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T H Corbett

Publications and source records attributed to T H Corbett.

At least 73 records · Page 4Linked to original sources
PubMed1982

In vivo kinetics of thymidylate synthetase inhibition of 5-fluorouracil-sensitive and -resistant murine colon adenocarcinomas.

The predictive utility of several biochemical parameters of 5-fluorouracil (5-FUra) action was evaluated in four murine colonic adenocarcinomas: 5-FUra-sensitive Tumor 38 and 5-FUra-resistant Tumors 07/A, 51 and 06/A. Thymidylate synthetase (TS) was determined by a tritiated 5-fluoro-2'-deoxyuridylate (FdUMP)-binding assay. Bolus 5-FUra (80 mg/kg, i.p.) administrated caused in all tumors a rapid decrease in free TS levels. Only Tumor 38, however, showed inhibition of TS to undetectable (less than 0.05 pmol/g) levels, which lasted up to 6 hr after treatment; correction for dissociation of endogenous TS: FdUMP:folate ternary complex during the TS assay was required. Total TS (free enzyme plus ternary complex) was determined with experimental conditions that achieved quantitative recovery of free TS from ternary complex. By 48 hr after 5-FUra, Tumor 38 showed a decrease in total TS proportional to the estimated log kill/dose of 5-FUra; in contrast, the resistant tumors showed no such decrease from pretreatment levels. Assay of FdUMP showed that the free nucleotide was formed rapidly in all tumors in excess over available TS-binding sites. However, tumor sensitivity did not correlate with peak or residual FdUMP levels or with deoxyuridylate levels, which were low and remained so in all tumors. Tumor sensitivity to 5-FUra also could not be explained by the small differences among the tumors in total perchloric acid-soluble metabolites of 5-FUra or drug incorporation into RNA. We conclude from these data that levels of free TS in the tumor after 5-FUra treatment are predictive of chemotherapeutic response in these murine models of human colonic adenocarcinoma.

Adenocarcinoma↗
PubMed1982

Toxicity and anticancer activity of a new triazine antifolate (NSC 127755).

A new triazine folate antagonist, 3-chloro-4-((4-(2-chloro-4-[4,6-diamino-2,2-dimethyl-s-triazin-1(2H)-yl]phenyl)butyl)) benzenesulfonyl fluoride compounded with ethanesulfonic acid (1:1) (NSC 127755), was highly active against four transplantable colon adenocarcinomas (36, 38, 10/A, 12/A) and the Dunning murine ovarian tumor M5076. Treatment schedule studies indicated that a prolonged time of exposure provided optimum antitumor activity for the compound. The combination of NSC 127755 plus 4-amino-1-[5-O-(1-oxohexadecyl)-beta-D-arabinofuranosyl]-2(1H)-pyrimidinone (palmO-ara-C, NSC 135962) was found to have therapeutic synergism against grossly evident colon adenocarcinoma 36.

Acetamides↗
PubMed1982

Response of transplantable tumors of mice to anthracenedione derivatives alone and in combination with clinically useful agents.

Other investigators have demonstrated that dihydroxyanthracenedione (DiOHA) and anthracenedione acetate (AA) are active against a broad spectrum of transplantable mouse tumors. DiOHA and AA are in clinical trial in the US; AA is in clinical trial in Europe. Because of the broad spectrum of activity of these DNA binders against murine tumors and due to their promising clinical utility, we have evaluated these agents in combination with a variety of clinically useful antitumor drugs. Studies were carried out against three colon adenocarcinomas (38, 06/A, and 11/A), three mammary adenocarcinomas (13/C, 16/C, and 14), and two lymphocytic leukemias (P388 and L1210). The therapeutic synergism of one of these combinations, DiOHA and cisplatin, has been previously reported. Four additional combinations which were found to have confirmed therapeutic synergism are reported here: DiOHA and palmO-ara-C, DiOHA or AA and 5-FU, DiOHA or AA and vincristine, and DiOHA and decarbazine. The combination toxicity indices (CTI; a measure of the degree of overlap in dose-limiting toxic effects) were obtained for all the following combinations: DiOHA and palmO-ara-C = 1.25-1.6; DiOHA or AA and 5-FU = 1.2-1.3; DiOHA or AA and vincristine = 1.6; and DiOHA and dacarbazine = 1.3-1.5. A CTI of 1.0 indicates complete overlap in dose-limiting toxic effects, eg, only 50% of the maximum tolerated dose of each agent can be used in combination. On the other hand, a CTI of 2.0 indicates no overlap in toxicity, and 100% of the maximum tolerated dose of each agent can be used in combination.

Animals↗
PubMed1981

Absence of delayed lethality in mice treated with aclacinomycin A.

Two compounds that bind to or intercalate with DNA (DNA binders), e.g., adriamycin and 'dihydroxyanthracenedione', 9,10-anthracenedione, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)-amino]ethyl]amino]-, dihydrochloride salt, consistently caused delayed lethality (20-200 days after treatment) if administered intraperitoneally (IP). Both of these agents contain para-hydroxyl groups in the ring adjacent to the quinone ring. Certain analogs of these compounds (aclacinomycin A and 'anthracenedione acetate', 9,10-anthracenedione, 1,4-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-, diacetate (salt), which do not contain para-hydroxyl groups, did not cause delayed deaths when injected IP. The only difference in the molecular structure (other than the nature of their amine salts) between dihydroxyanthracenedione and anthracenedione acetate lies in the para-hydroxyl groups in the ring adjacent to the quinone ring. Another compound that binds to DNA, m-AMSA, which has neither the quinone function nor the para-hydroxyl groups, did not cause delayed deaths after IP administration.

Aclarubicin↗
PubMed1981

Carcinogenesis.

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Anesthetics↗
PubMed1980

The cell population kinetics and response to an S-phase specific agent of three transplantable colon tumor lines.

The relative cell population kinetics of three transplantable murine colon tumor lines (Colon 26, 36 and 38) with different histological and metastatic characteristics were studied in relation to the response of each line to an S-phase specific agent. The mean doubling times for the three lines between 0.1 and 1.0 g are similar (4.2 days) but marked differences are apparent in times to tumor appearance (0.1 g) and in median days to death. The length of the cell cycle is about one day and the length of the S-phase 10-11 hr for Colon 36 and 38. The length of the cell cycle in Colon 26 is difficult to estimate by conventional methods but probably exceeds 24 hr and the S-phase is 10-11 hr; [3H]TdR pulse labeling indices for Colon 36 and 38 decrease with time and tumor size from about 0.45 in 0.1 to 0.2 g tumors to about 0.33 at 3 g. The decrease in the [3H]TdR labeling index for Colon 26 is more pronounced (from about 0.38 at 0.1 g to 0.21 at 1.0 g). The shapes of the PLM curves and the [3H]TdR labeling index data are consistent with the observed sensitivity to an S-phase specific agent (Palmo-AraC, NSC 135962) in Colon 36 and the minimal response observed in Colon 26. Colon 38 is intermediate between Colon 36 and Colon 26 in kinetic properties and in response to the S-phase agent.

Adenocarcinoma↗
PubMed1978

EM changes and other toxic effects of firemaster BP-6 (polybrominated biphenyls) in the mouse.

Groups of Swiss ICR mice were fed 1000 ppm polybrominated biphenyls (FireMaster BP-6) in rodent chow for 4, 8, 11, and 14 days. Control groups were fed standard rodent chow without FireMaster BP-6. Animals were killed at the end of each feeding period and the livers examined by electron microscopy. EM changes noted were progressive increase in size of hepatocytes, a decrease in rough endoplasmic reticulum, a marked increase in smooth endoplasmic reticulum, mitochondrial degeneration, increased lysosomes, and a decrease in glycogen. In addition, there was increasing proliferation of microvilli in bile canaliculi with increasing feeding times. A group of mice fed 1000 ppm FireMaster BP-6 in rodent chow for 11 days had livers with a mean of 13.93% of total body weight as compared with 6.49% for the control group (P=0.02). Tissue distribution following ingestion of 100 ppm FireMaster BP-6 for 14 days was studied. Twelve weeks post-feeding, the tissue concentrations of hexabromobiphenyl in order of highest concentration to lowest were as follows: perithymic fat, perirenal fat, adrenal glands, thymus gland, liver and stomach.

Animal Feed↗
PubMed1978

Studies of the growth, population kinetics, and host lethality of CD8F mammary adenocarcinoma.

First-generation transplants of spontaneous mammary adenocarcinomas in CDSF mice have been included in the tumor panel used for the screening of potential anticancer chemotherapeutic agents. Studies were undertaken to evaluate the growth and kinetic characteristics to provide a better understanding of the basic biology of the tumor system. The spontaneous mammary adenocarcinomas are highly variable in growth rate, and this characteristic is seen to a lesser extent in the transplanted tumors. The doubling time of the transplants is usually, but not always shorter than the doubling time of the donor tumor at a similar mass. The median length of the cell cycle obtained from pooled data from first-generation transplants of four donor tumors is 15.6 hours with a median S phase of 9.5 hours. The thymidine indices (TI) ranged from a mean of 0.28 at 100 mg to a mean of 0.20 when tumors ranged from 3 to 6 g. The mean TI of tumors of all sizes is 0.27. The cell cycle parameters and TIs appear to be characteristic of the tumor system and apparently do not vary with characteristics of the donor tumor. These studies also indicate that these kinetic parameters are not responsible for the variation in volume doubling time of the transplanted tumors.

Adenocarcinoma↗
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↗
PubMed1977

Retinoic acid-binding protein in normal tissues and experimental tumors.

The tissue distribution of retinoic acid-binding protein (RABP) has been determined for tissues of chick embryos and young and adult rats and mice and has been compared with other published data. Although no species variability has been detected with tissue distribution of RABP, relatively more of the protein is detected in the tissues of young animals than in those of adult ones. This protein is below the limits of detection in the adult rat or mouse brains, whereas it was present in abundance in the embryonic and young brains. RABP is present in the epithelial cells but not in the connective tissue of skin. Besides brain, skin, testis, and eye, RABP is also detected in small quantities in the bladder prostate, uterus, trachea, and mammary glands of rats and mice. Although RABP could not be detected in normal lungs, this protein is found to be present in Lewis lung tumors and in lungs with metastatic Lewis lung foci. Of four chemically induced transplantable colon tumors of mice, two highly metastatic ones contained RABP, whereas the two nonmetastatic lines as well as normal colon did not.

Age Factors↗