Farrell had an interesting set of points he reviewed on

Quote:

farrell90  
Monday, 06/19/17 12:06:12 AM
Re: Morfeyus post# 186333

Post # of 186428 
Well the short answer is we will have to wait for the clinical trials to see if Kevetrin is effective against Testicular cancer.

There are a couple of factors which make Testicular cancer unique.

First of all it has a higher response and cure rate even in metastatic cancer then most cancers with the current chemotherapy regimens. The chemotherapy appears to be synergistic with surgery and radiation.

The other point is Testicular cancer has a low rate of P53 abnormalities which may mean Kevetrin might not be as effective. Testicular cancer is one of the few cancers with a higher level of native P53 which may play a role in its response to chemotherapy.

This may be an explanation of why Kevetrin seemed to be synergistic to radiation and other chemotherapy in the preclinical studies. The idea is if you raise the level of P53 in the tumor { as seems to occur in testicular cancer and with Kevetrin}the effectiveness of the treatment increases [leading to apotosis and tumor cell death}.

Below is a short note that reviews P53 and Testicular cancer:

To understand why, it might be useful with a summary recap of the mechanisms involved. There are different kinds of chemotherapeutic agents, and until the discovery of cisplatin, testicular cancer actually responded very poorly to the chemotherapeutic drugs thrown at it. This changed in the 1960s when cisplatin was discovered.

Cisplatin is a drug that binds quite hard to DNA and ruins the structure in a way that makes the DNA replication machinery grind to a stop and break the DNA strands whenever the cell starts preparing for division. This results in lots of double strand breaks which often are irreparable. Cells have a sensing machinery that detects this, and then triggers multiple signaling cascades that either result in the cell deciding to stay alive and fix what can be fixed, or to enter a self destruct program called apoptosis. The former is what chemoresistant tumors do, whereas the latter is what we want to achieve with the treatment. Maybe the most important regulator of this decision making is a tumor suppressor protein called p53 (a simple summary of its function can be found on this Wikipedia page), and loss of p53 function is very common in most human cancers.

As it happens, testicular cancer is a bit unusual in that p53 mutations are very uncommon. On the contrary, p53 can even be upregulated in these tumors, which probably translates to an even stronger drive to go into apoptosis when faced with irreparable DNA damage. In the 1980s, the standard cisplatin treatment was improved by combining it with two other drugs (bleomycin and etoposide) that mess up the DNA through other mechanisms, resulting in even higher cure rates. Considering the high sensitivity these tumors have to DNA damage, it makes perfect biological sense.

https://www.quora.com/Why-does-testicular-can...emotherapy

A more detailed explanation:

http://www.pnas.org/content/95/11/6163.full



farrell90  
Monday, 06/19/17 12:38:19 AM
Re: farrell90 post# 186368

Post # of 186428 
More on P 53 and Testicular cancer. Why Kevetrin may theoretically more likely to benefit Platinum resistant tumors such as Ovarian cancer and less likely to benefit Testicular Cancer.

http://www.pnas.org/content/95/11/6163.full

One response to genotoxic stress involves the p53 tumor suppressor gene product (9, 10). This nuclear phosphoprotein accumulates after DNA damage and controls cellular proliferation predominantly through its activity as a transcription factor. The expression of downstream genes contributes to tumor suppression either by activating cell cycle arrest, possibly to give the cell time to repair the damage and avoid genetic instability, or by initiating apoptosis in the injured cell. The fact that the loss of p53 activity promotes malignant transformation is confirmed by the high incidence of mutations in this gene in a wide spectrum of human cancers (11, 12). Moreover, a nonfunctional p53 might provide the ensuing tumors with resistance to chemotherapy by protecting the cells from drug-induced apoptosis. In this regard, the status of the p53 gene in a tumor can be an indicator of the clinical prognosis of a cancer patient (13).

Testicular tumors are atypical because the p53 gene is usually not mutated in this type of cancer (14–16). In addition, testicular tumors express high levels of the p53 protein, a characteristic that is usually a manifestation of a genetic mutation (17, 18). Recently, experiments with murine testicular teratocarcinoma cell lines demonstrated that the elevated levels of p53 protein did not result in increased transcriptional activity of p53-regulated genes (16), suggesting that the protein was predominantly inactive. Upon exposure of the cells to the DNA-damaging agent etoposide, however, their p53-mediated functions were restored, including activation of the programmed cell death pathway.

farrell90  
Monday, 06/19/17 12:53:31 AM
Re: farrell90 post# 186370

Post # of 186428 
More from the same article:

Previous work investigated the relationship between the status of the p53 gene and cellular sensitivity to cisplatin, with contradictory results (19–27). The present study addresses the issue of cell type by investigating the p53 response to cisplatin in murine testicular teratocarcinoma cells. These cell lines resemble testicular cancer, for which cisplatin is a particularly effective treatment, in that the product of a wild-type p53 gene is overexpressed (32, 43).

Treatment of the p53+/+ teratocarcinoma cells lines with etoposide both induces and activates the p53 protein (16). Similarly, we report here that the p53 protein was elevated and transcriptionally active in the testicular teratocarcinoma cells after a 2 h exposure to cisplatin. One mechanism of p53 cellular accumulation is inhibition of the protein degradation pathway (28), and in support of this hypothesis the half-life of the p53 protein was prolonged in cisplatin-treated cells. In contrast to the rapid protein induction observed at the same drug concentration, however, protein stabilization was not immediately apparent and was only manifest after a much longer exposure to the drug (24 h). This result, coupled with the observation that the DNA-damaging agent did not result in increased levels of p53 mRNA, suggests that the rapid induction of the p53 protein by cisplatin occurs at least in part through a translational mechanism. Experiments with human leukemic blast cells also provided evidence for translational control of p53 expression (44). Cells collected from different patients with acute myelogenous leukemia displayed variable levels of p53 protein expression that did not correlate with the levels of mRNA. In addition, a comparison of acute leukemia cell lines demonstrated that the p53 mRNA was preferentially associated with the large polysomes in cell populations with larger ratios of p53 protein to mRNA. In fact, it is possible that p53 is involved in autoregulatory control of its expression, because the protein binds to, and inhibits the translation of, its own mRNA (45, 46).

Although the data presented here suggest that the unusual sensitivity of testicular cancer to cisplatin is not due solely to a wild-type p53 gene, it is impossible to make such a conclusion without in vivo evidence. A mutation in the p53-gene is an indicator of poor prognosis in patients with well or moderately differentiated ovarian cancer (56); however, overexpression of both wild-type and mutated p53 was found in advanced ovarian carcinomas refractory to cisplatin-based chemotherapy (57). In light of the results presented, both here and elsewhere (27), it would be informative to investigate whether the few testicular cancer patients who fail cisplatin-based chemotherapy have developed p53 mutations.

farrell90  
Monday, 06/19/17 12:59:10 AM
Re: farrell90 post# 186371

Post # of 186428 
Another abstract outlining Testicular ca and p53:

http://onlinelibrary.wiley.com/doi/10.1002/mc...references

Mutations in the p53 gene are common in many cancers. They have been documented to occur in about 55% of all cancers of 51 different cell and tissue types. These mutations are accompanied by overexpression of the p53 protein in the nucleus of the cell, and this protein has lost its tumor suppressor function. In this study, 25 testicular germ-cell (TGC) tumors were tested for p53 mutations and the level of p53 protein expression. While 67% of the tumors overproduced the p53 protein in the nucleus of 10-60% of their cells, in all cases the DNA sequence of exons 4-9 of the p53 gene was wild type. In this tumor type, there was apparently no selection pressure for p53 mutations. The mdm-2 gene resides on chromosome 12 (12q13-q14), a chromosome often altered in TGC tumors. mdm-2 gene amplification (2.5- to 10-fold) was detected in three (12%) of these TGC tumors. These three tumors, and eight additional TGC tumors, overexpressed mdm-2 mRNA. There was a good correlation between overexpression of p53 protein and overexpression of mdm-2 mRNA (P = 0.01). This may well result from the fact that the level of mdm-2 mRNA is regulated by the p53 level. These studies demonstrate that TGC tumors fail to be selected for p53 mutations but nonetheless frequently expressed high levels of wild-type p53 protein in the cell nucleus. Perhpas this produces the excellent response to radiation and chemotherapy of these tumors, which generally have a good prognosis. Wild-type p53 may mediate apoptosis in these cells in response to the DNA damage. © 1995 Wiley-Liss