formation when compared with the eyes infused with only BSS (BSS vs. HDP-PMEG: estimate = 1.14, OR = 3.1, p = .027). A single intravitreal 104 ng (equivalent to 3 µg for rabbit eye) of HDP-PMEG significantly inhibit laser-induced fibrovascular proliferation in rat eye by 55% (least square mean pixel, BSS = 4763569.5 vs. HDP-PMEG = 2148129.7, p < .0001, generalized estimating equation [GEE]). Retinal fluorescein angiography showed the odds for BSS intervened eyes to have higher-rated FA leaking grades were 38.5 times compared with HDP-PMEG treated eyes (p < .0001, GEE). Our study results indicate that single intravitreal HDP-PMEG may be a promising ocular drug delivery as a perioperative intervention to prevent PVR reoccurrence following primary surgical management.

Vanadium mediated apoptosis and cell cycle arrest in MCF7 cell line

Vanadium is a metal widely distributed in the environment. It is also a dietary micronutrient. It has shown insulin mimetic and chemopreventive properties and has been considered as an important pharmacological agent. In this study, we evaluated the apoptogenic role of vanadium on human breast cancer cell line MCF7. Exposure of MCF7 cells to vanadium led to the induction of apoptosis in a dose-dependent manner. Percentage of apoptosis was maximum (42.5%) at the highest non-toxic dose (250 microM). It was found that vanadium treatment brought about a prominent chromatin condensation, cell cycle arrest leading to apoptosis. These apoptosis based assays demonstrate that vanadium has the potential to be developed into an anti-cancer drug in the near future.

In vivo synergy combining oxaliplatin with AVE8062, a vascular-disrupting agent

13074 Background: AVE8062 is a synthetic, water-soluble compound, analog of Combretastatin A4, currently in Phase I clinical trials. It inhibits tubulin polymerization through binding to the colchicine site of tubulin. In vivo, it induces rapid tumor blood flow shutdown and necrosis, leading to tumor regressions (Proc AACR, 2002). Previously (Proc AACR, 2003), we reported a high synergy resulting from the combination of AVE8062 with either cisplatin or carboplatin in a preclinical in vivo model. We report here the combination data of AVE8062 with oxaliplatin. Methods: A 3-arm dose-response study was performed comparing the single agents and their combination. Synergy was defined as a log cell kill (lck) of at least 1 log superior to the lck of the best single agent. The AVE8062 / oxaliplatin simultaneous combination was evaluated in female BALB/c mice bearing advanced stage (250mg) SC murine colon C51 adenocarcinoma. Drugs were administered IV with 2 intermittent injections, 4 days apart. The combination arm was evaluated over 7 dose levels. Results: At the Highest nontoxic dose (HNTD - 58 mg/kg/inj), AVE8062 was found active: 0.9 lck, 1/5 partial regression (PR) and no complete regression (CR). At the HNTD (7 mg/kg/inj), oxaliplatin was found highly active [5.8 lck, 5/5 CR, no tumor free survivors (TFS)]. The HNTD for the combination (58 mg/kg/inj of AVE8062 with 7 mg/kg/inj of oxaliplatin) was well tolerated with 11.7% body weight loss at nadir. The combination was highly active over the 2 highest dose levels with TFS on day 148 post tumor implantation (4/6 TFS at combination HNTD and 6/6 TFS at 80% HNTD). A high antitumor activity was maintained at 60% HNTD (5.9 lck, 6/6 CR and no TFS). The lowest dose tested, corresponding to 1/10 of the HNTD fractions, was found active with a lck of 1.0 and no regression. Conclusions: The combination of AVE8062 with oxaliplatin was found highly synergistic (superior activity than either of the single agents alone). The combination was well tolerated with a combination toxicity index of 2, indicating that there was no overlap in host toxicity. These data provide a good rationale to perform Phase I combination trials combining AVE8062 with oxaliplatin. [Table: see text]

Toxicity of Subretinal Ribozyme to the Proliferating Cell Nuclear Antigen and 5-Fluorouracil in Rat Eyes

Purpose: To investigate the subretinal toxicity profile of the ribozyme to the proliferating cell nuclear antigen (PCNA-Rz) and 5-fluorouracil (5-FU), as well as the highest nontoxic subretinal dose of the mixture of the two agents in rat eyes. Methods: Brown-Norway rats received subretinal injections of 1 μ g, 10 μ g, and 100 μ g/μ l PCNA-Rz and 0.06 μ g/μ l, 0.3 μ g/μ l, and 1.5 μ g/μ l 5-FU in the right eyes, and the left eyes were injected with H-BSS as control. Each dose was tested on 5 eyes in a 5 μ l volume. In a second study, a combination of 5-FU (1.5 μ g/μ L) with varying 10–30–50 μ g/μ l doses of PCNA-Rz was tested in a regimen of four sequential subretinal injections. Toxicity was monitored by biomicroscopy, indirect ophthalmoscopy, electroretinography (ERG), and histology. Results: The highest nontoxic dose for subretinal PCNA-Rz was 10 μ g/μ l, whereas 100 μ g/μ l showed disturbance of pigmentation with corresponding histological changes of retinal photoreceptor loss and retinal pigment epithelium proliferation or irregularities. Subretinal injection of all three doses of 5-FU did not show any toxicity. Serial injections of a mixture of 1.5 μ g/μ l 5-FU with 10 μ g/μ l of PCNA-Rz was found to be safe in rat eyes. Conclusions: Subretinal injections of the combination of PCNA-Rz (10 μ g/μ l) and 5-FU (1.5 μ g/μ l) demonstrated to be safe in rat eyes during the course of this study, even with a multiple administration of four injections.

Effect of prostaglandin A1 in porcine cells persistently infected with classical swine fever virus.

Cyclopentenone prostaglandins are potent inhibitors of a wide variety of RNA and DNA viruses. In this report we describe that prostaglandin A1 (PGA1) potently inhibited the replication of classical swine fever virus in cultures of PK-15 cells. The highest non-toxic dose (5 microg/ml) inhibited virus yield in 99% at the initial phase of infection and in 77% in persistent infected cells. However when PGA1 was removed from persistently infected cells, the inhibition of virus replication was partially reverted.

Mutagenicity testing of (±)-camphor, 1,8-cineole, citral, citronellal, (−)-menthol and terpineol with the Salmonella/microsome assay

The essential oils and their monoterpenoid constituents have been widely used as fragrances in cosmetics, as flavouring food additives, as scenting agents in a variety of household products, as active ingredients in some old drugs, and as intermediates in the synthesis of perfume chemicals. The present study was undertaken to investigate the mutagenic potential of six monoterpenoid compounds: two aldehydes (citral and citronellal), a ketone ((±)-camphor), an oxide ( 1,8-cineole, also known as eucalyptol), and two alcohols (terpineol and (−)-menthol). It is part of a more comprehensive toxicological screening of monoterpenes under way at our laboratory. Mutagenicity was evaluated by the Salmonella/microsome assay (TA97a, TA98, TA100 and TA102 tester strains), without and with addition of an extrinsic metabolic activation system (lyophilized rat liver S9 fraction induced by Aroclor 1254). In all cases, the upper limit of the dose interval tested was either the highest non-toxic dose or the lowest dose of the monoterpene toxic to TA100 strain in the preliminary toxicity test. No mutagenic effect was found with (±) camphor, citral, citronellal, 1,8-cineole, and (−)-menthol. Terpineol caused a slight but dose-related increase in the number of his + revertants with TA102 tester strain both without and with addition of S9 mixture. The results from this study therefore suggest that, with the exception of terpineol, the monoterpenoid compounds tested are not mutagenic in the Ames test.

An Animal Model for Cidofovir (HPMPC) Toxicity: Intraocular Pressure and Histopathologic Effects

Intravitreal cidofovir has been shown to be a long acting and highly efficacious treatment for CMV retinitis; however decrease in IOP is an adverse effect. We wanted to determine the effect of cidofovir on intraocular pressure (IOP) in the guinea pig, and rabbit eye to develop an animal model of cidofovir induced ocular hypotony and to study the histopathology of this toxicity. Twenty-eight guinea pig eyes were injected with cidofovir yielding final intravitreal concentrations of 25, 200, 625 and 2000 μg ml−1. Eighteen eyes of pigmented rabbits were injected with cidofovir yielding final intravitreal concentrations of 625 and 2000 μg ml−1. A carefully calibrated low volume displacement manometer system using a micro-transducer was used to determine the IOP measurements in the guinea pig and rabbit eyes. Histology was evaluated using light and electron microscopy. Injection of 6.25 μg of cidofovir intravitreally (vitreous concentration of 25 μg ml−1) is the highest non-toxic dose in the guinea pig; the IOP was unchanged at two and four weeks after injection with this dose; histologically the eyes were normal. A single injection of 50 μg of cidofovir intravitreally (vitreous concentration of 200 μg ml−1) caused a long lasting (9.3 mmHg) decrease in IOP (approximately 50% of baseline). At this dose there were only mild and variable histologic changes in the ciliary body and the retina. Higher doses of 156.25 μg and 500 μg of cidofovir (vitreous concentrations of 625, and 2000 μg ml−1, respectively) caused moderate to severe ciliary body and retinal changes. In rabbit eyes there was a mild but statistically insignificant pressure drop with doses of 875 μg cidofovir intravitreally (vitreous concentration of 625 μg ml−1); retina was within normal limits after injection with this dose, there were mild changes in the ciliary body. There was a total destruction of ciliary body and loss of nonpigmented epithelial cells with injections of 2800 μg of cidofovir intravitreally (vitreous concentration of 2000 μg ml−1); retina was relatively well preserved. The guinea pig eye shows similar reduction in IOP and ciliary body changes as are seen in the human eye after intravitreal cidofovir and also appears to have a similar dose-response curve. However, the reduction of IOP caused by cidofovir occurs in the guinea pig eye at a concentration 40 times higher than was observed in the human eye.

Preclinical antitumor activity of CI-994.

CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma #03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (> 50 days) was tolerated with no gross toxicity. Doses > or = 90 mg/kg/injection caused lethality after 4-5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.

Therapeutic activity of CPT-11, a DNA-topoisomerase I inhibitor, against peripheral primitive neuroectodermal tumour and neuroblastoma xenografts.

The anti-tumour activity of CPT-11, a topoisomerase I inhibitor, was evaluated in four human neural-crest-derived paediatric tumour xenografts; one peripheral primitive neuroectodermal tumour (pPNET) (SK-N-MC) and three neuroblastomas. Two models, SK-N-MC and IGR-N835, were established in athymic mice from a previously established in vitro cell line. Two new neuroblastoma xenograft models, IGR-NB3 and IGR-NB8, were derived from previously untreated non-metastatic neuroblastomas. They exhibited the classic histological features of immature neuroblastoma along with N-myc amplification, paradiploidy, chromosome 1p deletions and overexpression of the human mdr 1 gene. These tumour markers have been shown to be poor prognostic factors in children treated for neuroblastoma. CPT-11 was tested against advanced stage subcutaneous tumours. CPT-11 was administered i.v. using an intermittent (q4d x 3) and a daily x 5 schedule. The optimal dosage and schedule was 40 mg kg-1 daily for 5 days. At this highest non-toxic dose, CPT-11 induced 100% tumour-free survivors on day 121 in mice bearing the pPNET SK-N-MC xenograft. For the three neuroblastoma xenografts, 38-100% complete tumour regressions were observed with a tumour growth delay from 38 to 42 days, and anti-tumour activity was clearly sustained at a lower dosage (27 mg kg-1 day-1). The efficacy of five anti-cancer drugs commonly used in paediatric oncology or in clinical development was evaluated against SK-N-MC and IGR-N835. The sensitivity of these two xenografts to cyclophosphamide, thiotepa and cisplatin was of the same order of magnitude as that of CPT-11, but they were refractory to etoposide and taxol. In conclusion, CPT-11 demonstrated significant activity against pPNET and neuroblastoma xenografts. Further clinical development of CPT-11 in paediatric oncology is warranted.

498 Evaluation of effect of the active metabolite of amifostine (AMI), WR-1065, on the cytotoxicity of anticancer drugs against human ovarian cancer

Ami protects normal but not tumor tissue from cytotoxic effects of radiation and chemotherapy. The effect of amifostine's active metabolite, the free thiol, WR-1065, on the cytotoxicity of standard anticancer drugs was tested against human A2780 ovarian cancer in vitro using the sulforhodamine B assay for viability. Dose response and IC 50 values were determined in triplicate for each drug in the presence and absence of the highest nontoxic dose of WR-1065. IC 50 values (molar cone) for the drug alone and following pretreatment with WR-I065 were: taxol 1.7 vs 1.3 × 10 −8 ; cisplatin 9.2 vs 3.1 × 10 −4 ; carboplatin 9.6 vs 8.9 × 10 −3 ; doxorubicin 5.6 vs 0.08 × 10 −4 ; mitoxantrone 7,9 vs 0.18 × 10 −6 ; 5FU 8.5 vs 8.5 × 10 −5 ; vinblastine 4.5 vs 3.3 × 10 −8 , respectively. The IC 50 differences ± pretreatment with WR-1065 were not statistically significantly different. These data expand upon previous reports showing that Ami or WR-1065 does not protect tumors from the cytotoxic effects of anticancer agents. Ami's ability to protect dose-limiting toxicity to normal tissues without protection of tumor should enhance the efficacy ratio of a variety of standard anticancer drugs.

Comparative efficacy of DMP 840 against mouse and human solid tumor models.

DMP 840 is a compound from a class of bis-naphthalimide antitumor agents that recently completed Phase I clinical trials at three North American centers and is currently undergoing Phase II testing. Preclinically, it was shown to have curative activity against a variety of human tumor xenograft models. To test DMP 840 both in vitro and in vivo for antiproliferative activity against predominantly mouse tumor models. A disk diffusion soft agar colony formation assay was used to determine the in vitro growth inhibitory activity against a selection of mouse and human tumor cell lines, and the comparable selective mouse solid tumors were used for in vivo testing. In vitro DMP 840 exhibited equal cytotoxicity for human tumors (including MX-1 directly cultured from nude mice), mouse tumors and normal cells. In vivo DMP 840 was only modestly active or inactive against the following mouse tumors: Mam 16/C, T/C = 30% (T/C = Percent Tumor Growth Inhibition); Mam 16/C/ADR, T/C = 33%; Colon 38, T/C = 9%; Panc 03, T/C = 53%; Colon 51/A, T/C = 28%; Panc 02, T/C = 52%; P388/0, 36% ILS (Percent Increased Life Span) and P388/ADR, 14% ILS. Furthermore, the antitumor activity was only observed at the highest non-toxic dose and was associated with a large body weight loss. In contrast, the agent was highly active against the human breast tumor MX-1 implanted subcutaneously in either athymic nude or SCID mice (Nudes: T/C = 0%; 1/5 cures; SCIDS: T/C = 0%; 5/5 cures). Although there was no selective cytotoxicity in our clonogenic assay for human versus mouse tumor cell lines, selective activity in vivo for human xenograft tumors was noted. Overall, this compound is rather unique in its differential degree of in vivo activity for human versus mouse tumors. Phase II trials, which are ongoing, will help determine if the preclinical in vivo selective activity of DMP 840 translates to clinical activity in man.

Phase I study of the novel distamycin derivative tallimustine (FCE 24517)

Tallimustine, a benzoyl nitrogen mustard derivative of the antiviral agent distamycin A, is a new alkylating agent which binds to A-T rich regions of DNA in the minor groove producing highly sequence-specific alkylations. Its main preclinical features are a significant antitumor activity in animal models and a lack of cross-resistance in vitro and in vivo with L-PAM. Myelotoxicity was dose-limiting in animals, with a more than 100-fold difference in bone marrow sensitivity between mice and dogs. Forty adult patients (pts) with solid malignancies were entered in the study. The drug was administered as an IV bolus every 4 weeks. CBC was repeated twice a week and serial assessments of renal function were performed in the week following the first cycle. From the starting dose of 50 micrograms/m2, corresponding to 1/3 of the highest non-toxic dose (HNTD) in dogs, there were increases through 10 dose levels, with reliance only on the features of the myelotoxicity observed. The main toxic effect was neutropenia which was dose-limiting, selective and short-lasting. Only previously-untreated pts received doses of 750 micrograms/m2 or more, with grade 4 neutropenia occurring in > or = 75% of the cycles. The maximally tolerable dose (MTD) was defined as 1250 micrograms/m2, with 3 of 3 pts developing febrile neutropenia requiring IV antibiotics. A platelet count of < 100 x 10(3)/microliters was observed in only one pt. Bone marrow aspiration performed in selected pts on days 8 and 15 confirmed a highly selective impairment by tallimustine of the myeloid lineage, with rapid recovery of the proliferative compartment. Pharmacokinetic studies performed at 1000 micrograms/m2 and 1250 micrograms/m2 showed a rapid fall of the plasma levels within the first 2 hours with drug concentrations between 100 ng/ml and 400 ng/ml within the first hour. A partial response of 4 months' duration was reported in one previously-untreated pt with cutaneous recurrences of malignant mesothelioma. The report of some antitumour efficacy, the high selectivity of neutropenia, the lack of significant non-hematological toxic effects and the occurrence of detectable but still low plasma drug concentrations suggest that further clinical evaluation of higher doses of tallimustine in combination with colony-stimulating factors would be justified.

Antitumor Effect of the New Rhodium(II) Complex: Rh2(Form)2(02CCF3)2(H20)2(Form = N,N’-di-p-tolylformamidinate)

The new rhodium(II) complex Rh2(Form) (O2CCF3)2(H2O)2 (Form = N,N'-di-p-tolyl formamidinate) was evaluated for its toxicity on the rat and for its efficacy against two tumors of this animal: the Yoshida ascites sarcoma and the T8 sarcoma of Guérin. The rhodium(II) formamidinate shows very low toxicity: in fact 150 mg/kg (the highest quantity of drug soluble in 4 ml of dimenthyl sulfoxide) is not toxic for rats. We were unable to establish the lethal dose or the highest nontoxic dose since larger mounts of complex require a dose of dimethyl sulfoxide (DMSO) that is itself toxic and the compound is insoluble in other solvents such as water or Tween. Doses of rhodium(II) formamidinate, varying from 3 to 30 mg/kg, were administered once by i.p., i.v., i.m. and intratumor (i.t.) route from 1 to 7 days after i.p. injection of 10(6) Yoshida ascites sarcoma cells and subcutaneous (s.c.) implantation of approximately 300 mg (corresponding to 2-3 x 10(7) living tumor cells) of T8 sarcoma of Guérin. The compound is active when administered i.p. 24 hours after Yoshida ascites sarcoma at the smallest dose tested (3 mg/Kg), increasing the average life span of 62.3% and allowing the survival of 50% of the rats. It is also active when administered i.p. at the highest dose tested (30 mg/Kg) 7 days after tumor cell challenge, increasing the average life span in 43.8% and allowing survival in 20% of the rats; it is not active after i.v. or i.m administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Final report of the phase i trial of the hypoxic cell radiosensitizer SR 2508 (etanidazole) radiation therapy oncology group 83-03

In a Phase I trial SR 2508 was administered by rapid intravenous infusion to 102 patients receiving radiation therapy. The dose-limiting toxicity was peripheral sensory neuropathy (PN) which was related to the cumulative dose administered. The highest single daily dose, 3.7 g/m 2, was tolerated without toxicity. The lowest cumulative toxic dose was 21.6 g/m 2, and the highest non-toxic dose was 40.8 g/m 2. Grade 1 neuropathies were mild and self-limited; grade 2 neuropathies were long-lasting and debilitating. In a retrospective analysis, the risk of developing neurotoxicity was related to the cumulative drug exposure calculated by the area-under-the-curve (AUC) of plasma concentration versus time. There was an increased incidence of neuropathy in patients with a cumulative AUC of ≥36 mM-hr. At a total dose of 34 g/m 2 over 6 weeks, the incidence of Grade 1 neuropathy was approximately 30%; no grade 2 neuropathy occurred at this dose and schedule. Additional toxicities observed included nausea and vomiting (6%), skin rash (4%), and transient arthralgias (3%). One patient had transient abnormalities in liver function tests of unknown etiology. (In a more recent Phase II trial neutropenia has been observed which may be related to SR2508). Approximately three times more SR 2508 is tolerable compared to misonidazole, and it appears that severe neuropathy can be avoided by monitoring individual patient pharmacokinetic parameters. Evaluation of the efficacy of this hypoxic cell sensitizer is in progress.

Disposition and metabolism of the antitumor glycoside phyllanthoside in mouse and beagle dog.

Phyllanthoside is a naturally occurring glycoside with activity against IP transplantable murine tumors. Phyllanthoside administered IV, to mice at a nontoxic dose of 16 mg/kg could not be detected in blood or plasma even 30 s after administration. There was rapid formation of a less polar metabolite, which disappeared with a half-life of about 10 min. When phyllanthoside was administered as an IV bolus to beagle dogs at doses of 0.1, 0.5, and 3.0 mg/kg the mean half-life of phyllanthoside elimination from plasma was 1.3 min and total body clearance 85.8 ml min-1 kg-1. A second phase of elimination was seen but could not be accurately defined. Only trace amounts of the less polar metabolite were detected in dog plasma. Infusion of phyllanthoside to beagle dogs at doses of 0.5 and 3.0 mg/kg over 70 min gave values for an initial half-life of 0.3 and 0.6 min, a terminal half-life of 99.4 and 16.5 min, and a total body clearance of 11.2 and 49.2 ml min-1 kg-1, respectively. The highest nontoxic dose of phyllanthoside in dog was 0.1 mg/kg, while doses of 0.5 mg/kg and 3.0 mg/kg resulted in ataxia and death of the dog. There was no difference in toxicity to dog according to whether phyllanthoside was given by IV bolus or continuous infusion. Isolated hepatocytes from rat metabolized phyllanthoside at a rate of 4.4 micrograms/min per 10(6) cells to form the less polar metabolite. Coculture with isolated hepatocytes decreased the cytotoxicity of phyllanthoside to A204 human rhabdomyosarcoma cell line growing in soft agarose. It is suggested that rapid metabolism of phyllanthoside in mouse as against dog might account for the lower toxicity of phyllanthoside in mouse, and might also account for the reported poor antitumor activity of IV-administered phyllanthoside in the mouse.

Initial report of the phase I trial of the hypoxic cell radiosensitizer SR-2508

From March 15, through August 31, 1983, 37 patients have been entered on the RTOG Phase I trial of SR-2508. The drug was given intravenously three times weekly for three weeks. The starting total dose was 11.7 g/m 2 and the highest total dose given was 32 g/m 2. The lower lipophilicity of SR-2508 has produced the expected decrease in terminal half-life (5.4 hrs) of drug excretion and increase in total drug excreted unchanged in the urine (71%) compared to misouidazole or desmethylmisonidazole. The maximum single dose (3.7 g/m 2) administered was well tolerated. With multiple doses peripheral neuropathy is the dose-limiting toxicity. The lowest cumulative dose producing toxicity was 21.6 g/m2, the highest non-toxic dose was 29.7 g/m 2. The use of an individual patient's drug exposure as measured by the area under the curve of drug concentration vs time may be an excellent predictor of toxicity. This may eventually permit individualization of dose and prevention of serious toxicity. A single dose of 2 g/m 2 will produce a tumor concentration of drug (approx. 100 μg/ml) that will yield a sensitizer enhancement ratio of 1.5 to 1.7. Using a starting dose of 2 g/m 2 three times weekly, patients are now being studied on a five week drug schedule to further evaluate predictability of drug toxicity in preparation for clinical trials of drug efficacy.