Non-chemotherapeutic agents that potentiate chemotherapy efficacy.

Human renal cell carcinomas display a characteristically high degree of intrinsic chemoresistance to a multitude of chemotherapeutic agents It was suggested previously, that P-170 glycoprotein contributes to this phenomenon in renal cell carcinoma indicated by elevated MDR-1 gene mRNA levels and by the expression of this specific resistance characteristic The P-170-related efflux mechanism can be inactivated by certain calcium antagonists P-170 was traced immunohistochemically using monoclonal antibody C 219 Concomitantly, we studied the enhancement of vinblastine cytotoxicity with 4 major classes of calcium-blocking agents in a microculture tetrazolium assay Seven different calcium antagonists were selected: verapamil (VPM, racemic form), its R-stereoisomer (R-VPM), diltiazem, flunarizine, nifedipine, and its derivatives nimodipine and nitrendipine Verapamil or R-verapamil causes a significant decrease of viable tumor cells as compared to vinblastine alone (P less than 0001) Similar effects were found with diltiazem, nifedipine, and its derivatives reaching approximately 70% of the VPM/R-VPM activity Flunarizine showed only minor enhancement of cytotoxicity P-170 expression was demonstrated in 18 of 32 tumors, and a relation to chemoresistance was evident None of the chemoresponders, but 18 of 25 (72%) of the highly resistant tumors, revealed this resistance factor It was concluded that certain calcium antagonists in combination with chemotherapy may well offer therapeutic options in renal cell carcinoma as they apparently inactivate the underlying mechanism conferring resistance The new stereoisomer R-VPM, in particular, may be used in clinical trials since it combines strong enhancement of vinblastine drug responsiveness with a 10-fold lower cardiovascular activity as compared to racemic VPM, thus allowing higher concentrations to be applied

https://cancerres.aacrjournals.org/content/canres/50/12/3670.full.pdf

Effects of Calcium Antagonists in Multidrug Resistant Primary Human Renal Cell Carcinomas

Knockout tournaments constitute a common format of sporting events, and also model a specific type of election scheme (namely, sequential pairwise elimination election). In such tournaments the designer controls the shape of the tournament (a binary tree) and the seeding of the players (their assignment to the tree leaves). In this paper we investigate the computational complexity of tournament schedule control, i.e., designing a tournament that maximizes the winning probability a target player. We start with a generic probabilistic model consisting of a matrix of pairwise winning probabilities, and then investigate the problem under two types of constraint: constraints on the probability matrix, and constraints on the allowable tournament structure. While the complexity of the general problem is as yet unknown, these various constraints -- all naturally occurring in practice -- serve to push to the problem to one side or the other: easy (polynomial) or hard (NP-complete).

/pdf/on-the-complexity-of-schedule-control-problems-for-knockout-187r2tkx2s.pdf

On the complexity of schedule control problems for knockout tournaments

Tournaments of heterogeneous candidates can be thought of as probabilistic mechanisms that select high-quality agents. We quantify the efficiency of such selection by the likelihood of selecting the best player, here termed the “predictive power.” We study three widely used tournament formats: contests, binary elimination tournaments, and round-robin tournaments. Using a simple model, we demonstrate analytically, and through simulations, how the predictive power of these formats depends on the number of players, noise level, and distribution of players' types. We also present the results of exploratory simulations for two alternative criteria of selection efficiency: the expected ability of the winner and the expected rank of the winner. All three criteria may exhibit unexpected nonmonotonic behavior as functions of the number of players and/or noise level. We discuss the conditions under which different types of behavior should be expected, and their implications for managerial decisions.

The Predictive Power of Three Prominent Tournament Formats

We consider a very natural problem concerned with game manipulation. Let G be a directed graph where the nodes represent players of a game, and an edge from u to v means that u can beat v in the game. (If an edge (u,v) is not present, one cannot match u and v.) Given G and a "favorite" node A, is it possible to set up the bracket of a balanced single-elimination tournament so that A is guaranteed to win, if matches occur as predicted by G? We show that the problem is NP-complete for general graphs. For the case when G is a tournament graph we give several interesting conditions on the desired winner A for which there exists a balanced single-elimination tournament which A wins, and it can be found in polynomial time.

Fixing a tournament

Simulations of various kinds of sporting tournament have been carried out to assess their relative ability to produce as winner the best of the entrants. A strong contender when it is necessary to play relatively few games is the seeded draw and process. When the players are closely matched and there can be more games the round robin played twice is most effective.

May the best man win

Verapamil increases the sensitivity of primary human colorectal carcinoma tissue to vincristine

An organ-culture system has been used to investigate the effect of certain gastrointestinal peptides on the morphology and cell proliferation of explants of azoxymethane (AOM)-treated colonic mucosa. Our aim was to ascertain whether such factors play a direct part in the maintenance of hyperplastic changes in the large intestine. Explants of AOM-treated colonic mucosa from 15 animals were maintained in a serum-free medium in the presence of either gastrin-17 (250 pg/ml and 250 ng/ml), peptide YY (80 pmol/l and 160 pmol/l) epidermal growth factor (EGF) (10 ng/ml and 100 ng/ml) or the C-terminal fragment of glucagon-37 (30 pmol/l) for a period of up to 7 days. Other explants (controls) received fresh medium only each day. After 1, 2, 3, 5 and 7 days of culture both experimental and control explants received vincristine (4 micrograms/ml) for 3 h prior to fixation. The proportion of vincristine-arrested metaphases within the explants was determined together with crypt length. Neither gastrin nor peptide YY was found to influence cell division at either concentration. Despite an initial inhibitory effect, both concentrations of EGF exerted a trophic effect which increased with time. The glucagon-37 fragment caused an immediate increase in proliferation which then declined as time progressed. None of these factors, however, were able to maintain the hyperplastic changes seen in the pre-culture samples of AOM-treated mucosae.

Effects of gastrointestinal peptides on azoxymethane-treated colonic mucosa in vitro.

A morphological method has been developed allowing measurement of the effect on intestinal epithelia of vincristine. In routinely prepared tissue sections the proportion of mitotic events progressing beyond metaphase is counted by microscopy. When estimated over a range of doses of vincristine this post-metaphase index (PMI) can be used to compare the sensitivity of differing intact tissues. Intestinal tumours were induced in rats by chemical carcinogenesis. Administration of vincristine in the presence or absence of verapamil was performed in these tumour-bearing animals. Sections were prepared from colonic and small-bowel tumours and from normal mucosa. The results show that verapamil increases the sensitivity of the tissues studied to vincristine. A dose dependent effect of verapamil on vincristine sensitisation was demonstrated in colonic tissues. These findings indicate a shared pharmacological property between the resistance of primary tumour tissue and the multidrug-resistance phenotype.

Verapamil sensitises normal and neoplastic rodent intestinal tissues to the stathmokinetic effect of vincristine 'in vivo'

A method is described enabling the direct measurement of vincristine resistance in intact tissues in vivo by morphological study. Using the metaphase arresting properties of the drug, counts were made of escaping anaphase and telophase mitotic figures at a range of doses. The proportion of post-metaphase mitotic figures is called the post-metaphase index (PMI). In 95 primary intestinal tumours induced by dimethylhydrazine (DMH) in rats, an increase in resistance to vincristine was shown over normal mucosa (P less than 0.001). The data were analysed by computer modelling and a linear relationship is demonstrated between the logit of the post-metaphase index, and log dose of vincristine. To achieve a PMI of 1% the fitted lines show an enhanced vincristine dose requirement over normal mucosa of 6 times in colonic tumours, and 8 times in small intestinal tumours. Non-neoplastic mucosa from the DMH-treated animals requires an enhanced dose of vincristine of 1.5 times, compared with normal mucosa, to achieve a PMI of 1%. Given current interest in the mechanism of vincristine resistance in cell lines this new approach provides a technique for assessing the resistance of solid tumours, both in vivo and in vitro, and for subsequent experimental manipulation.

Demonstration of vincristine resistance in primary intestinal neoplasms in the rat by the 'post-metaphase index'.

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