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Biomedical subjects

G L Wampler

Publications and source records attributed to G L Wampler.

53 records · Page 3Linked to original sources
PubMed1979

Synthesis of hydroxy- and amino-substituted benzohydroxamic acids: inhibition of ribonucleotide reductase and antitumor activity.

Benzohydroxamic acids inhibit mammalian ribonucleotide reductase and exhibit antineoplastic activity in L1210 leukemic mice. Five new hydroxy- and amino-substituted benzohydroxamic acids (3,4- and 3,5-OH, 3,4-NH2, 2,3,4- and, 3,4,5-OH) were prepared and tested along with 12 previously reported benzohydroxamic acids (BHA) for enzyme inhibition and antitumor activity. The most potent enzyme inhibitor in this series was 2,3,4-OH-BHA (ID50 = 3.5 microM), which is 140 times more potent than hydroxyurea, but its toxicity limited the antitumor activity to a 30% increase in life span of L1210 bearing mice at 125 (mg/kg)/day ip for 8 days. The most effective antitumor agent in this series was 3,4-OH-BHA which prolonged the life span of L1210 bearing mice 103% at 600 (mg/kg)/day ip for 8 days.

Animals↗
PubMed1979

An improved method for analyzing survival data from combination chemotherapy experiments.

In this paper, we present a new method for analyzing survival data from combination chemotherapy experiments. The analysis consists of relating survival to the dosage level of each drug in the combination and using response surface techniques to determine the importance of drug interactions and to estimate optimal doses. A combination experiment using cyclophosphamide, mechlorethamine, and mitomycin C in early L1210 leukemia, advanced L1210 leukemia, and advanced P388 leukemia is used to illustrate the analyses. A therapeutic synergism has been shown. As a result of the various drug interactions, the predicted optimal dose of mitomycin C is found to be zero. This result was duplicated in each tumor system studied.

Animals↗
PubMed1978

Phase II study of vinblastine, methyl-CCNU, and medroxyprogesterone in advanced renal cell cancer.

One hundred and sixty-five patients with advanced renal cell cancer were evaluable for combination or single-agent therapy with methyl-CCNU, vinblastine, and medroxyprogesterone. A low order or response was observed, and these agents were not proven effective as treatment for metastatic renal cell cancer. Performance status and a relatively long symptom-free interval from primary tumor to metastatic disease were found to be the most prognostically significant factors for survival.

Adenocarcinoma↗
PubMed1978

Antitumor activity of amidoximes (hydroxyurea analogs) in murine tumor systems.

A series of amidoximes was prepared and evaluated for possible antitumor activity against L1210 leukemia. Three of the most active compounds in the L1210 system, formamidoxime, acetamidoxime, and 2-aminoacetamidoxime hydrochloride, were also active against P388 leukemia. Acetamidoxime was marginally active against Lewis lung carcinoma. The active amidoximes showed best activity against L1210 leukemia when given two times daily, 5 hours apart, for 8 days. Most of the amidoximes produced excessive central nervous system stimulation.

Amines↗
PubMed1978

Combination chemotherapy: arriving at optimal treatment levels by incorporating side effect constraints.

This paper represents a method for determining optimal dose levels in a drug combination by analyzing the dose-response surfaces estimated from experimental data. In addition to using the presence or absence of a favorable response (in this instance, survival for at least twice the median untreated lifespan of B6D2F1 female mice bearing advanced sc implanted L1210 leukemia), the presence or absence of associated side effects is also employed (in this instance, Day-12 weight loss). The technique is potentially superior to existing methods of responding to the occurrence of treatment side effects due to its ability to take into account interactions between drugs. Since this method offers a way to determine optimal dose by including nonlethal toxicity information; it should find application in clinical situations.

Animals↗
PubMed1977

On determining the levels of treatment to optimize the probability of a favorable response.

This paper presents a statistical method for analyzing the dose response surface associated with treatments resulting from combinations of any number of cytotoxic agents. The results of such an analysis are the dosages of each agent in the combination which will maximize the probability of a favorable response. An example utilizing a combination of hexamethylmelamine and ICRF-159 is presented. The predictive ability of the model is verified by a kappa 2 goodness of fit test. The advantages of such a method relate to its potential applicability to more complex experimental situations where multiple drugs are used in combination and/or where variations in timing of drug administration exist.

Altretamine↗
PubMed1975

Antitumor activity of tetraacetylglucosamine mustard.

1,3,4,6-Tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranose is active against L1210 leukemia, giving over 100% increased life-span at optimal dose. Against P388 leukemia, it gives 200% increased life-span with long-term survivors. The compound is most active when given i.p., but shows some activity when given s.c. than p.o., and is more potent (therapeutic and toxic effect) than mechlorethamine on both a molar and a mg basis. Of importance, the schedule dependency for the administration of 1,3,4,6-tetra-O-acetyl-2-(di-2-chloroethyl)amino-2-deoxy-D-glucopyranose in L1210 leukemia differs from most alkylating agents in that it is best given by multiple daily injections rather than as a single large injection on Day 1. This characteristic can be attributed to the amino-glucose moiety.

Acetylglucosamine↗
PubMedDate not supplied

Analysis of "early" thymidine/inosine protection as an adjunct to methotrexate therapy.

The feasibility of "early" thymidine and inosine protection of methotrexate (MTX) toxicity is evaluated in this paper. This approach is based on the proposition that the most vulnerable period for susceptible host cells to MTX toxicity is an interval following a pulse of MTX when the MTX monoglutamate level is high. In contrast, tumor cells that accumulate active MTX polyglutamyl derivatives are exposed to the cytotoxic effects of MTX, not only when the monoglutamate levels are high, but also over the much longer interval during which polyglutamyl derivatives are retained within these cells. The protecting agents employed, thymidine and inosine, circumvent the antipurine and antipyrimidine effects of MTX, but neither agent inhibits the transport or the polyglutamylation of MTX. Nucleoside protection given over 6 hours after MTX markedly decreased toxicity to normal BDF1 mice at MTX doses up to 150 mg/kg/day for 3 consecutive days. The LD10 for unprotected mice was 14 mg/kg/day, while the LD10 for the protected mice was 114 mg/kg/day, a greater than eightfold increase in the drug dose delivered. MTX with early nucleoside protection produced a 50% increase in median life span in tumor-bearing mice at doses of drug that were toxic to unprotected mice. Flow cytometric analyses indicated that consecutive daily pulses of MTX with early nucleoside protection alter the cell cycle distribution. By 24 hours after the last of three daily pulses of MTX, the G1 component was maximal (80% of the cell population), with less than 2% of the cells in G2M and 17% of the cells in S phase. This distribution persisted for 24 hours, after which a normal pattern emerged, a process that was accelerated by neither thymidine/inosine nor leucovorin. These studies support the concept that toxicity to the host is initiated largely in the interval shortly after MTX administration. The data indicate that early nucleoside protection permits the repetitive administration of much higher doses of MTX than can be given with MTX alone. This approach may be useful not only in the treatment of human neoplasms but in the treatment of other disorders, such as rheumatoid arthritis, psoriatic arthritis, or psoriasis. Finally, this paper considers the potential advantages of early thymidine/inosine protection in comparison to leucovorin rescue with the administration of low or moderate doses of MTX.

Animals↗
PubMedDate not supplied

Antileukemic effect of homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenyl]acetic acid.

The homo-aza-steroidal ester of [p-[bis(2-chloroethyl)amino]phenyl]acetic acid, 3beta-hydroxy-13alpha-amino-13,17-seco-5alpha-androstan-17-oic-13,17,-lactam p-bis(2-chloroethyl)aminophenylacetate (ASE), gives a greater than 50% increased lifespan over controls in the treatment of L1210 leukemia by the ip, sc, and oral routes of administration and a greater than 150% increased lifespan in the treatment of P388 leukemia by the ip route (the only route tested). Both a daily and a Day 1, 5, and 9 treatment schedule are essentially equally effective. In this study, ASE is compared to the parent compound phenesterin which is inactive in both of these tumor lines. To our knowledge ASE is the first steroidal alkylating agent to show activity in the L1210 leukemia.

Animals↗