Determination of the anthrapyrazole anticancer drug CI-941 in plasma and urine by solid-phase extraction and high-performance liquid chromatography.
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Anthraquinones↗
Biomedical subjects
A H Calvert
Publications and source records attributed to A H Calvert.
Estimation of the in vitro and in vivo inhibitory effects of antifolates upon thymidylate synthase (TS) in whole cells.
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Animals↗
The pharmacokinetics and toxicity of the anthrapyrazole anti-cancer drug CI-941 in the mouse: a guide for rational dose escalation in patients.
CI-941 is a new synthetic DNA-binding agent selected for phase I clinical evaluation. The drug has broad-spectrum antitumour activity against a number of murine tumours and, in contrast to doxorubicin, is unlikely to induce cardiotoxicity by a free-radical-mediated mechanism. In this study the toxicity and pharmacokinetics of CI-941 were studied in the mouse to enable the implementation of a pharmacokinetically guided dose-escalation strategy in patients. Following a single i.v. bolus injection in mice, CI-941 induced dose-dependent leukopenia. The white blood cell counts were suppressed on day 3 by 18%, 50% and 65% of control, at doses of 10, 15 and 20 mg/kg CI-941, respectively. Other toxicities such as weight loss, alopecia, diarrhoea and convulsions were observed at doses greater than 20 mg/kg. Lethality studies in female Balb-c mice resulted in an LD10 value of 20 mg/kg (95% confidence limits; range, 19-21 mg/kg) and an LD50 value of 22 mg/kg (95% confidence limits; range, 21-23 mg/kg). The pharmacokinetics of CI-941 were studied at four dose levels from 1/10 of the LD10 to the LD10 (20 mg/kg). The drug was rapidly cleared from the plasma (250-400 ml/min per kg) at a rate approaching the cardiac output of mice, displaying triphasic plasma pharmacokinetics. The area under the plasma CI-941 concentration vs time curve (AUC) was linear with respect to the dose, up to and including 15 mg/kg (AUC = 110 microM x min at 15 mg/kg), but became non-linear at 20 mg/kg (AUC = 277 microM x min). Despite 80%-84% plasma protein binding, CI-941 was rapidly and extensively distributed into tissues, especially the kidney. Following i.v. bolus injections at doses of 1.5 and 15 mg/kg, elimination of the parent compound by urinary excretion accounted for 12%-18% of the delivered dose. A phase-I starting dose (based on that equivalent to 1/10 of the LD10 in the mouse) of 5 mg/m2 CI-941 is recommended for single administration schedules. In addition, a pharmacokinetically guided dose-escalation strategy, based on achieving a target AUC of 110 microM x min, is proposed.
Animals↗
Carboplatin and etoposide pharmacokinetics in patients with testicular teratoma.
The pharmacokinetics of carboplatin and etoposide were studied in four testicular teratoma patients receiving four courses each of combination chemotherapy consisting of etoposide (120 mg/m2 daily x 3); bleomycin (30 mg weekly) and carboplatin. The carboplatin dose was calculated so as to achieve a constant area under the plasma concentration vs time curve (AUC) of 4.5 mg carboplatin/ml x min by using the formula: dose = 4.5 x (GFR + 25), where GFR is the absolute glomerular filtration rate measured by 51Cr-EDTA clearance. Carboplatin was given on either day 1 or day 2 of each course and pharmacokinetic studies were carried out in each patient on two courses. Etoposide pharmacokinetics were also studied on two separate courses in each patient on the day on which carboplatin was given and on a day when etoposide was given alone. The pharmacokinetics of carboplatin were the same on both the first and second courses, on which studies were carried out with overall mean +/- SD values (n = 8) of 4.8 +/- 0.6 mg/ml x min, 94 +/- 21 min, 129 +/- 21 min, 20.1 +/- 5.41, 155 +/- 33 ml/min and 102 +/- 24 ml/min for the AUC, beta-phase half-life (t 1/2 beta), mean residence time (MRT), volume of distribution (Vd) and total body (TCLR) and renal clearances (RCLR), respectively. The renal clearance of carboplatin was not significantly different from the GFR (132 +/- 32 ml/min). Etoposide pharmacokinetics were also the same on the two courses studied, with overall mean values +/- SD (n = 8) of: AUC = 5.1 +/- 0.9 mg/ml x min, t 1/2 alpha = 40 +/- 9 min, t 1/2 beta = 257 +/- 21 min, MRT = 292 +/- 25 min, Vd = 13.3 +/- 1.31, TCLR = 46 +/- 9 ml/min and RCLR = 17.6 +/- 6.3 ml/min when the drug was given alone and AUC = 5.3 +/- 0.6 mg/ml x min, t 1/2 alpha = 34 +/- 6 min, t 1/2 beta = 242 +/- 25 min, MRT = 292 +/- 25 min, Vd = 12.5 +/- 1.81, TCLR = 43 +/- 6 ml/min and RCLR = 13.4 +/- 3.5 ml/min when it was given in combination with carboplatin. Thus, the equation used to determine the carboplatin accurately predicted the AUC observed and the pharmacokinetics of etoposide were not altered by concurrent carboplatin administration. The therapeutic efficacy and toxicity of the carboplatin-etoposide-bleomycin combination will be compared to those of cisplatin, etoposide and bleomycin in a randomised trial.
Antineoplastic Agents↗
Thymidylate synthase: a target for anticancer drug design.
N10-Propargyl-5,8-dideazafolic acid (CB3717) has proved to be an interesting recent addition to the spectrum of antifolate drugs. Its sole biochemical locus of action appears to be thymidylate synthase, an inhibitory effect which is potentiated by intracellular polyglutamation. The drug has shown a spectrum of clinical activity and toxicity which is unusual for an antimetabolite. It seems likely that the former is attributable to its inhibition of TS, whilst the latter relates to the drug's poor aqueous solubility at physiological pH. Seminal to the discovery of a new generation of more selective thymidylate synthase inhibitors has been the observation that the C2 desamino derivative (CB3804) retains the useful TS-inhibitory and cytotoxic properties of CB3717. It is some two orders of magnitude more water soluble than CB3717 at physiological pH and appears not to produce, in the mouse, the liver and kidney toxicities which have restricted the wider use of CB3717. Thus, in desamino CB3717, it has proved possible to separate the structural features determining antitumor activity from those which are responsible for its systemic toxicities. These encouraging results prompted systematic structure-activity studies of other C2-modified quinazolines, which revealed that the desirable properties of the desamino compound are not unique. Results with two other CB3717 analogues, the C2-methyl (CB3819) and C2-methoxy (CB3828), have been discussed in the present paper. All three CB3717 analogues exhibit TS-inhibitory activities which are broadly comparable to those of the parent drug. In continuous culture CB3828 is as cytotoxic as CB3717, while CB3804 and CB3819 are at least an order of magnitude more potent. As with the desamino derivative (CB3804), so CB3819 is substantially more water soluble than CB3717 and is apparently devoid of its major toxicities. However, the effects of CB3828 on whole cell TS inhibition, both in vitro and in vivo, are rapidly reversible upon removal of exogenous compound, while the inhibition is sustained in similar experiments with the other three compounds. It is likely that these effects relate to the extent to which the various derivatives are converted to polyglutamate species and retained intracellularly. With the exception of CB3828, all are good substrates for FPGS, and the polyglutamate derivatives of CB3717, CB3804 and CB3819 are better TS inhibitors than the corresponding monoglutamates. CB3804 and CB3819 are less toxic and are cleared from the plasma much more rapidly than CB3717, so that the rate and extent of their polyglutamation may be an essential prerequisite of pharmacological activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Quinazoline antifolate thymidylate synthase inhibitors: nitrogen, oxygen, sulfur, and chlorine substituents in the C2 position.
The synthesis of 16 new N10-propargylquinazoline antifolates with methylamino, ethylamino, (2-aminoethyl)amino, [2-(dimethylamino)ethyl]amino, (2-hydroxyethyl)amino, (carboxymethyl)amino, dimethylamino, imidazol-1-yl, methoxy, ethoxy, phenoxy, 2-methoxyethoxy, 2-hydroxyethoxy, mercapto, methylthio, and chloro substituents at C2 is described. In general, the synthetic route involved the coupling of diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate (5a) with 6-(bromomethyl)-2-chloro-3,4-dihydro-4-oxoquinazoline in N,N-dimethylformamide with calcium carbonate as the base, displacement of the C2-chloro substituent with nitrogen and sulfur nucleophiles, and deprotection using mild alkali. The C2-ether analogues were most conveniently prepared by coupling 5a with 6-(bromomethyl)-2,4-diakoxy(or diphenoxy)quinazolines. In this series the final deprotection step with aqueous alkali gave simultaneous selective hydrolysis of the C4-alkoxy or C4-phenoxy substituent. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). As a measure of cytotoxicity, they were examined for their inhibition of the growth of L1210 cells in culture. The C2-methoxy analogue 11a was equivalent to the previously described tight binding TS inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717, ICI 155387, 1a) against the TS enzyme and exhibited enhanced potency in culture. The C2-methoxy substituent also gave a 110-fold enhancement in aqueous solubility relative to the C2-amine. These results suggest that 11a will be an interesting compound for further study as a potential antitumor agent in vivo. A further series of 2-methoxyquinazoline antifolates with modified alkyl substituents at N10 is also described. None of these analogues equalled the activity of 11a. Thus the propargyl group appears to be the optimum N10 substituent in both 2-amino- and 2-methoxyquinazoline antifolates.
Animals↗
Quinazoline antifolates inhibiting thymidylate synthase: 2-desamino derivatives with enhanced solubility and potency.
The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity. The insolubility is caused by the 2-amino-3,4-dihydro-4-oxopyrimidine moiety of the drug which stabilizes the solid state by intermolecular hydrogen bonding. In examining this moiety we have removed the 2-amino group and now report on 2-desamino-10-propargyl-5,8-dideazafolic acid (8e) and four analogues with H, Me, Et, and allyl at N10. 3,4-Dihydro-4-oxo-6-methylquinazoline was solubilized by alkylating the lactam nitrogen with chloromethyl pivalate. Reaction with N-bromosuccinimide gave the corresponding 6-bromomethyl compound, which was coupled with diethyl N-(4-aminobenzoyl)-L-glutamate or the appropriate N-substituted derivative thereof. The quinazoline N3 nitrogen and carboxyl groups in the product were simultaneously deprotected by cold alkali in the final step to give the desired five antifolates. These were tested against L1210 TS and it was found that removal of the 2-amino group caused a slight (3-9-fold) loss of TS inhibition. 8e was only 8-fold a lesser TS inhibitor than the parent drug. Inhibition of rat liver dihydrofolate reductase was reduced by over 1 order of magnitude for three compounds tested. All five analogues were more cytotoxic to L1210 cells in culture than their 2-amino counterparts; 8e was 8.5-fold more active with an ID50 of 0.4 microM. This remarkable result probably owes to increased cellular penetration. 8e was 5-fold more soluble than 1 at pH 5.0 and greater than 340-fold more soluble at pH 7.4.
Animals↗
Cisplatin/carboplatin cross-resistance in ovarian cancer.
Forty-six patients who were treated with cisplatin or carboplatin for ovarian cancer developed resistant disease (no change in measurable disease or progressive disease) and 'crossed over' to the other platinum compound. Three patients (6.5%) responded to this second treatment but these patients had no survival advantage compared to the non-responders. One responder had progressive disease on cisplatin before crossing over to carboplatin.
Adult↗
Carboplatin dosage: prospective evaluation of a simple formula based on renal function.
A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.
Antineoplastic Agents↗
Introduction: a history of the progress of anticancer chemotherapy.
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Antineoplastic Agents↗
Quinazoline antifolates inhibiting thymidylate synthase: computer modelling of the N10 substituent.
The synthesis and biological properties of N10-(2,2,2-trifluoroethyl)-5, 8-dideazafolic acid are described. It was fivefold less active as an inhibitor of L1210 thymidylate synthase (TS) than its N10-ethyl congener and sevenfold less active as an inhibitor of the growth of L1210 cells in culture. CNDO calculations were performed on the following N10 substituents in a model fragment of 5, 8-dideazafolic acid: propargyl, ethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl and methyl. The resulting values of partial charge on the distal terminus of the substituent correlated with the TS inhibition induced by the substituent. In particular, the mildly net positive charge on the acetylenic hydrogen in the propargyl substituent (+0.064) was not matched by any other in the series. N10-propargyl-5, 8-dideazafolic acid continues as the best inhibitor in this series.
Animals↗
Formation and retention and biological activity of N10-propargyl-5,8-dideazafolic acid (CB3717) polyglutamates in L1210 cells in vitro.
The formation, retention and biological activity of the polyglutamate metabolites of the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) has been investigated in L1210 murine leukaemia cells grown in vitro. CB3717 polyglutamates were measured by HPLC using high specific activity 3H-CB3717. Following the exposure of cells to 50 microM CB3717 for 6, 12 and 24 hr total cellular radioactivity corresponded to 4.5 +/- 1.5, 6.8 +/- 3.6 and 5.9 +/- 3.4 microM drug derived material, respectively. Of this material, greater than 70%, 57 +/- 3% and 51 +/- 5% was in the form of unchanged CB3717 at 6, 12 and 24 hr respectively. The remaining radioactivity was associated with polyglutamate metabolites of CB3717, predominantly the tetra and pentaglutamate forms. Following the removal of extracellular drug after incubation for 24 hr and resuspension in drug free medium, unchanged CB3717 was lost rapidly from the cells such that after 6 hr it accounted for only 5% of total cellular radioactivity. In contrast, levels of CB3717 tetra and pentaglutamates declined solely due to dilution during cell division. Measurement of the whole cell TS activity by 3H-deoxyuridine incorporation into DNA indicated that, despite the loss of unchanged CB3717 from the cell, enzyme activity remained suppressed (less than 10% of control) for at least 24 hr after resuspension in drug free medium. The TS inhibitory activity of the polyglutamated metabolites of CB3717 was investigated using enzyme purified from L1210 cells. As inhibitors, the metabolites were 26-, 87-, 119- and 114-fold more potent than CB3717 as the di-, tri-, tetra- and pentaglutamate forms, respectively. However, as inhibitors of dihydrofolate reductase prepared from rat liver, CB3717 polyglutamates were no more than 5-fold More potent than the parent compound. This study has shown that CB3717 can undergo polyglutamation in tumour cells and that the metabolites are preferentially retained giving rise to prolonged TS inhibition. By virtue of their potent TS inhibitory activity these metabolites are, therefore, most probably the intracellular effectors of CB3717 cytotoxicity.
Animals↗
Carboplatin or cisplatin?
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Antineoplastic Agents↗
Development of an assay for the estimation of N10-propargyl-5,8-dideazafolic acid polyglutamates in tumor cells.
A method is described herein for the isolation and quantitation of polyglutamates of the thymidylate synthase (TS) inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in tumor cells exposed to the drug in vitro. Cells were incubated with 50 microM 3H-CB3717 for 12 h and then disrupted by sonication. CB3717 and its polyglutamates were extracted by boiling in 0.01 M Tris-HCl pH 10. The extract was concentrated by lyophilization and analyzed by reverse phase HPLC (10 x 0.46-cm Polygosil 5-micron C18 column) using linear gradient elution (5-16% acetonitrile in 0.1 M sodium acetate, pH 5, over 15 min, 2 ml/min). Recovery of radioactivity at each stage of the method was greater than 70%. CB3717 and its polyglutamates were identified by co-chromatography with synthetic standards and by inhibition of partially purified TS. Quantitation was by means of radiochemical analysis. The 3H-CB3717 used in these studies was prepared by catalytic tritiation of diethyl-(2-chloro-4-nitrobenzoyl)-L-glutamate followed by consecutive alkylation with propargyl bromide and 2-amino-6-bromomethyl-3,4-dihydro-4-oxoquinazoline hydrobromide. The free diacid was prepared as required by hydrolysis in sodium hydroxide and purified by HPLC. Tritiation in only one position was confirmed by 3H NMR. Following the exposure of L1210 leukemia cells to 50 microM 3H-CB3717 for 12 h the total cellular radioactivity level was approximately 7 microM, of which 27% was present as polyglutamated metabolites with four and five glutamate residues.
Animals↗
Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer.
Fifty-two patients with progressive advanced breast cancer were treated with the novel antifolate CB 3717 (N10-propargyl-5,8-dideazofolic acid) which inhibits thymidylate synthetase. Forty-six patients were pretreated with hormones, 43 with cytotoxic chemotherapy and 39 patients with both treatments. Eight of 48 patients (16.6%) evaluable for response had partial responses (confidence limits 7.4-30.2%, 95% confidence level) following CB 3717 administration. Liver function abnormalities, reversible in most cases, were the most commonest toxicities and were frequently accompanied by malaise. Severe renal failure occurred in eight patients, five of whom had had partial responses to CB 3717. This study shows the importance of thymidylate synthetase as a target for therapy but the clinical value of CB 3717 is limited by its hepatic and renal toxicities.
Acute Kidney Injury↗
High dose carboplatin in the treatment of lung cancer and mesothelioma: a phase I dose escalation study.
Sixteen patients with lung cancer or mesothelioma have been treated with escalating doses of carboplatin. Five patients (10 courses) were given 800 mg/m2, four patients (five courses) 1200 mg/m2 and seven patients (eight courses) 1600 mg/m2. Myelosuppression was the major toxicity encountered. The median duration of grade 4 neutropenia ranged from 1 day (800 mg/m2) to 11 days (1600 mg/m2) and the median duration of grade 4 thrombocytopenia ranged from 1 day (800 mg/m2) to 7 days (1600 mg/m2). The median fall in haemoglobin (Hb) ranged from 2.2 g/l (800 mg/m2) to 3.6 g/l (1600 mg/m2). Nephrotoxicity was encountered at all dosages and was in part, though not entirely, dose related. 2/9 patients receiving 800 mg/m2 and 4/6 of the patients receiving 1600 mg/m2 had a fall in glomerular filtration rate (GFR) greater than 25% but less than 50%. 800 mg/m2 of carboplatin was well tolerated, the performance status in 9/10 (90%) courses being 0-1 (ECOG scale). At 1600 mg/m2 in 6/8 (75%) courses the performance status was 2-4. There was one treatment-related death from neutropenia at this dose level. The severity of nausea and vomiting was not dose related but other toxicities including diarrhoea, alopecia, mild neuropathy and ototoxicity and possible CNS toxicity occurred at doses of 1200 mg/m2 and over. 5/7 patients with small cell lung cancer achieved a complete or partial response to treatment.
Adult↗
Plasma free platinum pharmacokinetics in patients treated with high dose carboplatin.
Plasma free platinum (less than 50,000 mol. wt) pharmacokinetics have been studied in eight patients treated with high-dose (800-1600 mg/m2) carboplatin as a 1 h infusion with moderate hydration. Following the infusion, levels decayed biphasically with half-lives (means +/- S.D.) of 83 +/- 15 min and 6.1 +/- 2.8 h. The plasma free platinum area under the concentration vs. time curve (AUC) at 1600 mg/m2 in five patients was 23 +/- 2 mg carboplatin/ml.min. Comparison with data at conventional doses (less than or equal to 500 mg/m2) gave no indication of non-linear kinetics. Total body clearance of free platinum was found to correlate with glomerular filtration rate (r = 0.769, P = 0.03), and haematological toxicity, white cell nadir and duration of thrombocytopenia, correlated with plasma free platinum AUC (r = 0.784, P = 0.02 and r = 0.885, P = 0.01, respectively). Persistence of platinum was demonstrated in tissues removed at autopsy from a patient who had received carboplatin 14 days earlier. Highest platinum levels were found in the liver, kidney, skin and small cell lung tumour.
Adult↗
Tumour necrosis factor in man: clinical and biological observations.
Eighteen patients with advanced cancer have been treated intravenously with human recombinant tumour necrosis factor (rhTNF). The drug produced febrile reactions at all doses although these were preventable by steroids and indomethacin. Doses at or above 9 x 10(5) units (400 micrograms)m-2 were associated with hypotension, abnormal liver enzymes, leucopenia and mild renal impairment in a substantial proportion of patients. RhTNF was cleared from plasma with a half life of approximately 20 minutes but non-linear pharmacokinetics lymphoma, improvements in their tumours were recorded. RhTNF was noted to produce rapid increases in serum C-reactive protein concentrations. Endogenous TNF levels were not found to be elevated in 72 cancer patients. TNF deserves further therapeutic evaluation and these observations support its biological importance as an endogenous pyrogen, mediator of acute phase protein responses, and a mediator of endotoxic shock.
Adolescent↗