Cancer Chemotherapy Ebook
This is true for both minor conditions and serious illnesses. For example, a study on female breast cancer survivors revealed that women who participated in support groups lived longer and experienced better quality of life when compared with women who did not participate. In the support group, women learned coping skills and had the opportunity to share their feelings with other women in the same situation.
Chemotherapy is often ineffective in the treatment of cancer the tumour cells of a large number of patients are either inherently drug-resistant or a drug-resistant phenotype may develop during the treatment. It is generally accepted that in the majority of the cases the molecular basis of multidrug resistance (MDR) is the overexpression of the so-called multidrug transporters. Elevated expression of these proteins was found in drug-resistant tumour cells of patients as well as in cell lines exposed to selection by increasing concentration of cytotoxic compounds. At the time of writing, it is well established that there are three major multidrug transporter proteins contributing to the MDR phenotype P glycoprotein (Pgp also known as multidrug resistance protein MDR1 or ABCB1, according to the Gene Nomenclature Database (http the multidrug resistance-associated protein 1 (MRP1 ABCC1) and the breast cancer resistance protein (BCRP ABCG2). The multidrug transporters belong to the ATP...
Another novel drug delivery system is to implant AED-containing polymers onto the seizure focus in the brain, thereby bypassing the BBB. This may allow the use of compounds that have anti-convulsant properties in vitro but that cannot be administered systemically either because of poor BBB penetration or because of significant systemic toxicity. Patients with epileptogenic lesions not amenable to resection, such as owing to the risk of damaging eloquent cortex, could have the polymers placed in the vicinity of the seizure focus. Advances in neurosurgical techniques have made possible the implantation of polymers of 2-3 mm in diameter into the brain stereotactically via cannulae, without resorting to craniotomy. Implantation of adenosine-releasing and GABA-releasing polymers into rat models of epilepsy reduced or attenuated seizures 63, 64 . Controlled-release polymers containing chemotherapy placed in the tumour bed during debulking operation have already been tested clinically in...
The patient underwent a right temporal lobectomy. Pathological examination of the resected tissue was consistent with hippocampal sclerosis. During the year that elapsed after our initial meeting, her father was diagnosed with Alzheimer's disease, her mother developed breast cancer, and a close male friend was diagnosed with testicular cancer.
Entitled to Respect A National Survey of Teens Attitudes and Behaviors About Epilepsy and Acceptance Executive Summary
Summary Entitled to Respect A National Survey of Teens' Attitudes and Behaviors About Epilepsy and Acceptance Executive Summary summarizes the results of a survey of teens' attitudes and behaviors about epilepsy. The survey consisted of a questionnaire that was distributed to teens throughout the United States by 20 affiliates of the Epilepsy Foundation from March through July 2001 in schools selected by the affiliates. The questionnaire asked about respondents' (1) demographics (2) awareness of epilepsy (3) knowledge of epilepsy (4) perceived stigmas associated with epilepsy and (5) awareness of muscular dystrophy, human immunodeficiency virus infection acquired immunodeficiency syndrome, arthritis, diabetes, breast cancer, and Parkinson's Disease. Results are based on 19,441 usable questionnaires. Thirty-six percent of the respondents felt that kids with epilepsy are likely to get picked on or bullied more than other kids. Only 25 percent felt this is unlikely to happen. Thirty-one...
Neuropathic pain is common and occurs in many diseases such as diabetes, paraneoplastic disorders, multiple sclerosis, systemic vasculitides, human immunodeficiency virus (HIV) and as a result of chemotherapy-associated neuropathy. Several of these conditions are also associated with seizures. Gabapentin and pregabalin both appear to be very effective for neuropathic pain 97, 98 . There is also evidence that oxcarbazepine and lamotrigine are effective 99, 100 . In addition, topiramate, levetiracetam and zonisamide are used, although there is less evidence supporting their effectiveness 101-103 .
In cancer cells, MDR1 overexpression can be constitutive, present before exposure to anticancer drugs, and in this situation is related to the cell type of origin of the malignancy and may be associated with chromosomal rearrangements 23 , It may also be increased or induced by exposure to anticancer drugs which may select out resistant cells, a phenomenon commonly utilized in vitro. Constitutive MDR1 expression confers intrinsic resistance while induction or selection of MDR1 overexpression by exposure to chemotherapy confers acquired drug resistance.
A major obstacle to the effective treatment of cancer is the intrinsic or acquired resistance to chemotherapeutic agents. One form of drug resistance, known as multidrug resistance (MDR), is a phenomenon whereby cells that acquire resistance to certain cytotoxic drugs generally demonstrate cross-resistance to other, sometimes structurally and functionally unrelated drugs. Several mechanisms that mediate MDR have been identified. P glycoprotein (Pgp) is a known mediator of MDR. However, failure to completely sensitize some drug resistant tumours to chemotherapy using Pgp-reversing agents suggests the existence of multiple mechanisms of cancer drug resistance. Selecting resistant cells to non-Pgp substrates would reveal novel mechanisms of resistance.
Some of the earliest modulators (first generation) were agents that were in clinical use and were found to have a general mild Pgp modulating ability. Examples are verapamil, cyclosporin and tamoxifen. The advantages with these agents were the general familiarity with longer-term use and knowledge of chronic toxicity. Limitations were the lack of specificity of action, poor therapeutic ratio and possibility of pharmacokinetic interaction with other drugs (particularly with agents such as cyclosporin). These agents were subsequently combined in different schedules with cyclical chemotherapy to see if the anticancer effect of chemotherapy could be enhanced.
Three types of drug efflux pumps, the multidrug resistance gene 1 (MDR1 or ABCB1)-encoded P glycoprotein, the multidrug resistance-associated protein (MRP or ABCC1) and breast cancer resistance protein (BCRP or ABCG2) may play an important part in the intrinsic or acquired defence of cells against drugs. Recent studies have begun to show the broad tissue distribution and drug substrate specificity of the seven MRP family members (MRP1-7 or ABCC1-6 and ABCC10). MRPs are (multispecific) organic anion transporters, which can transport negatively charged anionic drugs and neutral drugs conjugated to glutathione, glucuronate or sulfate. MRP4 and MRP5 broaden the spectrum of drug resistance to nucleotide analogue drugs. Some MRPs can also transport neutral drugs if co-transported with glutathione. MRP1 and MRP5 are abundant in almost every organ and are prominently present in the brain. High levels of MRP1 are present in the epithelium of the choroid plexus. Using mutant mice...
Multidrug resistance in a series of mammalian cell lines (Kartner et al 1983). The gene encoding Pgp was cloned and named the MDR1 gene expression of this gene was found in a variety of cancers. In some tumours expression was found at the time of diagnosis (kidney, colon and adrenocortical) while in others, expression was found after relapse and treatment failure (breast cancer, lymphoma and leukaemia) (Sandor et al 1998). The potential relevance of this for clinical oncology received a boost in 1981 when Tsuruo observed that verapamil was able to overcome this MDR phenotype (Tsuruo et al 1981). Subsequently, it was recognized that several compounds already in use in the clinic were able to inhibit Pgp in the laboratory. In addition to verapamil, these 'first generation' compounds included quinidine, amiodarone, nicardapine, nifedipine, quinine, tamoxifen and cyclosporin (Table 1) (Ferry et al 1996).
Are able to kill certain parasites and on the other hand are not going to cause too much harm to the host organism when applied in effective doses. This is a paradigm that has driven both antibiotic development and also the concept of cancer chemotherapy. Many years later Erlich lamented that drug resistance has followed the development of new drugs 'like a faithful shadow'.
Therefore have to be combined with other therapeutic agents such as chemotherapy. The initial step in clinical development of these agents is to demonstrate that the modulator can be administered safely with manageable toxicity. Once this is determined, the Pgp modulator can be used in combination with other Pgp substrates, to improve the therapeutic efficacy of the latter. The toxicity seen with Pgp modulator trials can also be predicted to a certain extent. Specificity of the modulator is of major importance and therefore significant toxicities were predictable particularly with first generation modulators such as verapamil (cardiac toxicity) or cyclosporin (immunosuppression). In general, second- and third-generation agents are much more specific and therefore nonspecific toxicity is minimized. As was previously mentioned, toxicity is also dependent on the normal distribution of Pgp in the body. In this regard, class effects such as ataxia and hyperbilirubinaemia were often seen as...
The diagnostic measures are the same as explored in the initial section of this chapter. Phenytoin, carbamazepine and phenobarbital are all potent enzyme-inducing AEDs thus these AEDs can interfere with many chemotherapeutic agents by accelerating their metabolism and reducing their therapeutic effects. This occurs with vinca alkaloids, methotrexate, taxanes and others. Likewise, some chemotherapy drugs can alter the pharmacokinetics of AEDs, resulting in decreased seizure control or toxicity, though this can usually be managed via serum levels and dose adjustments. Other agents, such as valproic acid, are enzyme inhibitors and can potentially increase the serum concentration of some chemotherapeutics. Newer AEDs, such as gabapentin, pregabalin and levetiracetam, are promising in treating seizures in patients with brain tumours as they have no known or expected interactions with chemotherapeutic agents 64, 65 .
Fraser, S.C.A., Ramirez, A.J., Ebbs, S.R. et al. (1993). A daily diary card for quality of life measurement in advanced breast cancer trials. Br J Cancer, 67, 341-6. Geddes, D.M., Dones, L., Hill, E. et al. (1990). Quality of life during chemotherapy for small cell lung cancer assessment and use of a daily diary card in a randomised trial. Eur J Cancer, 26, 484-92.