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Biomedical subjects

G L Neil

Publications and source records attributed to G L Neil.

At least 19 recordsLinked to original sources
PubMed1985

Acivicin in 1985.

This review, as its title indicates, views acivicin at a particular point in the ongoing process of its development. There is a large body of biochemical information which permits the formulation of a number of hypotheses regarding the drug's optimal regimen, mechanism of CNS toxicity, and potential role in combination chemotherapy. We have attempted to survey those data and to project some avenues of future research which may circumvent the drug's limitations. Current deficits exist in our information, particularly in the area of the clinical activity spectrum of acivicin. Yet the final definition of the set of human tumors in which acivicin may find clinical utility will probably not occur until we have defined the optimal regimen for the drug, both as a single agent and in combination, and have identified and addressed the toxic effects which limit its use. A coordinated effort between the preclinical pharmacologists and clinicians will be necessary in the next few years, if acivicin is to play an important role in the treatment of human malignancies.

Animals↗
PubMed1981

Acivicin. An antitumor antibiotic.

Acivicin [(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid; AT-125; NSC-163501] is a fermentation product of Streptomyces sviceus which is active in a variety of mouse tumor models including the L1210 and P388 leukemias, the M5076 ovarian carcinoma, and the MX-1 human breast tumor xenograft. Antitumor activity is probably mediated through the inhibition of enzymes catalyzing amido transfer from L-glutamine, especially CTP synthetase and XMP aminase. In mice, acivicin is absorbed systemically via the p.o., I.P., and S.C. routes and is predominantly excreted in the urine in unchanged form. Although a wide variety of toxicities, including myelosuppression, were noted in dogs and monkeys, vomiting, diarrhea, and pathologic lesions of the GI tract predominated in both species. A marked cumulative toxicity was noted in dogs with 16 mg/m2/day being the lethal dose on the daily x 5 schedule compared to 1000 mg/m2 on the single-dose schedule. An interesting phenomenon was noted in mice wherein older male mice were more resistant to the toxic effects of the drug than female or younger male mice. This sex and age difference in susceptibility to acivicin toxicity was shown to be correlated with differences in pharmacokinetics; older male mice cleared acivicin at approximately twice the rate of females or younger males. No sex differences in toxicity were noted in dogs or monkeys. Because of its activity in mouse tumor systems and acceptable preclinical toxicology patterns, the drug is being introduced into clinical phase I studies under the sponsorship of the National Cancer Institute.

Animals↗
PubMed1981

Sex- and age-related mouse toxicity and disposition of the amino acid antitumor agent, acivicin.

Studies of acivicin [(alpha S,5S)-alpha-amino-3-chloro-2-isoxazoline-5-acetic acid, AT-125] plasma levels in ICR, B6D2F1 and CD2F1 mice after single dose i.p. administration showed that total body clearance of drug by male mice was ca. twice the clearance by females of the same strain. Clearance was also greater in older (22-25 g) than in younger (15-18 g) ICR mice. Testosterone pretreatment increased the clearance of acivicin by ICR female mice to that of males. Sex- and age-related differences in pharmacokinetics were more pronounced than strain differences. Excretion studies showed that 53 to 82% of doses were recovered unchanged in the urine with no significant differences between sexes in urinary recovery. In tissue distribution studies in ICR mice, the tissue/plasma concentration ratios at each sampling time were similar for both sexes in all tissues analyzed except kidney (male range: 7-22; female range: 1.5-2.5) and muscle (male range: 5-9; female range: 0.8-1.4). Testosterone pretreatment of females increased the kidney/plasma concentration ratio of acivicin to that of males. Acivicin was also shown to be more toxic (as indicated by LD50) to female than to male mice of the B6D2F1 and CD2F1 strains, in agreement with previous studies in ICR mice. The disposition data suggest that the sex- and age-dependent toxicity of acivicin in mice is due to differences in pharmacokinetics which, in turn, may be related to renal excretion mechanisms.

Age Factors↗
PubMed1979

Therapy for mouse tumors and human tumor xenografts with the antitumor antibiotic AT-125.

The antimetabolite antibiotic L-(alphaS,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) showed significant antitumor activity against L1210 and P388 mouse leukemias and the M5076 mouse ovarian tumor. Depending on the schedule of administration, increases in lifespan of greater than 100% were observed. Activity was observed after ip, oral, or sc inoculation of AT-125 in mice inoculated with L1210 by the ip route. Lewis lung carcinoma and B16 melanoma were not affected by AT-125. The compound was used to treat human tumor xenografts in athymic (nude) mice. The MX-1 mammary tumor regressed when treated with either 8 or 16 mg/kg/day for 10 days, while a dose of 32 mg/kg was toxic. On an every-4-days x 3 schedule there was a marked slowing of MX-1 tumor growth at 50, 100, and 200 mg/kg. The LX-1 lung tumor xenograft growth was slowed significantly by a dose of 32 mg/kg. Growth of colon tumors, CX-1, CX-2, and CX-3, was not affected by AT-125.

Animals↗
PubMed1978

Detection and assay of antitumor antibiotics.

Cell culture techniques and antimicrobial systems can be used as detection systems for new antibiotic structures. Antimicrobial systems by virtue of their speed, economy, ease of use, and adaptation to chromatographic (bioautographic) techniques are definitely superior for assay and for dereplication purposes. A prescreen assay system which combines the advantages and minimizes the disadvantages of the two approaches is described.

Animals↗
PubMed1978

A multi-end point in vitro system for detection of new antitumor drugs.

By utilizing new types of producing microorganisms and isolating these on rather unusual growth media, we hope to produce new classes of antitumor drugs. In the detection system, we included the highly sensitive L1210 in vitro assay. But be requiring additional antimicrobial activity, we were able to eliminate rather early most of the previously known drugs from further work-up. The screening protocol was arranged so as to detect antimetabolites of a few rationally selected compounds.

Animals↗
PubMed1977

Partial synchronization of L1210 cells by 5-fluorouracil and its use in drug combinations.

When L1210 cells growing logarithmically were exposed for 8 hr to a nonlethal dose of 5-fluorouracil (FU) (0.25 microgram/ml), the percentage of cells in S phase increased from 74.9% in the asynchronous culture to 93% in the FU-treated culture. This resulted in increased cell-kill by S-phase-specific inhibitors [1-beta-D-arabinofuranosylcytosine (ara-C), 5-hydroxy-2-formylpyridinethiosemicarbazone] when they were added to a culture partially synchronized by pretreatment with FU. For example, 2 hr exposure to ara-C alone or ara-C plus FU (added simultaneously to asynchronous culture) gave 28.8 and 25.8% survival, respectively, compared to 6.8% survival when ara-C was added for 2 hr to the partially synchronized culture. Eight to 12 hr after FU removal, the culture became asynchronous, such that ara-C addition at this time did not result in increased cell-kill. Cultures pretreated with FU were also highly sensitive to vincristine and Adriamycin. Adriamycin acted synergistically with FU (after 8 hr pretreatment) in killing L1210 cells.

Animals↗
PubMed1977

Pharmacology of 5'-esters of 1-beta-D-arabinofuranosylcytosine.

Pharmacological studies of 5'-esters of 1 beta-D-arabinofuranosylcytosine (ara-C) were performed in three species (mouse, pig, and man). In mice, after a single i.p. injection of a suspension of tritiated 1-beta-D-arabinofuranosylcytosine 5'-palmitate (PalmO-ara-C) at a therapeutic dose of 150 mg/kg, 30% of the administered radioactivity was recovered in the urine in 24 hr and 56% was recovered after 7 days. Excretion was less rapid after s.c. administration. ara-C and 1-beta-D-arabino furanosyluracil each accounted for about 50% of the excreted radioactivity, and no PalmO-ara-C was found. Plasma ara-C concentrations of greater than 0.1 microng/ml were detected 24 hr after i.p. administration of PalmO-ara-C (150 mg/kg). Single doses of PalmO-ara-C were effective against L1210 leukemic mice when administered 5 to 7 days before tumor inoculation. In a pig, after i.m. injection of tritiated PalmO-ara-C (60 mg/kg, two sites), only 7% of the administered radioactivity was recovered in the urine over a 1-week period. Similar low rates of excretion were also observed in patients treated i.m. with PalmO-ara-C or 1-beta-D-arabinofuranosylcytosine 5'-benzoate. N ara-C was detected in the plasma, which is consistent with the absence of clinical toxicity or myelosuppression in Phase 1 trials of PalmO-ara-C at doses up to 1500 mg/sq m every 3 weeks for as many as eight courses.

Animals↗
PubMed1977

Antitumor activity and preliminary drug disposition studies on chartreusin (NSC 5159).

Chartreusin has exhibited significant therapeutic activity against three experimental mouse tumors (ascitic P388, L1210 leukemia, and B16 melanoma) when tumor cells were inoculated i.p. and drug was administered i.p. In further testing against P388 leukemia, no activity was observed when drug was administered p.o., s.c., or i.v. Chartreusin was very slowly absorbed from the small intestine, thus explaining the lack of activity when administered p.o. When given i.p., the drug precipitated in the peritoneal cavity and was slowly absorbed over several hr. The strong activity observed by this route was related to the prolonged and intimate contact of drug with tumor cells in the peritoneal cavity. Upon s.c. administration, extensive precipitation occurred. Subsequent dissolution and absorption from the injection site were very slow, and measured plasma and tissue levels were quite low. Biliary excretion of chartreusin, the predominant route of elimination. was very rapid, with 80 to 100% of the dose appearing as unchanged drug in the bile within 6 hr after i.v. administration. Rapid biliary excretion after i.v. administration was reflected in a rapid decline in plasma and tissue concentrations to levels (shown by in vitro cell kill experiments) less than those necessary to kill P388 cells. When the bile ducts of i.v.-dosed leukemic mice were ligated, therapeutic activity was observed, confirming that the physiological disposition of chartreusin exerts a major influence on its therapeutic utility.

Animals↗
PubMed1976

Nucleic acids. 16. Orally active derivatives of ara-cytidine.

Water-soluble derivatives of ara-cytidine (cytarabine, Cytosar) were prepared and tested for antitumor, immunosuppressive, and antiarthritic activities in animals after oral administration. The compounds tested included the 5'-palmitate, 5'-benzoate, and 5'-adamantoate esters of ara-cytidine, made water soluble by use of their hydrochloride salts of peptidyl derivatives, and two basic 5' esters (5'-nicotinoate and 5'-quinuclidinate) as their hydrochloride salts. Five of the compounds had antitumor activity superior to that found with ara-cytidine itself after oral administration in the L1210 leukemic mouse assay. One of these, 5'-adamantoyl-ara-cytidine hydrochloride, had antitumor activity after oral administration approaching that achieved with parenterally administered ara-cytidine.

Administration, Oral↗
PubMed1976

Combination chemotherapy of L1210 leukemia with 1-beta-D-arabinofuranosylcytosine and 5-azacytidine.

1-beta-D-Arabinofuranosylcytosine (cytarabine; ara-C) and 5-azacytidine (5-azaCR), cytosine nucleoside antimetabolites with different mechanisms of action, are both effective in the treatment of human leukemia, and the clinical use of these two agents in combination has been suggested. We have studied the therapeutic effect in L1210 leukemic mice of single i.p. doses of ara-C and 5-azaCR in combination. Therapeutic effects observed depended markedly on the sequence and time interval between the doses of each agent. Antagonism was observed when both agents were administered simultaneously. The optimal therapeutic effect was observed when 5-azaCR was administered after ara-C at a time when tumor DNA synthesis had maximally recovered after the ara-C dose. The dose-interval effect and correlation with recovery of DNA synthesis capacity were also observed in studies in vitro in which the survival of L1210 cells in culture was examined. ara-C was shown to inhibit the incorporation of [4-14C]-5-azaCR-derived radioactivity into DNA of L1210 cells in culture, and the therapeutic effects observed are interpreted in terms of these latter results and the mechanisms of action of the two agents.

Animals↗