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Sloth bears are non-carnivorous yet they attack more people than any other bear. They often stand up and charge explosively if a person mistakenly gets too close. Here, we argue that their aggression toward humans is an extension of their behavior toward tigers, which are their only natural predator. Interactions between sloth bears and tigers have not previously been studied because scientists have rarely observed such events. We collected and examined 43 videos or photo documentations of sloth bear-tiger interactions posted on the internet or social media from 2011 to 2023, mainly by tourists visiting tiger parks in India. We observed that sloth bears were most likely to stand up and charge if they first became aware of the tiger at close range (<3 m away). This aggressive-defensive strategy, intended to dissuade the tiger from attacking, appeared to be successful, in that 86% of interactions ended with no contact, whereas four (9%) culminated in the bear's death. We propose that a myrmecophagous diet led to this species' aggressive behavior: (1) their long, blunt front claws, well adapted for digging termites and ants, hamper their ability to climb trees for escape, and (2) they walk with their head down focused on scents underground, and make considerable noise digging and blowing soil, enabling tigers to approach quite closely without being detected. Sloth bears have coexisted with tigers or other (now extinct) large felid predators for their entire evolutionary history. Whereas their aggressive behavior has served them well for millions of years, more recently, people's fear of and retaliation against sloth bears represents a major threat to their survival. Understanding how sloth bears react to tigers provides guidance for reducing attacks on humans, thereby contributing to sloth bear conservation. Our investigation was made possible by passive citizen scientists, who unknowingly collected valuable data., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

Sloth bears behave aggressively toward humans when threatened and are among the most dangerous wildlife in India. Safety messaging for those who live in sloth bear country must be accurate to be effective, and messaging may need to be modified to account for regional differences in human-bear relationships. The timing of sloth bear attacks on the Deccan Plateau of Karnataka, both by season and by time of day, deviated enough from those reported in other areas such that it warranted further investigation. We compared data from eight studies of human-sloth bear conflict from across the Indian subcontinent and explored possibilities as to why differences exist. Seasonally all studies reported that human-sloth bear conflict was highest when human activity in the forest was greatest, though the season of highest human activity varied significantly by region (χ 2  = 5921, df = 5, P < 0.001). The time of day that the majority of attacks occurred also varied significantly by region (χ 2  = 666, df = 5, P < 0.001), though human activity was relatively consistent. We speculated that the rate of day attacks on the Deccan Plateau was lower due to the reduced probability of encountering a sleeping bear as they are concealed and secure in shallow caves. Additionally, the rate of attacks was significantly higher at night on the Deccan Plateau because people often to work into nighttime. We concluded that slight differences, or different emphasis, to bear safety messaging may be necessary on a regional basis to keep the messaging accurate and effective., (© 2022. The Author(s).)

Exotic invasive species can directly and indirectly influence natural ecological communities. Cheatgrass (Bromus tectorum) is non-native to the western United States and has invaded large areas of the Great Basin. Changes to the structure and composition of plant communities invaded by cheatgrass likely have effects at higher trophic levels. As a keystone guild in North American deserts, granivorous small mammals drive and maintain plant diversity. Our objective was to assess potential effects of invasion by cheatgrass on small-mammal communities. We sampled small-mammal and plant communities at 70 sites (Great Basin, Utah). We assessed abundance and diversity of the small-mammal community, diversity of the plant community, and the percentage of cheatgrass cover and shrub species. Abundance and diversity of the small-mammal community decreased with increasing abundance of cheatgrass. Similarly, cover of cheatgrass remained a significant predictor of small-mammal abundance even after accounting for the loss of the shrub layer and plant diversity, suggesting that there are direct and indirect effects of cheatgrass. The change in the small-mammal communities associated with invasion of cheatgrass likely has effects through higher and lower trophic levels and has the potential to cause major changes in ecosystem structure and function.

The goal of many metabolomic studies is to identify the molecular structure of endogenous molecules that are differentially expressed among sampled or treatment groups. The identified compounds can then be used to gain an understanding of disease mechanisms. Unfortunately, despite recent advances in a variety of analytical techniques, small molecule (<1000 Da) identification remains difficult. Rarely can a chemical structure be determined from experimental "features" such as retention time, exact mass, and collision induced dissociation spectra. Thus, without knowing structure, biological significance remains obscure. In this study, we explore an identification method in which the measured exact mass of an unknown is used to query available chemical databases to compile a list of candidate compounds. Predictions are made for the candidates using models of experimental features that have been measured for the unknown. The predicted values are used to filter the candidate list by eliminating compounds with predicted values substantially different from the unknown. The intent is to reduce the list of candidates to a reasonable number that can be obtained and measured for confirmation. To facilitate this exploration, we measured data and created models for two experimental features; MS Ecom₅₀ (the energy in electronvolts required to fragment 50% of a selected precursor ion) and HPLC retention index. Using a data set of 52 compounds, Ecom₅₀ models were developed based on both Molconn and CODESSA structural descriptors. These models gave r² values of 0.89 to 0.94 depending on the number of inputs, the modeling algorithm chosen, and whether neutral or protonated structures were used. The retention index model was developed with 400 compounds using a back-propagation artificial neural network and 33 Molconn structure descriptors. External validation gave a v² = 0.87 and standard error of 38 retention index units. As a test of the validity of the filtering approach, the Ecom₅₀ and retention index models, along with exact mass and collision induced dissociation spectra matching, were used to identify 1,3-dicyclohexylurea in human plasma. This compound was not previously known to exist in human biofluids and its elemental formula was identical to 315 other candidate compounds downloaded from PubChem. These results suggest that the use of Ecom₅₀ and retention index predictive models can improve nontargeted metabolite structure identification using HPLC/MS derived structural features.

The carbon-hydrogen bond dissociation enthalpy (BDE) concept is evaluated as a potential computed indicator of stability of pharmaceutical drug substance candidates - specifically for oxidative stability of these molecules. Computational methods are discussed. Accuracy and validity of the methods are evaluated. BDEs are computed for several well-known molecules, for which stability and degradant identification information is known. Anecdotal correlations are noted between the lowest BDE energies of familiar molecules (sertraline, ezlopitant and related structures, ziprasidone, trovafloxacin, and varenicline), the sites of oxidative lability on these molecules and the identities of oxidative degradants. A low BDE may correlate in general with a reactive site on a molecule, not just an oxidatively susceptible one., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Electrospray mass spectral observation directly on a sample of a derivatized protein, such as porcine somatotropin (pST), affords a method for evaluating the degree of substitution of this protein. Derivatization of the lysine residues and the terminal amino residue here by formation of a Schiff base with a small aromatic aldehyde (in this case, o-vanillin) affords stabilization of the protein so that it may be used in a controlled release veterinary pharmaceutical formulation. This method permits direct observation of substitutions, optimization of manufacturing procedures for producing a commercial product, and permits quality evaluation of material.

A multifaceted approach was successfully used to identify three of four unknown degradants in degraded low dose tablets. Accelerated solvent extraction (ASE) was found to be an invaluable tool in this multifaceted approach. ASE was capable of extracting four individual degradants of an active pharmaceutical component from 10 tablets into 15 mL of solvent with approximately 100% recovery for each degradant. Using ASE instead of manual extraction led to the extraction and isolation of the degradants in 1 day instead of 7 days. One of the degradants was extracted by ASE, isolated by semi-prep HPLC, and identified by LC-MS and NMR spectroscopy. The structures of two of the remaining three degradants were confirmed by synthesis of authentic samples, while the fourth degradant is yet to be identified.

A multidisciplinary team approach to identify pharmaceutical impurities is presented in this article. It includes a representative example of the methodology. The first step is to analyze the sample by LC-MS. If the structure of the unknown impurity cannot be conclusively determined by LC-MS, LC-NMR is employed. If the sample is unsuitable for LC-NMR, the impurity needs to be isolated for conventional NMR characterization. Although the technique of choice for isolation is preparative HPLC, enrichment is often necessary to improve preparative efficiency. One such technique is solid-phase extraction. For complete verification, synthesis may be necessary to compare spectroscopic characteristics to those observed in the original sample. Although not widely practiced, an effective means of getting valuable structural information is to conduct a degradation study on the purified impurity itself. This systematic strategy was successfully applied to the identification of an impurity in the active pharmaceutical ingredient 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-[4-(1-hydroxy-1-methyl-ethyl)-furan-2-sulphonylurea. Identification required the use of all of the previously mentioned techniques. The instability of the impurity under acidic chromatographic conditions presented an additional challenge to purification and identification. However, we turned this acidic instability to an advantage, conducting a degradation study of the impurity, which provided extensive and useful information about its structure. The following discussion describes how the information gained from each analytical technique was brought together in a complementary fashion to elucidate a final structure.

Several chromanol drug substance candidates exhibit unconventional behavior under the soft ionization conditions of fast atom bombardment and electrospray ionization in the mass spectrometer. Under FAB, these compounds produce radical cation molecular ions rather than protonated molecular ions. Similarly, under acidic mobile phase conditions in an electrospray LC-MS experiment, they produce radial cation molecular ions. Upon changing to a neutral, ammonium acetate-containing mobile phase, the molecular ion species is an ammonium adduct. The two example compounds behave conventionally under negative ion detection, both being free carboxylic acids and forming abundant [M - H](-). Examination of structural analogs indicates that the chromanol, methoxyl and chroman compounds behave this way. Oxidation to a chromanone causes formation of a conventional [M + H](+). Oxidation to a chromene produces even more complex behavior-namely a mixture of [M - H](+), M(+') and [M + H](+). We propose that, for these compounds, elimination of a valence electron to form the radical cation is the more energetically favored reaction than attachment of a proton.

CP-93,393 is a drug candidate at Pfizer. Flow-injection analysis-mass spectrometry (FIA-MS) was used to monitor reaction completion for CP-93,393 reaction mixtures. FIA-MS provides essentially instantaneous results, is relatively simple to operate, and is a universal system that can be used to monitor any reaction as long as the product has a molecular weight that differs from the molecular weights of the reactants. The mass spectrometer for these studies employed atmospheric pressure chemical ionization. Samples were introduced into the mass spectrometer with a flowing stream of solvent.

An orthopedic instrument, the Shutt Suture Punch System, has allowed rapid (less than 1 minute) and safe introduction of the suspending suture through the sacrospinous ligament, especially in the morbidly obese patient. Residents-in-training have performed the sacrospinous vaginal suspension on 30 patients without complications. The remaining aspects of the operation are unchanged.

Femoral gland secretions were collected from 21 captive adult male green iguanas (Iguana iguana) in Orotina, Costa Rica, and San Diego, California, during the breeding (November) and nonbreeding (March) seasons. Lipids were extracted with methylene chloride, weighed, separated by thin-layer chromatography, and analyzed by gas chromatography-mass spectrometry. Free and esterified C14-C26 fatty acids, 5β-cholestan-3α-ol (epico-prostanol), cholest-5-en-3β-ol (cholesterol), cholest-5-en-24-methyl-3β-ol (campesterol), cholesta-5,22-dien-24b-ethyl-3β-ol (stigmasterol), cholesta-8,24(5α)-dien-4,4,14α-trimethyl-3β-ol (lanosterol), cholest-5-en-24-ethyl-3β-ol (β-sitosterol), and two uncharacterized sterols were indicated. More lipids were recovered from femoral gland secretions obtained during the breeding than the nonbreeding months, indicating that secretion deposits may be more detectable during the mating season.

Beef strip loins were packaged and stored for up to 28 days at 3°C in high-oxygen barrier film under vacuum and in 100% CO(2), 40% CO(2)/60% N(2) and 20% CO(2)/80% O(2). As storage progressed, loins packaged and stored in 20% CO(2)/80% O(2) developed strong off-odors. 1-hexene, methyl thiirane, ethyl acetate, benzene and 1-heptene were detected in these packaged loins beginning at 7 to 14 days of storage. With the exception of 1-hexene, these compounds were not consistently detected in loins stored in vacuum, in 100% CO(2), or in 40% CO(2)/60% N(2), and these packaged loins developed much less off-odor during storage than loins packaged and stored in 20% CO(2)/80% O(2). A large number of volatile compounds from the headspace of the packaged loins originated from the packaging material. Lactobacillus plantarum became the dominant flora on loins stored under vacuum and under 40% CO(2)/60% N(2) while Leuconostoc mesenteroides subsp. mesenteroides predominated in loins stored in 100% CO(2). Pseudomonas putida eventually dominated on loins stored in 20% CO(2)/80% O(2)., (Copyright © 1991. Published by Elsevier Ltd.)

Twenty-eight patients with colon carcinoma metastatic to the liver were treated with continuously infused intra-arterial 5-fluorouracil deoxyriboside (5-FUdR) and cyclical whole-liver radiation (2000-3000 rad). Survivorship ranged from 25 days to almost 4 years and was a clear function of the extent of liver dysfunction at the time of initiation of this treatment. Difficulties in establishing the objective complete response rates in patients with minor imaging abnormalities were frequently noted. Both extracorporeal and permanently implanted arterial infusion devices have been employed, the results favoring the internal infusion units. Under ideal circumstances (early treatment, disease limited to the liver, and a permanent indwelling pump), a median survivorship of approximately 2 years can be projected with a significant number of patients rendered free of progressive cancer in the liver for months to years. The dose-limiting feature of this approach is treatment-related to hepatitis, which proved lethal in one of 28 patients thus far treated. Preclinical studies on the original and reduction of drug- and x-ray-induced liver toxicity should have high research priority.

The scent gland secretions of Dumeril's ground boa (Acrantophis dumerili), pooled from two adult males and a female, were analyzed by gas chromatography-mass spectrometry. 2-Hydroxy-propanoic acid, hexadecanoic acid, cis-9-octadecenoic acid, octadecanoic acid, cholesterol, and 5-cholesten-3-one were indicated. These results are compared with those obtained in analyses of the scent gland secretions of other snakes.

We have studied 21 patients infused for 72 hours with 5-Fluorouracil (5-FU) at progressive doses combined with hyperfractionated radiation. The schedule was chosen as being one capable of inducing 5-FU radiosensitization (RS). All patients were started at a daily 5-FU dose of 40 mg/kg/24 hours; doses were then escalated with each subsequent treatment cycle to limiting toxicity or until taken off study. Patients received between one and six infusion cycles. Every treatment cycle included coincident hyperfractionated radiation to various body areas including the abdomen, chest, and head and neck region. Radiation fractionation was invariant; 1,000 rad were delivered in four equal fractions. Two fractions of 250 rad each were given on days 1 and 2 of each three day 5-FU cycle, i.e. at approximately 0, 8, 24, and 32 hours into the drug infusion. Patients were followed for toxicity; serum 5-FU concentrations were determined using a high pressure liquid chromatographic assay. 5-FU clearances were calculated from the mean serum drug levels and the infused drug dose. The toxicity spectrum was not found to be significantly different from infused drug alone in this dose range save when the head and neck region received coincident irradiation. In that region the two anticipated toxicities combined in what appears to be a synergistic fashion to enhance mucositis. Most toxicities including gastrointestinal and bone marrow appeared dependent on the mean serum 5-FU level as did mucositis itself. 5-FU clearance was found to be non-linear in this dose region but did not appear influenced by radiation to any part of the body. This study shows that 72-hour infused 5-FU can be combined with external beam radiation and will produce reasonably predictable toxicity patterns which depend on the region of the body being irradiated. 5-FU toxicity correlates with mean serum drug level which is itself dependent on 5-FU clearance. Minor variations in 5-FU clearance therefore probably contribute to the natural range found in the dose-response relationship for infused 5-FU toxicities. Future studies should integrate this understanding of 5-FU pharmacokinetics into treatment regimens. The combination of infused 5-FU and coincident radiation appears useful in treating several tumor types, particularly squamous and squamous-like cancers. However, further scheduling and radiation fractionation studies are desirable to optimize 5-FU RS in man and to quantify late effects.

HT-29 human colon tumor cells growing as spheroids have been evaluated as a model system for measuring the response of human colon tumor cell to antineoplastic agents. HT-29 cells have been capacity to form spheroids up to 1 mm or more in diameter when grown in spinner culture. The multicellular HT-29 spheroids develop hypoxic centers reflecting the cellular conditions found in human cancer treatment, i.e., nutritionally deficient hypoxic cells that are felt to be a significant source of both radiation and chemotherapy clinical treatment failures. Spheroids of increasing size were radiated and then dispersed into single cells for colony survival assay. Compared with irradiated single cell suspensions, the spheroid cells demonstrated a significant increase in radioresistance. Growing spheroids developed a complex radiation survival curve which was variable with respect to size of the spheroid. The drug 5-Fu was studied to examine in a preliminary fashion its interaction with these resistant cell fractions. In direct cytotoxicity assay, 5-fluorouracil (5-FU) exhibited both cytotoxic and cytostatic effects when the drug was present at a concentration greater than 0.4 microgram/ml. The interaction of 5-FU with x-rays in the HT-29 spheroids was complex and dependent on the type of assay employed (spheroid size versus clonogenicity). The effect of allopurinol, an agent that protects cells from 5-FU toxicity was examined. Allopurinol at a concentration of 100 microgram/ml was found to protect these human colonic carcinoma cells from the cytotoxic effects of 5-FU under conditions resembling those found in vivo. Overall, this HT-29 spheroid system appears to b an interesting model for studying a variety of drug/x-ray interactions in vitro and may prove capable of answering specific questions of preclinical and clinical relevance.

We have studied the pharmacology of iv and oral tegafur (FT) and compared the results with similar studies using continuously infused 5-FU. All patients received daily abdominal irradiation as well as FT. In eight patients receiving 1.0 g/m2 of iv FT, serum FT levels were essentially the same as those in five patients receiving the same dose of oral FT. Oral FT appeared well-absorbed, even with abdominal irradiation. The mean serum FT achieved on a daily basis was a linear function of the oral FT dose between 1.0 and 2.5 g/m2 and was consistently about 1000-fold higher than the resultant 5-FU level. The major FT metabolite, dehydro-FT (DHFT), was persistently present at about ten times the 5-FU level. Because of their long half-lives, both FT and DHFT accumulate during continuous therapy. When the mean serum 5-FU levels with oral FT were compared to those found during continuous 5-FU infusions, we found that oral FT was the equivalent of low-level 5-FU infusion. Oral FT at 1.0 g/m2 was the equivalent of about 11.5 mg/kg/24 hours of 5-FU, increasing to about 17.5 mg/kg of 5-FU for oral FT at 2.5 g/m2. The pharmacologic properties of FT appear to dictate its most useful schedule (continuous oral dosing in multiple doses) and explain why FT alone is not ideal as a 5-FU pro-drug. In addition, insight into the pharmacokinetic limitations of FT also suggests means by which its usage may be improved, including its potential application as a radiosensitizer.

We have treated 24 patients with squamous carcinoma of the head and neck and advanced regional (N2-3) disease. The regimen consisted of 3 cycles, each of 28 days. Cyclophosphamide (1 gm/m2 I.V.) was given on day 1, bleomycin (15 u I.M.) on days 2, 4, 9 and 11, and ionizing radiation (60Co, 180 rad/fraction) days 1-5, and 8-12. No therapy was given on days 13-28. After three cycles of therapy, 13 patients had a complete response; following further therapy (surgery, interstitial or external beam radiation), 16 patients were free of disease. However, remissions were not durable and 11/16 patients recurred loco-regionally with a median time to recurrence of 5 months; most (7/11 also developed distant metastases. These patients have biologically aggressive disease and may have a worse prognosis than patients who are Stage IV based on a T4 primary lesion only.

Inhibition of acetylcholinesterase activity by Al3+ has been examined by initial velocity kinetics and by a first-order kinetic method. Both methods yield an inhibition constant of approx. 1.7 mM at 0.1 M ionic strength. The initial velocity study indicates a noncompetitive mechanism of inhibition by Al3+. Inhibition at 10 mM ionic strength shows a Ki of 0.03 mM. Evaluation of the ionic strength dependence concurs with the results of Nolte et al. (Biochemistry 19 (1980) 3705). An effective charge in the binding site of -9 predicts the ratio of inhibition constants at high and low ionic strength. Extrapolation to zero ionic strength gives a Ki0 = 0.34 microM.

The results of 51 patients with metastatic spinal cord compression were analyzed. There were seven paralyzed patients, three received radiotherapy (RT) alone and four received laminectomy (L) + RT. No patient regained any motor function. Of six ambulatory patients, half received RT and half L + RT. All remained ambulatory after the treatment. Of 38 paraparetic patients, 20 underwent L + RT. Their complete, partial and nonresponse (CR, PR, NR respectively) rates were 25%, 60% and 15%, respectively. This result was clearly better than 18 other patients treated by RT alone of which only 22% regained ambulation (CR = 22%) while 67% were NR and 11% had a PR. In this series combined modality therapy appears better in paraparetic patients. Five patients with radiosensitive tumors all had CR/PR whether treated by RT or L + RT. Patients with epithelial tumors treated by L + RT had a PR (CR + PR) of 71% while RT alone gave only 25%. On the basis of this analysis we conclude: (1) ambulatory patients respond satisfactorily to RT alone; (2) paraparetic patients with radiosensitive tumors do well with RT alone while such patients with epithelial tumors merit L + RT; but (3) paraplegic patients rarely benefit from either modality; (4) pain control appears a useful measure of minimally adequate radiation dose in individual patients.

A continuous spectrophotometric procedure is presented for the measurement of the kinetic properties of acetylcholinesterase (EC 3.1.1.7) with its natural substrate, acetylcholine. The procedure is based upon the production of stoichiometric quantities of H+ upon hydrolysis of substrate. The spectrophotometric reporter is the pH indicator dye, phenol red and the procedure yields continuous time courses for hydrolysis of substrate. Further, this phenol red system and an adaptation of the Ellman et al. (1961, Biochem. Pharmacol. 7, 88-95) procedure for acetylthiocholine as substrate, are described as a rapid screening technique for reversible competitive and noncompetitive inhibitors of acetylcholinesterase activity. The methods are illustrated by determinations of KI for edrophonium, decamethonium and Al3+.

An equimolar mixture of DL-[alpha-2H]- and DL-[alpha-13C]mandelate, when incubated with mandelate racemase (EC 5.1.2.2), shows conversion of singly labeled mandelate to unlabeled mandelate, due to solvent exchange of the alpha proton, while the level of doubly labeled mandelate remains at a constant low level. Similarly, an equimolar mixture of unlabeled and DL-[alpha-2H,alpha-13C]mandelate, when incubated with the enzyme, shows conversion of doubly labeled mandelate to singly labeled mandelate, due to solvent exchange, while the level of unlabeled mandelate remains constant at 50%. Incubation of an equimolar mixture of DL-[alpha-3H]mandelate and DL-rho-chloromandelate. These results indicate that mandelate racemase does not catalyze an intermolecular proton transfer to achieve racemization. These data are necessary, but not sufficient, results to indicate that mandelate racemase operates via a one-acceptor mechanism, in which the proton abstracted from one stereochemical face of a substrate molecule is returned to the opposite face of the same carbon of the substrate molecule.

Eighteen patients with advanced epithelial cancers of the head and neck region were studied for their tolerance and response to combined cycles of 120-hour infused 5-fluorouracil (5-FU) and external-beam radiation therapy. 5-FU infusions were given under conditions where radiosensitization would be expected at the higher infusion doses. Coincident radiation treatments were given as four sequential daily fractions of 250 rad each administered during days 1 through 4 of each five-day infusion cycle. The patients were rested for at least nine days after each cycle or longer until toxicity was resolved. The regimen was then repeated in each patient for a total of five treatment cycles. Thereafter therapy was consolidated, usually by boost radiation without drug. In sequential patient subsets the infusion load was progressively escalated in a phase I format. The complete response rate for stage IV patients was 75% with survival benefit compared to prior results. 5-FU dose-dependent combined modality loco-regional toxicity was demonstrated without significant enhancement of systemic toxicity of any form; 5-FU dose-dependent enhanced responsiveness and survival benefit is also suggested. Further scheduling and response studies of 5-FU under radiosensitizing conditions appear warranted.

We have treated 11 patients with squamous cell anal carcinoma using a regimen of repeated cycles of 120-hour infused 5-FU (25 mg/kg/24 hours) and x-rays. Total radiation doses were between 3000 (palliative) and 4750 (curative) rads. Unlike all other equivalent combined-modality studies, no alkylating agent or drug other than 5-FU was used. With follow-up between 1 and 4 years, there has been only one local recurrence (coincident with terminal disseminated disease in a stage III patient treated palliatively). All other patients have maintained local control. Inclusion of alkylating agents (eg, mitomycin) in this approach can be questioned if the patient is willing to accept somewhat greater acute but reversible toxic effects.

We have treated 15 patients with advanced gastrointestinal carcinoma with a cyclical regimen of combined Ftorafur (N1-((2-furanidyl-))-5-Fluorouracil, a 5-FU pro-drug) and external beam radiation. The Ftorafur (FT) was administered orally in daily doses of between 1.0 and 2.5 g/m2/day in 3 divided doses in a Phase I format. The drug was given daily for 5 days along with conventional X ray treatment portals and daily radiation doses of 250 rad on each of the first 4 days of each treatment cycle. The patients were then rested for a minimum of 10 days or until all significant side effects had passed. The total number of 1,000 rad cycles and radiation dose were dictated by tolerance and by normal organ dose limitations. The most common toxicity in general, and the most common limiting toxicity was nausea and vomiting, in contrast to oral FT alone where diarrhea is more prominent. Stomatitis was seen only once and no other form of serious toxicity was encountered. Two-thirds of the patients responded in subjective terms (pain relief). There was 1 partial response to FT alone (pulmonary metastases outside the treatment field). The sole patient whose treatment field was outside the abdomen (chest portals for esophageal carcinoma) developed pneumonitis which contributed to his death. No other delayed effects were noted. Serum FT levels were related to the ingested dose and in the microgram range while serum 5-FU levels were in the nanogram range indicating slow decomposition of FT into 5-FU. The therapy was reasonably well tolerated at doses of 2.0 g/m2/day or lower with abdominal radiation. FT offers the potential for replacing intra-venous infused 5-FU as a clinical radiosensitizer.

Daily 24-hour serum levels of ftorafur (FT), 5-FU, and a major FT metabolite, dehydroftorafur (DFT), were monitored by high-performance liquid chromatography as part of a phase I study designed to evaluate FT as a radiosensitizing 5-FU pro-drug in patients with advanced gastrointestinal cancers. At a daily iv bolus FT dose of 1.0 g/m2, 5-FU was not detected in serum concentrations above the reliable assay limits of approximately 25 ng/ml; FT did not generate the extracellular (serum) 5-FU concentrations required for sensitization by 5-FU per se. DFT was present in every patient serum tested and was confirmed to be a metabolite of FT by in vitro conversion to 5-FU. Chemical ionization solid-probe mass spectrometry of the DFT metabolite indicates the dehydro FT structure proposed by other researchers. In six of eight patients monitored, a consistent relationship was noted between serum levels of FT and DFT.

Thirty patients with locally advanced nonresectable non-small cell bronchogenic carcinoma were studied for tolerance and response to 120-hour continuously infused 5-FU (IFU) combined with chest x-ray therapy. The IFU was escalated in patient groups from 20 to 35 mg/kg/24 hours. Radiation was also escalated in patient subsets from 200 to 400 rads/fraction using a split-course technique to a total dose of 5000 rads. Tolerance was exceeded by IFU doses of 35 mg/kg/day. The complete response rate was ten of 28 patients (36%); a complete response was associated with a significantly prolonged survival. Radiosensitization of lung cancer by IFU appears clinically feasible in man.

The relationships between the administered dose, clearance, and the toxicity spectrum of 5-fluorouracil (5-FU) administered as 72-hour constant infusion have been studied in 21 patients with advanced cancer. This was done as a pilot study for possible future combination using 5-FU as a radiosensitizer. Individual patients tolerated up to 65 mg/kg/24 hours, but serious toxicity appeared once as low as 35 mg/kg. Limiting toxicity proved to be "mixed" with upper intestinal symptoms (nausea and vomiting), stomatitis, and central nervous system signs all occurring in various patients. Central nervous system effects (both cerebellar and vomiting) proved as troublesome as stomatitis. There was only a general link between the administered dose and the subsequent toxicity grade, but a reasonably quantitative relationship emerged when the serum 5-Fu levels obtained and the degree of patient toxicity were compared. The clearance of 5-FU was confirmed to be nonlinear over the entire dose range studied (25-65 mg/kg/24 hours), consistent with a two-compartment model of drug metabolism. One compartment appears to be systemic (extra-hepatic) metabolism (probably anabolic removal) which is saturated at just below 15 mg/kg/day. Doses above that level lead to drug accumulation. No steady state was reached, contrary to previous reports. At the higher infusion rates, clearance progressively approaches that predicted by the assumption that the second compartment is splanchnic blood flow and catabolism. While 5-FU can be administered as a 72-hour infusion as one possible schedule for use as a single agent or for combined modality studies, CNS effects are quite troublesome in comparison to longer infusions to toxicity.