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At least 19 recordsLinked to original sources
PubMed1977

Mathematical model for cyclocytidine pharmacokinetics.

The pharmacokinetics of the drug cyclocytidine in humans were modeled by using a physiological and anatomical approach. Each pertinent tissue is represented by a single compartment, and these compartments are linked together by the circulatory system. Each compartment is then represented by an ordinary differential equation that represents the rate of change in drug concentration as function of convecting transport, metabolism, and urinary clearance. The models for cyclocytidine and cytarabine are linked together by a hydrolysis term in each equation set. The resulting equation sets are then solved numerically to predict the concentration of both drug species in situ. The models use physiological blood flows, tissue volumes, and clearance parameters. The results of the model show that cyclocytidine can act as a reservoir for cytarabine in vivo over the time studied. This effect is confined to relatively long times and relatively low plasma concentrations.

Ancitabine↗
PubMed1976

A new hamster fibrosarcoma model for in vitro/in vivo evaluation of cancer chemotherapeutic agents.

A hamster fetal cell clone has been developed for in vitro chemotherapeutic studies as well as in an in vivo fibrosarcoma model system. Highly reproducible quantitative in vitro chemotherapeutic data can be obtained with this cell line within 5 days, and as few as 10(2) cells produce rapidly growing fibrosarcomas when injected subcutaneously into adult hamsters. We found using these cells in vitro that 1-beta-D-arabinofuranosylcytosine (ara-C) can antagonize the effect of 5-azacytidine (aza-C) if given simultaneously or if aza-C treatment is preceded by a 2-hr exposure to ara-c. Using the same cell line as in vivo model for chemotherapy it was also shown that ara-C and cyclocytidine significantly inhibited tumor growth. This hamster cell line may be quite useful as an in vitro/in vivo model system for the study of cancer chemotherapeutic agents.

Ancitabine↗
PubMed1978

Stimulation of secretion of epidermal growth factor and amylase of cyclocytidine.

Radioimmunoassays and immunocytochemical techniques were used to assess the effect of cyclocytidine, an antitumor agent, on the level and localization of Epidermal Growth Factor (EGF) in the submandibular gland of the male mouse. A single intraperitoneal injection of 150 mg/kg of cyclocytidine caused, within 6 h, a degranulation of the granular convoluted tubules (GCT) cells and reduced the concentration of immunoreactive EGF in gland extracts by more than 90%. This effect was largely abolished by the administration of dibenzyline but not by propranolol, indicating that the secretory effect of the drug on the GCT cells is mediated by alpha-adrenergic receptors. By immunocytochemical staining revealed the same trends in changes in EGF concentration as the radioimmunoassays. However, even at the peak of the cyclocytidine effect there were cells which retained their secretory granules and apparently their EGF complement. In addition, there was a lobular variation in the secretory response. Cyclocytidine caused a transiet increase in the blood level of EGF. Furthermore, it stimulated amylase secretion from the gland, which also involved alpha-adrenergic receptors. Cyclocytidine will be useful in future analyses of the release of various biologically active substances from the GCT cells of the mouse submandibular gland.

Adrenergic alpha-Antagonists↗
PubMed1979

Physiologically based pharmacokinetic models for anticancer drugs.

The rationale and history of the development of physiologically based pharmacokinetic models are briefly reviewed in this paper. The methods of model construction and the previous application of this type of model to anticancer drugs are discussed. Future research should be focused on the following areas: (1) interspecies scaling, (2) the effects of disease states on the pharmacokinetics of anticancer drugs, and (3) the applications of pharmocokinetics to the studies of growth behavior of cancer cells. The ultimate goal will be to utilize this basic information to design an optimal dosage regimen and treatment schedule for the safe and effective cancer chemotherapy of each individual patient.

Ancitabine↗
PubMed1979

The enzymatic hydrolysis of the phosphate ester bond in some thionucleotides.

We prepared the 5'- and 3'-O-phosphorothioate esters of the antitumor agent O2 : 2'-anhydro-1-beta-D-arabinosylcytosine. We also included in this study esters of 2'-thio-2'-deoxycytidine, namely, 2'-S-dCyd-2' : 3'-P, 2'-S-dCyd-2'-P, and 2'-S-dCyd-3'-P, along with natural nucleotides. These compounds were subjected to the action of Escherichia coli alkaline phosphatase, potato acid phosphatase, and bovine pancreatic ribonuclease A. The data were analyzed by Lineweaver-Burk plots to obtain Km and KI values. Only 2'-S-dCyd-2'-P was a substrate for alkaline phosphatase; the anhydro-araCyt phosphorothioates were good competitive inhibitors, while 2'-S-dCyd-3'-P did not associate with the enzyme. Acid phosphatase hydrolyzed all four monoesters investigated, including the S-phosphorothioate. The cyclic phosphorothioate, 2'-S-dCyd-2' : 3'-P was neither hydrolyzed by, nor associated with, ribonuclease A. ORD spectroscopy was also used in an attempt to relate the structural features of analogs to the peculiarity of their hydrolysis.

Acid Phosphatase↗
PubMed1992

Effects of nerve growth factor on cyclocytidine-induced growth responses of sympathectomized parotid or parotid of partially desalivated rat.

Cyclocytidine (CC), a potent antitumor agent, caused a 2.4- to 3.9-fold increase in [3H]thymidine uptake of rat parotid gland after 3 days of daily administration of the CC in a dose of 500 mg/kg body weight. Gland weight also was increased. Ablation of the submandibular-sublingual glands prior to initiation of the CC regimen prevented the usual CC-induced increase in [3H]thymidine uptake but this inhibition was partially reversed when nerve growth factor (NGF) was administered with the CC; values for [3H]thymidine uptake into parotid DNA were 81, 54, and 73% of those of glands of intact CC-treated rats. Submandibular gland ablation did not prevent the usual CC-induced increase in parotid size, and administration of NGF had no effect. Sympathectomy of the salivary glands also inhibited the thymidine increase in parotid gland usually induced by CC but in addition it also inhibited the usual CC-induced increase in gland weight. NGF, however, failed to reverse the effects of sympathectomy on [3H]thymidine uptake or gland size: both remained at the same level observed in sympathectomized parotid not given NGF.

Ancitabine↗
PubMed1977

Fluorinated Pyrimidine nucleosides. 1. Synthesis of a nitrogen analogue of the antitumor agent 2,2'-anhydro-1-beta-D-arabinofuranosyl-5-fluorocytosine hydrochloride.

The nitrogen-bridged compound 2,2'-anhydro-1-beta-D-arabinofuranosyl-2,4-diamino-5-fluoropyrimidinium chloride (2), an analogue of the antitumor agent anhydro-ara-FC (1), has been synthesized. 5-Fluorocytidine was converted into 1-beta-D-ribofuranosyl-2,4-diamino-5-fluoropyrimidinium chloride (4), but cyclization of 4 was not achieved due to a competing side reaction. The nitrogen bridge was therefore introduced by cyclization of 5-fluoroisocytidine (10) to give the 2,2'-imino-bridged compound 16. The latter was converted into 2 by the standard procedure of thiation, S-methylation, and treatment with ammonia. Compound 2, as well as a number of the synthetic intermediates, was tested for activity against S180 sarcoma in mice. None of the new compounds exhibited any antitumor activity.

Ancitabine↗
PubMed1977

Antiviral activities of acyl derivatives of 2,2'-anhydro-1-beta-D-arabinofuranosylcytosine and 1-beta-D-arabinofuranosylcytosine in cell culture.

Antiviral activities of acyl derivatives (3'-O-octanoyl and 3'-O-decanoyl) of 2,2'-anhydro-1-beta-d-arabinofuranosylcytosine (cyclo-C) and 1-beta-d-arabinofuranosylcytosine (Ara-C) were compared with other antiviral nucleosides, and some biological characteristics of the antiviral activity were investigated. Among those synthesized acyl derivatives, 3'-O-decanoyl ara-C was the most active against deoxyribonucleic acid viruses, with an activity comparable to that of Ara-C. Acyl derivatives of cyclo-C were somewhat less active than their Ara-C counterparts. In the value of therapeutic index, 1-beta-d-arabinofuranosyladenine was superior to the others, followed by 5-iodo-2'-deoxyuridine. In comparing the sensitivity of two serotypes of herpes simplex virus it was found that Ara-C and its ester, as well as its cyclo-C counterpart, were more active against the type 2 than the type 1 strain. The activity of 3'-O-decanoyl Ara-C, like that of its parent, was diminished by treatment with cytidine deaminase from mouse kidney, but 3'-O-decanoyl cyclo-C was resistant to this treatment. In comparative studies of 3'- and 5'-O-acyl Ara-C's, antivaccinia virus activity of 3'-O-palmitoyl Ara-C was significantly superior to its 5'-counterpart. The inhibitory activity of 5'-O-decanoyl Ara-C was markedly reduced by the presence of a threefold molar excess of eserine sulfate, a choline esterase inhibitor, whereas the 3'-acyl Ara-C was not affected by the inhibitor in any combination. This result indicates that enzymatic hydrolysis of the 3'-ester to Ara-C, which is inhibited by eserine sulfate, did not occur in this cell culture.

Acylation↗
PubMed1978

[Chemotherapy of gastrointestinal tumors (review of the literature)].

There exist no common recommendations for palliative therapy of gastrointestinal cancer. Fluorouracil has been used for a long time, remission rates reported range from 0% to 80%. In larger series they figure about 20% but without prolongation of survival in responders. Although this drug is used for 20 years optimal dose and timing is still unknown. By combination of fluorouracil with other drugs remission rates were improved and in responders survival was prolonged (mitomycin C and/or adriamycin in gastric cancer, methyl-CCNU in colorectal cancer). The results of adjuvant chemotherapy of gastrointestinal cancer are contradictory, the routine usage is not recommendable. Adjuvant as well as palliative chemotherapy must be improved by controlled clinical trials.

Ancitabine↗
PubMed1992

Studies on the regranulation of salivary gland serous cells. An electron microscopical study in the rat.

The degranulation and regranulation process was investigated after alpha-adrenergic stimulation on the rat submandibular gland. The submandibular gland in rat contains both serous and mucous cells. It has earlier been shown that serous cells filled with heavy-metal granules, are markedly more radiosensitive than cells without granules. In experiments with emptying the serous cell of their content of granules by administering an alpha-adrenergic stimulant, cyclocytidine, there has been found a decrease in irradiation damage in salivary gland tissue after irradiation. Injection of cyclocytidine, 150 mg/kg, was given i.p. to the rat. After 1 h there was almost complete depletion of granules in the serous cells, no morphological aberration was seen in the mucous cells. This effect still remained after 6 h. A beginning of regranulation with apical granules was seen 12 h after injection. After 24 h an almost complete regranulation had occurred in the salivary gland serous cells. The mucous cells did not show any morphological aberration. Our intent is to reduce unwanted salivary gland damage in patients with head and neck cancer when treated with radiotherapy. Depletion of heavy-metal granules in serous cells, before irradiation may diminish morphological destruction in the salivary glands. As a nearly total degranulation is present between 1-6 h after stimulation, this should be the optimal time for radiotherapy.

Ancitabine↗
PubMed1978

Tyramine-like effect of cyclocytidine (2,2'-anhydro-1-beta-arabinofuranosylcytosine hydrochloride), an antineoplastic agent.

Since cyclocytidine (2,2'-anhydro-1-beta-arabinofuranosylcytosine hydrochloride) was introduced as an antineoplastic agent for the treatment of lymphatic leukemia, sinus acceleration and an increase in systemic blood pressure has been reported as its systemic effects in the clinical cases. These cardiovascular effects of cyclocytidine were observed also in anesthetized dogs, but not in reserpine-pretreated animals. Increases in heart rate and in systemic blood pressure were prevented by propranolol and phentolamine, respectively. The mechanism of these sympathomimetic effects was further analysed in the excised, blood-perfused canine sinoatrial node and papillary muscle preparations with a support dog. Positive chronotropic and inotropic responses to cyclocytidine were abolished by desipramine, propanolol, and pretreatment with reserpine but not by tetrodotoxin and hexamethonium. The tyramine-like actions of cyclocytidine at adrenergic neuronal terminals were discussed in conjunction with the uptake mechanism of the drug into the tumor cells.

Ancitabine↗