Tuesday, April 30, 2013

THE PROOF IS IN!

Docetaxel-cisplatin might be superior to docetaxel-capecitabine in the first-line treatment of metastatic triple-negative breast cancer
ANOTHER CONFIRMATION THAT TRIPLE NEGATIVE  BREAST CANCER IS ANOTHER BEAST ALL TOGETHER.  AS WE HAVE SHOWN, HERE THE RECEPTORS ARE COMPLETELY DESENSITIZED, YOU HAVE TO GO TO MEDICATION DEALING WITH THE FIRST AND SECOND LAWS TO ATTACK THE CELL.  YOU HAVE TO GO "NUCLEAR" BY BREAKING DNA AND INTERFERING WITH MACROTUBULES.
WHAT IS UNCLEAR YET IS HOW THE DISEASE FINALLY ESCAPE.  CISPLATIN RESISTANCE MAY BE THROUGH INCREASING REPAIR OF DNA.

"These data demonstrated that overexpression of c-erbB-2/neu can lead to intrinsic Taxol resistance independent from mdr-1 mechanisms.

"AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol"

  • Shubha Anand
  •  They suggest that AURORA-A amplification will predict poor responsiveness to Taxol and other agents that target the spindle checkpoint. If so, inhibitors of Aurora-A activity may be a valuable adjunct to these agents in the treatment of cancers that overexpress AURORA-A.

"Defective microtubule-kinetochore attachment and spindle formation

Why should elevated Aurora-A activity result in cell cycle abnormalities and chromosomal instability? The yeast ortholog of mammalian Aurora kinases, IPL1p, has been implicated in the mechanisms that regulate the attachment of chromosomes to the mitotic spindle during the metaphase-anaphase transition during mitosis. Several data suggest that IPL1p may work at a proximal position in these mechanisms to regulate steps in the capture of microtubules by kinetochores Biggins et al. 1999 and Li et al. 2002, and after capture, to stabilize correctly attached kinetochores by sensing the tension exerted via bipolar microtubule attachment (Biggins and Murray, 2001). These functions are apparently dependent upon the kinase activity of IPL1p (Biggins et al., 1999).

ALSO:
.".. Aurora-A overexpression in mammalian cells dysregulates these processes," Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp
Authors:
Yan Li,"
-----------------------------------------OTHER CONTINUE TO BELIEVE:
" Resistance to chemotherapeutic drugs generally, and to Taxol in particular, takes many forms. The best understood mechanism of resistance to Taxol involves the multidrug-resistance phenotype, mediated by the P-glycoprotein efflux pump"
" drug-resistant cancer cell lines and human tumor tissues have been shown to harbor tubulin gene mutations, alterations in total tubulin content, altered microtubule polymer levels, altered expression of tubulin isotypes, and altered microtubule-associated protein expression (1320). All of these modifications in tubulin could, directly or indirectly, influence microtubule dynamics. Because suppression of microtubule dynamic instability is the event most sensitive to the lowest concentrations of Taxol, we have hypothesized that drug-sensitive and -resistant cells might display altered dynamic instability profiles that could ultimately be responsible for the resistance."

Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics

A. Gonçalves*
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LAI ET AL BELIEVE
" Taxol (paclitaxel) resistance represents a major challenge in breast cancer treatment. The TAZ (transcriptional co-activator with PDZ-binding motif) oncogene is a major component of the novel Hippo-LATS signaling pathway and a transcriptional coactivator that interacts with and activates multiple transcription factors to regulate various biological processes. Here, we report that elevated levels of TAZ found in human breast cancer cells are responsible for their resistance to Taxol."
" higher level of TAZ in mammary cells may be responsible for their resistance to Taxol."
 AND SAY ALL THIS COULD BE PREDICTED!

Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells

Satoshi Nakayama1
THESE AUTHORS CONTEND:

"We found that changes in CDK1 specific activity after paclitaxel treatment predicted the paclitaxel sensitivity of breast cancer cells and xenograft tumors. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel."
FURTHERMORE
" We found that an increase in CDK1 specific activity after paclitaxel treatment correlates with sensitivity of the xenografts to paclitaxel, and a lack of change in CDK1 specific activity correlates with a lack of sensitivity of the xenografts to paclitaxel. These findings indicate that analysis of CDK1 activity could be a powerful approach for predicting paclitaxel sensitivity."
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MOST INTRIGUING THOUGH :

"MICRORNA-125B CONFERS THE RESISTANCE
OF BREAST CANCER CELLS TO
PACLITAXEL THROUGH SUPRESSION OF PRO-APOPTOTIC BCL-2 ANTAGONIST
KILLER 1 ( BAK 1) EXPRESSION"
MING ZHOU ET AL
THIS APPEAR TO BE THE STUFF TO BELIEVE IN BECAUSE IT GOES ALONG WITH HYPOXIA
WE KNOW THAT ENDOTHELIAL DISTURBANCE BY CHEMOTHERAPY INDUCES HYPOXIA OR HYPOXIC CONDITION STRESSING THE CELL, AND INDIRECTLY INDUCING THE MTOR FOR SURVIVAL.   THIS IS MY FAVORITE CHOICE AND CREATE AN OPPORTUNITY FOR MTOR INHIBITION AFTER FAILURE OF CHEMOTHERAPY!
MTOR EQUAL SURVIVAL

Expression of the anti-apoptotic gene survivin correlates with taxol resistance in human ovarian cancer

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IF YOU WONDER ABOUT TAXOTERE  :   NO CROSS RESISTANCE!

No cross-resistance of taxotere and taxol to conventional chemotherapeutic agents against gastric cancers as detected by MTT assay.

Maeda S, Saikawa Y,
" both intrinsic and acquired TXT-related drug resistance in these PAC cell lines is mainly mediated by P-gp, but had no relationship to MRP and LRP expressions"  lIU ET AL!
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IN PROSTATE CANCER THIS IS NOT GOOD NEWS HOWEVER GIVEN THE CURRENT PATTERNS OF TREATMENT IN THIS DISEASE

"Abiraterone before Taxotere/Docetaxel chemotherapy may cause resistance to Taxotere/Docetaxel
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