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F M Schabel

Publications and source records attributed to F M Schabel.

At least 55 records · Page 3Linked to original sources
PubMed1976

Studies with 2,5-piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride. III. Biochemical and therapeutic effects in L1210 leukemias sensitive and resistant to alkylating agents: comparison with melphalan, cyclophosphamide, and BCNU.

2,5-Piperazinedione, 3,6-bis(5-chloro-2-piperidyl)-,dihydrochloride (NSC-135758) selectively inhibits DNA synthesis in L1210/0 leukemia and in cyclophosphamide-resistant L1210 (L1210/CPA). Melphalan (L-PAM) inhibits nucleic-acid synthesis but not protein synthesis in L1210/0 and L1210/CPA. CPA selectively inhibits DNA synthesis in L1210/0 but does not inhibit DNA synthesis in L1210/CPA. NSC-135758 is as active in vivo against L1210/CPA and BCNU-resistant L1210 (L1210/BCNU) as it is against L1210/0. It is inactive against ic implanted L1210/0. These data clearly indicate important differences in the biologic activity of this compound compared to either CPA or BCNU. L-PAM is similar to NSC-135758 in activity against L1210/CPA and L1210/BCNU.

Animals↗
PubMed1976

Growth support of small B16 melanoma implants with nitrosourea-sterilized fractions of the same tumor.

B16 melanoma cells sterilized in vitro with 1,3-bis(2-chloroethyl)-1-nitrosourea or in vivo with trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, have been used to enhance the percentage of tumor takes with small s.c. implants of viable cells and to reduce the latent period between tumor implantation and palpability. The admixture of trans-1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea-inactivated cells with viable cell implants reduced the number of cells required to produce tumors in 50% of the animals by approximately 3 log10 units and markedly reduced the time of tumor appearance from implants of up to 10(6) cells. Similar results were obtained with 1,3-bis(2-chloroethyl)-1-nitrosourea-sterilized cells. The growth-supporting effect obtained with the nitrosourea-inactivated cells appeared to be as pronounced as that previously reported, for this tumor system, with radiation-inactivated cells.

Animals↗
PubMed1976

Nitrosoureas: a review of experimental antitumor activity.

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are very similar in biologic mechanism of action, and therefore resistance to one alkylating agent probably predicts cross-resistance to all alkylating agents, may no longer be tenable. If not, then alkylating-agent drug combinations, either used alone or combined with other treatment modalities (eg, surgery) which have been reported to result in therapeutic improvement in a number of experimental murine tumor systems, may be indicated for serious consideration as surgical adjuvant chemotherapy by surgeons or as primary therapy by medical oncologists.

Animals↗
PubMed1975

The mechanism of action of 3-deazauridine in tumor cells sensitive and resistant to arabinosylcytosine.

Deazauridine inhibited growth of tumor cells in culture and in culture and in vivo; this agent was significantly more effective against L1210/AraC than against the parent sensitive line. Inhibition of growth of tumor cells in culture was prevented by uridine and cytidine and was partially alleviated by deoxycytidine, but not by deoxyuridine or thymidine. DeazaUR inhibited nucleic acid synthesis but not protein synthesis in tumor cells in culture; deoxycytidine alleviated inhibition of nucleic acid synthesis. The labeling of pyrimidine ribonucleotides by 6-14C-orotic acid was inhbited by deazaUR. DeazaUR treatment of tumor cells in culture resulted in increased uptake of cytidine-3H into RNA, whereas uridine-3H uptake into RNA was inhibited. Labelling of DNA by uridine-3H/ and cytidine-H was inhibited by deazaUR. Pools of CMP, CDP, and CTP decreased markedly during deazaUR treatment of L1210 cells in culture and in vivo. These observations in growing cells pointed to deazaUR inhibition of the synthesis of cytidylic acid. Deazauridine 5'-triphosphate was found to be an inhibitor of the synthesis of CTP from UTP catalyzed by enzyme preparations from L1210 cells. This observation is in agreement with those of McPartland et al.19 that deazaUTP inhibited CTP synthetase purified from calf liver. Deazauridine treatment of L1210 cells in culture stimulated the uptake of deoxycytidine-3H into DNA while inhibiting the uptake of 3H-labeled deoxyuridine, thymidine, deoxyadenosine, and deoxyguanosine. Intracellular pools of dCTP were decreased by deazauridine treatment in L1210 cells in culture and in vivo. Deazauridine 5'-diphosphate inhibited the enzymatic reduction of pyrimidine ribonucleoside 5'-diphosphates to the corresponding deoxyribonucleotides. These results are consistent with the view that deazauridine, after its uptake and intracellular phosphorylation, strongly inhibits the formation of CTP. This is considered to be the primary metabolic effect of the analog. A secondary effect appears to be an inhibition of dCTP formation.

3-Deazauridine↗
PubMed1975

Concepts for systemic treatment of micrometastases.

If total tumor cell kill is a requirement for "cure," as it probably is for at least some tumors, treatment of micrometastases containing less than or equal to 10-6 viable tumor cells is a problem facing all cancer therapists. Metastatic tumor cell foci of less than or equal to 10-6 cells, particularly if widely disseminated, are, in the main, grossly undetectable and are, therefore, the proper targets for the chemotherapist and the immunotherapist. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable cells undergoing active cell replication) is inversely related to population size. Micrometastases should, therefore, be more sensitive to antimetabolite (cell-cycle-specific) anticancer drugs than the larger, grossly apparent, primary tumor from which they were derived. In fact, drug response of the primarytumor may not reliably predict the sensitivity of micrometastases to cell-cycle-specific drugs. In addition, optimal drug treatment scheduling for effective, but noncurative, drugs against clinically recognized tumors may not predict optimal scheduling of the same drugs against micrometastases. This is shown particularly in cell-cycle-specific drugs, since the generation time of tumor cells in small population foci (less than 10-7 cells) is often significantly shorter than in larger population foci (greater than 10-7 cells). Since first-order cell kill kinetics characterizes effective drug kill of tumor cells and the best currently known anticancer drugs have variable but generally limited tumor cell kill potential, drug treatment of likely micrometastases should be started as soon after the end of likely noncurative radiologic or surgical treatment as possible. Experimental data indicating that significantly smaller numbers of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence suggest that small populations of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than similar sized populations remaining in situ after surgery. Experimental data supporting the above concepts are presented and discussed.

Antimetabolites↗
PubMed1975

Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure.

In an effort to establish an animal colon tumor model suitable for biological and chemotherapy studies, 82 colon tumors were induced and transplanted in four different inbred strains of mice. Four colon tumors survived the first transplant and are now in serial passage. All are suitable for chemotherapy trials. Two tumors are highly metastatic, and at least one of these is known to be suitable for surgery-chemotherapy adjuvant studies. The effective colon carcinogens contained a (see article) molecular similarity.

Adenocarcinoma↗
PubMed1972

3-Deazauridine: inhibition of ribonucleic acid virus-induced cytopathogenic effects in vitro.

3-Deazauridine, a synthetic analogue of uridine and a potential antitumor agent, was found to possess antiviral activity against a number of ribonucleic acid-containing animal viruses in mammalian cell culture. Inhibition of virus-induced cytopathogenic effects by 3-deazauridine was observed in cells infected with rhinovirus types 1A and 13, coxsackievirus type A21, and PR-8 influenza virus, but not in cells infected with poliovirus type 2 or echovirus type 12. The extracellular yield of progeny influenza virus was found to be significantly reduced in titer in 3-deazauridine-treated Madin-Darby canine kidney cell cultures at 12 to 24 hr after infection. Although the precise biochemical mechanism of action of this antimetabolite's antiviral activity is not known, the compound does not appear to exert a direct virucidal effect on the influenza virion itself.

Animals↗