Marro <m...@w...pl> napisał(a):

> Witam
>
> Prosze o dokladniejsze przetlumaczenie okreslenia "drug resistance
> and multidrug resistance modulators". Czy chodzi tu o modulatory
> opornosci lekowej? Nie za bardzo znam sie na farmacji, wiec jak
> ktos wie co moze oznaczac w/w termin, m=F3glby przyblizyc mi o co
> chodzi.
>
> Pozdro

moze raczej ''modulatory odpornosci na leki''.
chodzi prawdopodobnie o substancje, ktore modyfikuja nabyta odpornosc
bakterii, wirusow czy komorek rakowych na dzialanie wybranych lekow, np.
antybiotykow. Powoduja, ze bakterie staja sie bardziej wrazliwe na dany lek
czyli zwiekszaja skutecznosc tych lekow.

dla zobrazowania problemu ten cytat z publikacji:

IN THE UNITED States, about 25,000 women are diagnosed with ovarian cancer
annually, the majority of them in an advanced stage of the disease.1 In up
to 80% of the cases, the tumor will initially respond to modern platinum-
based combination chemotherapy, but 5-year survival rates in advanced-stage
disease remain disappointingly low.2 The main reason for these low cure
rates is the presence and selection of tumor cell clones that are resistant
to cytotoxic drugs. One of the best known mechanisms of drug resistance
occurring at the cellular level is the phenomenon of classical multidrug
resistance (MDR). MDR, in a strict sense, is the phenotype of cellular cross-
resistance to a broad range of structurally and functionally unrelated
cytotoxic agents. This type of resistance typically involves natural
products, including cytotoxic drugs used in the treatment of ovarian cancer,
such as taxanes (paclitaxel), anthracyclines (epirubicin and doxorubicin)
and epipodophyllotoxins (etoposide).3,4 A common feature of the MDR
phenotype is the decreased intracellular concentration of the cytotoxic
agents administered, resulting from an energy-dependent efflux mechanism.
This efflux function can be exerted by P-glycoprotein (Pgp), a 170-kd
transmembrane glycoprotein overexpressed in a range of mammalian cell lines
selected for MDR.5

We have previously shown that the expression of Pgp is an independent marker
of prognosis in a group of untreated Fédération Internationale de
Gynécologie et Obstétaique stage III ovarian cancer patients.6 Also, we
demonstrated, in accordance with Holzmayer et al,7 that pretreatment Pgp
expression predicted drug resistance in patients with advanced ovarian
cancer, if at least one MDR-related compound was used in the actual drug
combination. A number of studies indicate the clinical relevance of Pgp
expression in a broad range of solid tumor types, but results are difficult
to interpret because of methodologic problems in the measurement of Pgp
expression and the impossibility of determining its functional status in
solid-tumor tissue sections.8,9

In vitro studies showed that Pgp-related MDR can be reversed by a number of
substances, and early clinical trials were performed using such drugs as
verapamil and cyclosporine. The serious toxicity, related to the high plasma
levels required for MDR reversal with these agents, together with a
disappointing efficacy, have prompted the development of more potent and
less toxic MDR modulators.10,11 Valspodar (PSC 833) is an MDR modulator that
is designed to reverse drug resistance mediated through Pgp. Valspodar is a
cyclosporine D analog that is nonnephrotoxic and nonimmunosuppressive.12,13
In vitro studies have demonstrated that valspodar is approximately five- to
30-fold more potent than cyclosporine.14 Whereas cyclosporine seems to exert
its modulatory effects on Pgp by competitive inhibition,15,16 valspodar is a
high-affinity, noncompetitive inhibitor of Pgp and a poor substrate for Pgp-
mediated transport.14 Preclinical data demonstrated that valspodar can
reverse MDR in leukemias and solid tumors in mice.17,18 Phase I/II trials
have established that whole blood concentrations of valspodar sufficient to
reverse MDR in resistant cell lines (1,000 to 2,000 ng/mL) can be achieved
and are well tolerated in cancer patients.19,20 Because Pgp has a
physiologic role in tissues normally responsible for the transport and
excretion of cytotoxic drugs, treatment with Pgp inhibitors delays the
elimination of some anticancer drugs. In phase I studies of cytotoxic drugs
administered in combination with valspodar, the dose-normalized area under
the curve (AUC) of doxorubicin increased by 61% to 74% and the mean AUC of
etoposide increased by 84%.12,19 Therefor, this pharmacokinetic interaction
requires appropriate dose reduction of the cytotoxic drugs that are Pgp
substrates to provide effective treatment without increasing toxicity.

In a recently reported study in patients with heavily pretreated refractory
ovarian cancer, retreatment with reduced doses of paclitaxel in combination
with valspodar produced objective tumor responses in patients with known
paclitaxel-refractory disease.20 Interim results indicate that two (4%)
complete responses (CRs) and two (4%) partial responses (PRs) were observed
in 49 assessable patients. Although the overall response rate was modest,
the combination of valspodar and paclitaxel was safe, tolerable, and
resulted in renewed responses in some patients with refractory ovarian
carcinoma. The objectives of the current study were (1) to determine the
safety and maximum-tolerated dose (MTD) of doxorubicin in combination with
valspodar and cisplatin, and (2) to determine the efficacy of the
combination of valspodar, cisplatin, and doxorubicin (administered at the
MTD) in patients with ovarian cancer refractory to the combination of
anthracyclines and cisplatin.

http://www.jco.org/cgi/content/full/19/12/2983




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