Use of AB-103 (a “dual antagonist”) in the treatment of bronchogenic carcinoma

Razis, Dennis V.; Ambrus, Julian L.; Ross, Charles A.; Stutzman, Leon; Sokal, Joseph E.; Rejali, A.M.; Bardos, Thomas J.

doi:10.1002/1097-0142(199007/08)14:4<853::aid-cncr2820140423>3.0.co;2-k

Cited by 9 publications

(3 citation statements)

References 11 publications

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“…I n both the pharmacologic and subsequent clinical studies, AB-100 and AB-103 (in which the aziridine ring carbons are unsubstituted methylene groups) behaved essentially like the typical 'ethylenimine-type' alkylating agents (e.g., TEPA, or thio-TEPA). Thus, their potent inhibitory activities against a spectrum of transplanted tumors in rodents Ambrus et al, 1959;Segaloff et al, 1959;Dunning et al, 1961), their marked chemotherapeutic activities in various human malignancies (McCracken and Wolf, 1960;Weeth and Segaloff, 1961;Ambrus et al, 1961;Razis et al, 1961 ;Ross et al, 1961 ;Hayes et al, 1961 ;Willett et al, 1962 ;Rosenstiel et al, 1963), together with their dose-limiting hematologic side-effects, could be attributed to the 'alkylating' aziridine function, while the carbamate portion of the molecule appeared to act mainly as a membrane transport 'carrier' or as a hydrophobic 'binding' group in a more or less selective manner. This was suggested by the fact that the benzyl carbamate analogue AB-103 appeared t o be more effective than the corresponding urethan analogue AB-100 against several but not all animal tumor systems as well as in the clinical studies against carcinomas of the lung and pancreas (Rosenstiel et al, 1963).…”

Section: Combination Chemotherapymentioning

confidence: 99%

Combination of chemotherapy with dual antagonists and radiotherapy in the treatment of neoplastic disease

Bardos

Ambrus

1971

Journal of Surgical Oncology

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The theoretical justification for combination chemotherapy and for the combination of radiation and chemotherapy in the treatment of neoplastic diseases is discussed. Literature on the synthesis and biological activity of the 'dual antagonist' group of drugs is reviewed, Studies on the radiation-potentiating effect of certain members of this group of drugs are reviewed, and prospects for therapeutic applications are discussed.

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Section: Combination Chemotherapymentioning

confidence: 99%

Combination of chemotherapy with dual antagonists and radiotherapy in the treatment of neoplastic disease

Bardos

Ambrus

1971

Journal of Surgical Oncology

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“…The synthesis (Bardos et al, , 1965aPapanastassiou and Bardos, 1962) and chemotherapeutic activities in animals Ambrus et al, 1959Ambrus et al, , 1961Mirand et al, 1961 ;Segaloff et aZ., 1959) and in man (Pacific Coast VA Group, 1962;Razis et al, 1961;Ross et al, 1960Ross et al, , 1962Ross et al, , 1963Velasco et al, 1964;Watne et al, 1962 ;Weeth et al, 1960) of a series of bis(1-aziridiny1)phosphinyl carbamates, termed 'dual antagonists,' were previously reported. It was found that introduction of alkyl substituents in the aziridine rings caused significant differences in the chemical reactivities as well as in the i n vitro and in v i v o biologic activities Chmielewicz et al, 1 9 6 7~;Delta et al, 1962;Stutzman et al, 1962).…”

Section: Introductionmentioning

confidence: 99%

Studies on the chemistry, antitumor activity, and pharmacology of ethyl Di‐(2,2 ‐dimethyl)ethylenamido phosphate (AB‐163)

Munson

Babbitt

Chmielewicz

et al. 1969

Journal of Surgical Oncology

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AB-163, a new alkylating agent containing the 2,2-&methylaziridine moiety, was found to be active against a number of transplanted and virus-induced tumor systems in mice. This compound hydrolyzes in water a t 37 C. The hydrolysis product was isolated and identified as ethanol and amino-tert-butyl phosphate. The compound was shown to react with the model nucleophile 4-(p-nitrobenzyl) pyridine (NBP) comparably to previously studied alkylating agents. The intravenous LD,, was 198 mg/kg and the intraperitoneal LD,,, was 159 mg/kg in ICR/Ha male mice. I n mice carrying Ehrlich ascites tumor (E-2), 30 mg/kg of AB-163 resulted in 95% tumor inhibition. I n Sarcoma-180 inoculated mice, 15 mg/kg caused a 20-30% apparent cure rate and a 62% tumor inhibition of the animals having tumors. Against Adenocarcinoma 755,40 mg/kg exhibited a 60% cure rate and 50% tumor inhibition of the animals with tumors. Leukemia LIZ10 treated on days 1-11 was cured in 20-30y0 of the animals receiving 30 mg/kg of AB-163 and there was a 76-170% increase in survival time in the remaining animals. In animals infected with Friend virus, a 40 mg/kg dose resulted in 65% reduction of splenic weight as compared to controls. Studies in dogs indicated that the main toxicity is hematopoietic depression. Terminally, depression of liver functions was observed. High doses produced central nervous system effects which manifested themselves in loss of appetite, vomiting, increased salivation, lethargy, and convulsions.

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“…The NMR spectra (in CDClJ of I-VI all contain the quartet corresponding to the methylene protons of the carbamate group (5.80 7) and (in some cases partially masked by the ring-methyl protons) the triplet of the carbamate methyl protons (8.70 7). In addition, the unsubstituted compound, I, shows a doublet corresponding to its eight ring protons split by the @-phosphorus atom (7.67 7, JPH = 14 c.P.s.).…”

mentioning

confidence: 99%