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Biomedical subjects

F M Schabel

Publications and source records attributed to F M Schabel.

At least 19 recordsLinked to original sources
PubMed1978

Patterns of resistance and therapeutic synergism among alkylating agents.

Alkylating anticancer drugs are varied in chemical structure, alkylating moieties, and likely mechanisms of cytotoxic activity for vital normal cells and sensitive tumor cells. This has been objectively documented by numerous examples illustrating: (1) different in vitro and in vivo reaction products; (2) greater than additive, additive, and less than additive cytotoxicity of drug combinations for vital normal cells in the mouse; (3) readily reproducible and often marked therapeutic synergism between a variety of 2-drug combinations of alkylating agents against a wide variety of histologic types of murine tumors, and (4) observed resistance and cross-resistance of a variety of murine tumors, selected for resistance to specific alkylating agents, compatible with recognized chemical and functional differences between these drugs. The most important observations on resistance and cross-resistance reported are: (a) L1210 cells selected for complete resistance to cyclophosphamide (CPA) retain full sensitivity to selected nitrosoureas (BCNU, CCNU, MeCCNU), chlorozotocin), dianhydrogalactitol, and cis-DDPt, while retaining marked but somewhat reduced sensitivity to L-PAM, piperazinedione, and thioTEPA. (B) L1210 cells selected for resistance to BCNU retain full sensitivity to CPA, L-PAM, and dianhydrogalactitol. They show complete cross-resistance to BIC and variable cross-resistance to other selected nitrosoureas and piperazinedione. (c) L1210/L-PAM has incomplete but marked resistance to L-PAM. It is similar to the parent drug-sensitive line (L1210/0) in response to BCNU, CCNU, MeCCNU, and BIC. It is variably (usually moderately) cross-resistant to CPA, chlorozotocin, dianhydrogalactitol, and thioTEPA, but is completely cross-resistant to cis-DDPt. These resistance and cross-resistance patterns, which are consistent with most other biological and chemical principles established with these alkylating agents, may be useful in selecting alkylating drug combinations for inclusion in chemotherapy protocols in man which, on the basis of diverse observations in animal tumor systems, appear to be clearly indicated.

Alkylating Agents↗
PubMed1978

Comparative antitumor activity of actinomycin analogs in mice bearing Ridgway osteogenic sarcoma or P388 leukemia.

Actinomycin (Act) analogs, differing in the chemical substitution(s) made at various positions in either their pentapeptide chain(s) or chromophore ring, were evaluated for their antitumor activity in mice bearing either Ridgway osteogenic sarcoma (ROS) or P388 leukemia. Of the analogs tested against advanced (2--3-g) ROS tumors, azetomicin I and Act III caused therapeutic responses which, although variable, were nevertheless indicative of antitumor activities greater than was found using Act D. Several other analogs, Act C2, 2-N-(gamma-hydroxypropyl)-Act D, Act X0delta, and azetomicin II, displayed antitumor activity in ROS-bearing mice which varied, in different experiments, from comparable to superior to that achieved using Act D. Additionally, Act Pip1beta and 3'-(4-cisCl-Pro)-Act were comparable to, and Act-2-hydroxy-C3 inferior to, Act D in activity against ROS. Both azetomicin I and II were as effective as Act D in mice bearing P388 leukemia. Moreover, a subline of P388 that is resistant to Act D was cross-resistant to both azetomicin I and II.

Animals↗
PubMed1978

Biology and therapeutic response of a mouse mammary adenocarcinoma (16/C) and its potential as a model for surgical adjuvant chemotherapy.

A mammary adenocarcinoma (16/C) was isolated and maintained in serial passage by transplantation of metastatic lung foci. This tumor originated as a spontaneous mammary adenocarcinoma in a C3H/He female mouse. It was selected as a model from greater than 50 mammary tumors studied because it was highly metastatic and because it responded to most of the agents reported to be active against breast cancer in women. Sc implanted 16/C tumors (in the 300--1000-mg range) metastasized to the lungs in greater than 75% of the mice and to the axillary lymph nodes in greater than 30%. This tumor has been tested for sensitivity to greater than 40 clinically used agents. Adriamycin was the most active single agent. Other active agents included cyclophosphamide, 5-fluorouracil, vincristine, melphalan, dibromodulcitol, maytansine, neocarzinostatin, palmO-ara-C, vinblastine, and VP-16-213. Agents most active against 40--1000-mg tumours were also most active against micrometastatic disease (eg, adriamycin). The converse was also true; agents inactive or marginally active against 40--1000-mg tumors were at best marginally active against micrometastatic disease (eg, BCNU). Tumors greater than 20 mg were not curable by chemotherapy alone, although adriamycin treatment caused complete regressions of 100--400-mg tumors in greater than 80% of the mice. Surgical removal of 300--1000-mg tumors plus therapy with adriamycin resulted in 40%--72% cures as compared to 0--26% cures with surgery only. Data resulting from treatment with other agents, singly and in combination, are presented.

Adenocarcinoma↗
PubMed1978

Therapeutic potentiation of nitrosoureas using chlorpromazine and caffeine in the treatment of murine tumors.

The therapeutic usefulness of chlorpromazine (CPZ) and caffeine (CAF) in combination with selected nitrosoureas was investigated in mice bearing L1210 leukemia, Lewis lung carcinoma, and B16 melanoma. We found that using BCNU with either CAF or CPZ was therapeutically superior to using either agent alone to treat mice bearing L1210 leukemia. Administering all three drugs in combination did not improve upon the therapeutic responses obtained with the two-drug combinations. In mice implanted with Lewis lung carcinoma or B16 melanoma, responses to treatment with the triple combination of methyl-CCNU, CAF, and CPZ suggested, but did not clearly establish, superiority over each two-drug combination or methyl-CCNU alone.

Animals↗
PubMed1976

Concepts for treatment of micrometastases developed in murine systems.

Small tumor cell foci, whether left in situ during primary surgical excision or escaping lethal radiation damage, as well as distant metastases, are the primary reason for treatment failure in man and are the proper targets for the chemotherapist and immunotherapist. Since cure probably requires reduction of the total body burden of tumor cells to very small numbers (possibly to less than one cell), and since first-order kinetics of tumor cell kill by drugs appears to be a natural law in cancer chemotherapy, drug treatment should be started as soon as possible after likely noncurative primary treatment with surgery or radiation. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable tumor cells undergoing active cell replication) is inversely related to population size. Tumor cells in micrometastases should, therefore, be more sensitive to anticancer drugs active against anabolizing cells than are tumor cells in the larger, grossly apparent primary tumor from which they were derived. This indicates the probability that micrometastases will be effectively responsive to more drugs than is the primary and clinically apparent tumor from which they came. Studies with at least four metastatic and uniformly fatal murine solid tumors (lung, breast, colon, and melanoma) have demonstrated significantly improved cure rates with drug treatment following surgical removal of the grossly apparent primary tumor than can be obtained with either surgery or drug treatment when used alone. Further, both disease staging and drug dosage have been shown to influence cure rates of combined-modality treatment. With several mouse tumors, a significantly smaller number of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence. This suggests that small numbers of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than smaller tumor cell populations remaining in situ after surgery.

Adenocarcinoma↗
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↗