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PubMed1990

Multidrug resistance to alkylating agents and platinum compounds: state of our knowledge.

Resistance to platinum-containing drugs and alkylating agents is multifactorial. Relapsed patients and those who have an incomplete response to induction chemotherapy are unlikely to achieve a complete response to other treatments. This pattern of resistance to therapy is very broad in that patients not only fail to respond to drugs from the same pharmacologic classes as used in primary treatment, but also do not respond to other available drugs or irradiation. Using ovarian cancer as a prototype tumor, researchers have initiated laboratory studies to determine the mechanisms responsible for this drug-resistance phenotype. Insights into this action may promote development of therapeutic strategies to prevent the onset of resistance or reverse resistance when it occurs.

Alkylating Agents↗
PubMed1983

[Interaction of bifunctional binuclear platinum compounds with IMP and poly(I)].

A study has been made of the IMP or poly(I) interactions leading to substitution of X and Y ligands in binuclear platinum complexes of the general formula: [X-Pt(dien)]m+-(CH2)6-[(dien)Pt-Y]n+ (NO3)m+n, where dien stands for diethylenetriamine, X = H2O, Y = Br, m = 2, n = 1 (I), X = Y = H2O, m = n = 2 (II), and X = Y = Br, m = n = 1 (III). These compounds were found to be bifunctional reagents. Two reactive groupings of (I) bind to poly(I) at different rates due to the higher reactivity of [(dien)Pt(H2O)]2+ as compared to [(dien)PtBr]+. It allows to introduce the reactive bromotriaminoplatinum group into polynucleotide structure by rapid reaction with aquatriaminoplatinum group of compound (I). Increase in free bromide ion concentration in solution inhibits the reactivity of bromotriaminoplatinum groups, thus making possible regulation of the reactivity of this group introduced into a polynucleotide. The results obtained suggest that heterobifunctional platinum compounds can be used for design of complementary addressed reagents - oligo- and polynucleotides carrying the reactive groups.

Chemical Phenomena↗
PubMed1992

[Pharmacological approach to the platinum compounds].

Cis-Diamminedichloroplatinum (II) (cisplatin) is one of the key drugs in the treatment of solid tumors. Cis-Diammine-1, 1-cyclobutanedicarboxylateplatinum (II) (carboplatin) and cis-diammine (glycolato)-platinum (254-S) are second-generation platinum-coordination complexes developed in recent years not only to reduce nephrotoxicity but also to have antitumor activity equivalent or superior to cisplatin. Comparative pharmacological study among these three compounds was performed. Six different small cell lung cancer (SCLC) and six non-small cell lung cancer (NSCLC) lines were exposed to different concentration of the three platinum compounds, cisplatin, carboplatin and 254-S in colony assay. The IC50 values for cisplatin, carboplatin and 254-wS in SCLC cell lines were significantly lower than those in NSCLC cell lines. In addition, the IC50s for carboplatin were significantly higher than those for cisplatin and 254-S in both SCLC and NSCLC lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/sqm cisplatin, 450 mg/sqm carboplatin, and 100 mg/sqm 254-S were each given to five patients by intravenous drip infusion over 30 min. Ultrafilterable platinum declined biexponentially for carboplatin and 254-S, whereas the free platinum of cisplatin fitted to a monoexponential equation. We reported the equation between nadir platelet count (NPC) and Ccr, by retrospective analysis in 38 "Training Set" patients; [NPC] = 2,783.4 x [Ccr.]- [NPC] = 2,783.4 x [Ccr.]- 64,264.7. To evaluate prospectively the equation in the "Test Set" patient and to refine it. Thirty four patients who entered phase II study of 254-S for NSCLC were prospectively analysed. Significant correlation was observed between observed NPC and predicted NPC which was calculated by the equation (R = 0.51). To refine the equation, all patients in both "Training Set" and "Test Set" were reanalyzed. Simple linear least model is shown as the best fit and refined equation is as follows: [NPC] = 2,201.7 x [Ccr.]-17,695.0. Bioassay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target. Biological comparison was performed on the basis of the antitumor activity of patient's plasma using the antitumor index (ATI). The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for the three agents against SCLC and NSCLC according to the following equation: [Reported Response(%)] = 11.5668 + 0.0014 x [ATI] (r = 0.97).

Carboplatin↗
PubMed2001

Gemcitabine in combination with new platinum compounds: an update.

Combinations of gemcitabine (Gemzar) with cisplatin (Platinol) are among the most active new chemotherapy regimens developed for advanced non-small-cell lung cancer. Carboplatin (Paraplatin) is a platinum analog devoid of many of the nonhematologic toxicities associated with cisplatin. Although few direct comparisons have been made, when administered by area under the concentration-time curve (AUC) dosing, carboplatin is probably equivalent to cisplatin in advanced non-small-cell lung cancer and provides an improved therapeutic index. Based on its favorable toxicity profile, carboplatin has supplanted cisplatin for use in combination with paclitaxel in several different tumor types. Initial trials combining gemcitabine and carboplatin using standard days 1, 8, and 15 dosing of gemcitabine suggested that thrombocytopenia was problematic. More recently, 21-day schedules in which gemcitabine is administered only on days 1 and 8 have demonstrated both efficacy and improved toxicity profiles. Here we review recent studies investigating gemcitabine plus carboplatin and preliminary data regarding combinations of gemcitabine with the new platinum analog oxaliplatin.

Antimetabolites, Antineoplastic↗
PubMed1986

Uptake of platinum compounds in human tumors. In vitro study.

The kinetics of intratumoral uptake of cisplatin, carboplatin (CBDCA) and TNO-6 were studied in vitro in fragments of tumors of the head and neck maintained in culture medium under conditions simulating therapeutic conditions of chemo-embolization. Cisplatin and TNO-6 are more rapidly taken up than CBDCA (carboplatin). With each of these compounds, after 24 hours a fraction of the platinum taken up is not irreversibly bound to the tissue. The rate of uptake and the proportion of platinum irreversibly bound depends a great deal on the tumor under study. The characteristics of the diffusion indicate that TNO-6 is better used with chemo-embolization than with systemic injection. The opposite finding is seen with carboplatin. Cisplatin appears to to be about equally well-suited for either method of injection.

Aged↗
PubMed1995

Pharmacokinetics and antitumor activity of a new platinum compound, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II), as determined by ex vivo pharmacodynamics.

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0-->infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053R > CBDCA > CDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P < 0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

Animals↗
PubMed1992

T-cell-dependent popliteal lymph node reactions to platinum compounds in mice.

The requirements for sensitization to complex salts of platinum were investigated in a mouse model by means of the popliteal lymph node (PLN) assay. A single subcutaneous injection of dissolved hexachloroplatinates without adjuvant induced a vigorous primary immune reaction in the draining PLN. Dose-dependent lymph node activation was determined by an increase in both PLN weight and cellularity. In C57BL/6 mice, peak reactions were obtained around day 6 after administration of 90-180 nmol Na2[PtCl6] or (NH4)2[PtCl6] per animal. Mice primed to [PtCl6]2- mounted an enhanced response upon local restimulation with suboptimal doses of the same but not unrelated compounds, indicating a specific secondary response. T cells were required to elicit PLN reactions to [PtCl6]2-, because athymic nude mice completely failed to respond, in contrast to their +/nu littermates. Differences between various inbred strains of mice revealed that Pt-induced PLN responses are genetically controlled. Moreover, the immunogenicity of Pt salts in mice is not confined to hexachloroplatinates, but other compounds, such as the antineoplastic agent cis-dichlorodiamine platinum, are able to induce comparable PLN reactions.

Animals↗
PubMed1985

In vitro binding of platinum compounds to human transferrin.

The binding of the antineoplastic drug cis-dichlorodiammineplatinum II (CDDP) and a related complex, potassium tetrachloroplatinite (K2PtCl4), to human transferrin in buffered anion solutions was studied over a period of two weeks. Separation of bound and free platinum was accomplished by gel chromatography with platinum analysis by atomic absorption spectrophotometry. The results demonstrated that K2PtCl4 was bound to a greater degree than CDDP in this system with 3-5 and 1-2 platinum atoms respectively, bound per transferrin molecule. However, it appears this interaction, which may involve the specific cation binding sites, does not play a significant role in the pharmacology of CDDP in vivo.

Bicarbonates↗
PubMed2005

Combination of chemotherapy without platinum compounds in the treatment of advanced non-small cell lung cancer: a systematic review of phase III trials.

Hitherto, platinum-based combinations are world-wide accepted regimens in the treatment of advanced non-small cell lung cancer (NSCLC) due to a clear survival improvement using various platinum-based doublets in comparison with best supportive care only. However, treatment-allocated time and period with high grade toxicity could be considered as wasted from the patient point of view and the high toxicity induced by platinum-based doublets urges the research of alternate treatments. Newest cytotoxic compounds as so-called third generation drugs (i.e. vinorelbine, docetaxel, paclitaxel and gemcitabine) yield a better efficacy/toxicity ratio. Platinum-free doublet regimens based on these new drugs are expected to offer the patients an improved survival without decreasing his quality of life. Recent update of ASCO guidelines recommended that "for stage IV NSCLC, [...] non-platinum-containing chemotherapy regimens may be used as alternatives to platinum-based regimens in the first line." In spite of this recommendation, the case of non-platinum containing regimen is still debatable and this review deals with methodological statements highlighted by the reports of 14 recently reported randomised studies comparing non-platinum with platinum-based doublets (174 words).

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

In vitro cytotoxicity, pharmacokinetics and ex vivo pharmacodynamics of a new platinum compound, cis-malonato [(4R,5R-4,5-bis(aminomethyl)-1,3-dioxolane-2-spiro-1'-cyclopentane] platinum (II).

The in vitro cytotoxicity of a new platinum complex, cis-malonato [(4R, 5R)-4,5-bis(aminomethyl)-1,3-dioxolane 2- spiro 1' cyclo-pentane]platinum(II) (SKI 2054R) and cisplatin (CDDP) was evaluated against two human stomach adenocarcinoma cell lines (MKN-45 and KATO III) and a human lung adenocarcinoma cell line (PC-14). The in vitro 50% inhibitory concentration (IC50) values of SKI 2054R and CDDP against MKN-45, KATO III, and PC-14 were 1.21 and 0.51, 2.11 and 0.83, and 2.90 and 0.77 micrograms/ml, respectively. The pharma-cokinetic and ex vivo pharmacodynamic studies on SKI 2054R and CDDP were performed in beagle dogs. Equitoxic doses of SKI 2054R and CDDP (7.0 and 3.0 mg/kg, respectively) were administered i.v. bolus to beagle dose in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the two drugs declined in a biexponential fashion. The mean area under the concentration-tine curve (AUC(0)--> infinity) determined for ultrafiltrable platinum derived from SKI 2054R, as an active component was 6.61 +/- 2.34 micrograms . h/ml (mean +/- S.D.), with an initial half-life of 0.26 +/- 0.14 h, a terminal half-life of 1.57 +/- 0.71 hour, a total clearance of 17.65 +/- 4.99 ml/min/kg, and a steady-state volume of distribution of 1.46 +/- 0.11 l/kg. The ex vivo antitumor activity of SKI 2054R was assessed using the ultrafiltrable plasma against MKN-45, KATO III, and PC-14 by tetrazolium-dye (MTT) assay and was compared with that of CDDP using the antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value recorded for SKI 2054R was higher than that noted for CDDP; however, statistical difference was not observed between SKI 2054R and CDDP, suggesting that the antitumor activity of SKI 2054R is comparable to that of CDDP. These results suggest that SKI 2054R is a new platinum complex which is worth being evaluated further.

Adenocarcinoma↗
PubMed1986

Noninvasive estimation of bound and mobile platinum compounds in the kidney using a radiopharmacokinetic model.

Nephrotoxicity remains a major limitation in the use of cisplatin [cis-diamminedichloroplatinum(II)]. Although several strategies are in use to limit this serious side effect, none is fully satisfactory. Classical pharmacokinetic studies of cisplatin have been based on blood and urine samples. As nephrotoxicity plays a significant role in the design of the therapeutic strategy, the kidneys should be considered as a separate state in any model formulated for ultimate control purposes. Previous studies of organ pharmacokinetics have relied on population measurements. The authors have developed an organ compartmental model from individual animal data obtained noninvasively. The eight-compartment model used to represent the distribution of cisplatin considers free and bound platinum in plasma, platinum in the erythrocytes, mobile and bound platinum in the kidneys, mobile and bound platinum in the tissues, and platinum in the urine. Data were collected from experiments with anesthetized female rats, after intravenous administration of [195mPt]cisplatin. Both arterial and bladder samples, and multiple images obtained with an Anger camera interfaced to a microcomputer were used. The model was estimated from individual data obtained after injection of a bolus of cisplatin (six animals). The model was validated by using it to predict data obtained from forcing the system with a different input function, a 0.5-h intravenous infusion (three animals). The results of this work show that it is possible to noninvasively study drug kinetics in organs that are not readily accessible to direct measurements in an individual, rather than relying on invasive measurements performed on a population.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

[The mechanisms of the hepatotoxicity of complex platinum compounds].

Cisplatin and platin given in LD50 to mice caused significant changes in hepatic metabolism. There was enhanced lipid peroxidation with accumulation of malonic dialdehyde, dienic conjugates, Schiff bases, decreased antiradical activity and alterations in the fractional composition of phospholipids with higher concentrations of membranotoxic ingredients. There was also an increase in the serum activity of transaminases and alkaline phosphatase.

Animals↗