PubMed Health⌕ Search

Biomedical subjects

K R Harrap

Publications and source records attributed to K R Harrap.

At least 55 records · Page 3Linked to original sources
PubMed1991

Platinum coordination complexes which circumvent cisplatin resistance.

In the search for a platinum complex capable of oral administration, the poor bioavailability of established drugs has been circumvented by the discovery of a novel class of platinum (IV) ammine/amine dicarboxylate dichlorides. These compounds, when administered orally to mice carrying the ADJ/PC6 plasmacytoma, exhibit antitumor selectivities far superior to those of cisplatin or carboplatin (given intraperitoneally). Oral activity comparable to that of intraperitoneal cisplatin and carboplatin has also been demonstrated in a panel of human ovarian tumor xenografts. Platinum (IV) ammine/amine dicarboxylates retain cytotoxicity in cultures of L1210/cisplatin and L1210/tetraplatin acquired resistant cells. This property does not translate into a cisplatin-resistant variant of the ADJ/PC6 tumor, in the example of JM221. This result reflects experience with tetraplatin, a drug currently in phase I study, which is comparably ineffective against an ADJ/PC6/cisplatin variant. It is a moot point whether either L1210 or ADJ/PC6/cisplatin-resistant variants are clinically predictive screening models, since this issue must be determined ultimately by clinical study. We have attempted to resolve this dichotomy through the establishment of human ovarian carcinoma lines, both in vitro and in vivo, where there is evidence that response to platinum coordination complexes in the several models reflects that of the donor patient's tumor to platinum-based clinical therapy. The data herein for platinum (IV) ammine/amine dicarboxylates in these models gives encouragement to the notion that these novel compounds may be of value as oral therapeutic agents, whilst also providing an important lead to the discovery and development of a new generation of platinum drugs possessing broad clinical utility.

Animals↗
PubMed1991

Historical aspects of glutathione and cancer chemotherapy.

This presentation sets in historical context the impact of glutathione and its metabolism upon the efficacy of several anticancer drugs. The basic biochemistry of the tripeptide is reviewed briefly, highlighting its role in oxido-reduction and in the gamma-glutamyl cycle. The ability of selective modulators of glutathione metabolism, such as buthionine sulfoximine, as adjuncts to chemotherapy is also discussed.

Animals↗
PubMed1991

The relationships between glutathione, glutathione-S-transferase and cytotoxicity of platinum drugs and melphalan in eight human ovarian carcinoma cell lines.

The role of glutathione (GSH) and GSH-S-transferase (GST) activity in modulating the cytotoxicity of four platinum drugs and melphalan was evaluated in eight human ovarian carcinoma cell lines. The cell lines were established from solid and ascitic tumours from pretreated and untreated patients, and showed a wide spectrum of sensitivity to several platinum II and platinum IV drugs; cisplatin, carboplatin, CHIP and tetraplatin. Intracellular glutathione concentration measured in the cell lines showed a significant (P = 0.05) correlation with IC50 values for cisplatin (r = 0.91), carboplatin (r = 0.87) and CHIP (r = 0.88). The correlation between GSH levels and IC50 values for melphalan (r = 0.76) or tetraplatin (r = 0.60) was not as significant. GST activity showed no correlation with IC50 values, for the four platinum drugs. To determine the significance of the elevated GSH concentration in the refractory cell lines, the effect of D,L-buthionine-S, R-sulfoximine (BSO) mediated GSH depletion on platinum drug cytotoxicity was examined in one of the most sensitive (CH1) and two of the least sensitive (relatively resistant; SKOV-3, HX/62) cell lines. Comparison was made with the effect of GSH depletion on melphalan cytotoxicity in these three lines. These lines were differentially sensitive to BSO, with the two most platinum drug resistant lines being more tolerant to BSO than the sensitive CH1 line. Depletion of cellular GSH, ranging between 61 and 88%, had a differential effect on the sensitivity to PtII vs PtIV drugs in the three cell lines: cytotoxicity of the PtIV drugs, tetraplatin and CHIP, was substantially enhanced in both the resistant and sensitive cell lines; in contrast, the cytotoxicity of the PtII drugs, cisplatin and carboplatin, was only significantly increased in one of the two relatively resistant lines (SKOV-3) and in the sensitive (CH1) line after GSH depletion. Moreover the dose modification factor (DMF) for the PtII agents were lower than those for PtIV agents in the three cell lines. The dose modification factor for tetraplatin after BSO treatment was similar to that observed for melphalan in all three cell lines. In the SKOV-3 cell line extending the BSO pretreatment period to 48 h from 24 h marginally reduced the cytotoxicity of cisplatin, whereas the cytotoxicity of the other three drugs remained similar to that observed after 24 h BSO pretreatment. In contrast, extending the BSO treatment to 24 h after drug exposure potentiated the cytotoxicity of cisplatin, CHIP and tetraplatin.(ABSTRACT TRUNCATED AT 400 WORDS)

Carboplatin↗
PubMed1991

The role of murine tumour models and their acquired platinum-resistant counterparts in the evaluation of novel platinum antitumour agents: a cautionary note.

Two murine tumour models, the L1210 leukaemia and the ADJ/PC6 plasmacytoma, have featured prominently in the preclinical development of platinum drugs. Mindful of the unequivocal need to discover new platinum-based drugs exhibiting activity in cisplatin/carboplatin refractory and relapsed cancers, and to devise clinically-predictive screening models, we have generated resistance in vivo in the ADJ/PC6 plasmacytoma to cisplatin (19- to 21-fold), to carboplatin (25-fold), iproplatin (greater than 14-fold) and tetraplatin (10-fold). The chemo-sensitivity profiles of these tumours have been compared with L1210 leukaemia lines resistant to either cisplatin (10-fold) or tetraplatin (34-fold). In cross-resistance studies, the L1210 and ADJ/PC6 resistant variants provided conflicting predictions of structures likely to circumvent cisplatin-acquired resistance. In particular, the L1210/cisplatin resistant model exhibited cross-resistance to carboplatin and iproplatin, whereas the diaminocyclohexane (DACH)-containing complex, tetraplatin, was even more active in the cisplatin resistant tumour than in the 'wild-type' tumour. The ADJ/PC6/cisplatin resistant tumour, however, was cross-resistant, not only to carboplatin and iproplatin, but also to tetraplatin. These data provide an important caveat on the adoption of single acquired resistant animal tumour models for platinum drug development.

Animals↗
PubMed1990

The establishment, characterization and calibration of human ovarian carcinoma xenografts for the evaluation of novel platinum anticancer drugs.

Twenty-three serially transplantable ovarian carcinoma xenografts have been established in female nude mice from forty-two donor samples provided by both previously treated and untreated patients. The lines are all of human karyotype and mirror the histopathology of the original explant. Sixteen examples have been calibrated against four reference platinum drugs: cisplatin, carboplatin, iproplatin, tetraplatin. Three distinct patterns of response were observed: (i) tumours which were comparably sensitive to all four drugs (2 lines); (ii) tumours which were comparably refractory to treatment with all four drugs (5 lines); (iii) tumours which exhibited "individual" patterns of response to the group of calibrating drugs (9 lines). The "response rate" overall of the tumour panel to each of the clinically used drugs was 44% (7/16), though the pattern of response was not identical for each drug. Only 2/16 tumours (13%) were sensitive to tetraplatin, these also being the same tumours which were particularly sensitive to the other three drugs. It was also possible to confirm in 8/9 lines that the therapeutic response of the xenograft reflected that of the corresponding patient's tumour to platinum-based chemotherapy. This tumour panel has now been adopted for evaluating novel platinum-based drugs designed specifically for the treatment of ovarian cancer.

Animals↗
PubMed1989

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↗
PubMed1989

Biological properties of ten human ovarian carcinoma cell lines: calibration in vitro against four platinum complexes.

Ten human ovarian carcinoma cell lines have been studied as a potential in vitro screen for the development of novel anticancer platinum complexes. Lines have been established and developed both from solid and ascitic tumours, from pretreated and untreated patients, and are available at a range of in vitro passage numbers. The biological properties of the lines were consistent with them being human, epithelial and of ovarian carcinoma origin. Using a tritiated thymidine or leucine uptake method, and a 96 hour continuous drug exposure, the lines have been calibrated against four platinum-containing chemotherapeutic agents: cisplatin, iproplatin, carboplatin and tetraplatin. Striking differences in cytotoxicity were observed across the lines for each agent. Some lines were consistently resistant, others generally sensitive, whereas some showed clear evidence of differential sensitivity to a particular agent. Statistical analysis (Spearman rank correlation) involving the six possible pairings of drugs showed that cisplatin, iproplatin and carboplatin elicit a very similar pattern of response in these lines whereas tetraplatin elicits a completely different response pattern. Similar cytotoxicity values were obtained using a soft agar cloning assay. Results using a tetrazolium dye reduction assay, however, gave somewhat higher and more variable values, particularly with tetraplatin. The thymidine uptake assay will be adopted in further studies on a selected panel of six lines. This panel encompasses the spectra of sensitivities identified for each of the four agents against the original ten lines and may provide a useful screening facility for the development of novel platinum drugs, in that it detects both cell line-determined and structure-determined differences in cytotoxicity.

Antigens, Neoplasm↗
PubMed1988

Inhibition of human leukaemic thymidylate kinase and L1210 ribonucleotide reductase by dinucleotides of adenosine and thymidine and their phosphonate analogues.

Dinucleotides of adenosine and thymidine in the ApnT series (n = 3,4,5 and 6) and their corresponding phosphonate analogues, where a methylene group replaces the oxygen between the alpha and beta phosphorus atoms adjacent to thymidine, have been evaluated as inhibitors of human leukaemic thymidylate kinase (dTMP kinase, EC 2.7.4.9) and ribonucleotide reductase (EC 1.17.4.1) from L1210 cells. Ap3T, Ap4T, Ap2cpT and Ap3cpT were poor inhibitors of both enzymes. Ap5T, Ap6T and their phosphonate analogues were potent inhibitors of dTMP kinase, possibly acting as bisubstrate analogues (IC50 values: Ap5T, 7.9 microM; Ap4cpT, 5.8 microM; Ap6T, 5.4 microM; Ap4cpT, 4.0 microM). For CDP reductase, where these compounds may bridge activity/effector sites on the M1 subunit of the enzyme, Ap5T and Ap6T were inhibitors with IC50 values of 14.4 microM and 20.3 microM respectively. The phosphonate series of compounds was far less active. The thymidine moiety of the compounds was essential for inhibition since Ap5A was inactive against both enzymes. dTTP, although a poor inhibitor of thymidylate kinase was a potent negative effector of CDP reductase (IC50, 19.3 microM). Significantly, Ap5T was not hydrolysed to release dTTP under the conditions of the assay. These studies show that the activities of both enzymes may be modulated by nucleotide analogues.

Adenosine↗
PubMed1988

The comparative tissues distribution of platinum and 14C in mice receiving 14C-labelled carboplatin.

Since the reactivity of carboplatin depends on the rate of removal of the 1,1-cyclobutanedicarboxylate ligand, the time course of this dissociation has been determined in various tissue and body fluids using 14C-labelled carboplatin (cis-diammine[1,1-cyclobutane-1-14C-dicarboxylate]platinum II). Mice received 14C-carboplatin (80 mg/kg; 1.1 mCi/kg, i.v.), and tissue was removed at times ranging from 5 min to 5 days posttreatment. Following solubilization, tissue aliquots were analyzed for platinum and 14C contents. Carboplatin remained intact for up to 2 h posttreatment, since the ratio of 14C: Pt in tissues (nmol/g) was unity. Thereafter, the 14C ligand was released from the molecule and preferentially removed from tissues, indicated by decreasing 14C: Pt ratios. The elimination half-lives for Pt varied between tissues (40-156 h). In contrast, the corresponding half-lives for the 14C species were similar in most types of tissue (18-35 h), although those in the liver and spleen were exceptional (210 and 90 h, respectively). At 5 days a maximum of 4%-24% of the total Pt in tissue might exist as intact drug. Thus, the metabolic handling of carboplatin varies according to the tissue, since the elimination of the 14C cyclobutane dicarboxylate species from most tissue was similar and Pt elimination was slower and tissue-dependent.

Animals↗
PubMed1988

Comparative distribution and excretion of carboplatin and cisplatin in mice.

The comparative distribution and excretion of Carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) and cisplatin have been investigated in Balb C- mice following i.v. administration of the maximally tolerated doses (MTDs) of the compounds. Although the concentrations of platinum in the plasma and tissues during the alpha-phase were much higher for Carboplatin than for cisplatin, reflecting the difference in the doses used (4 vs 80 mg/kg), the tissue-to-plasma ratios were similar. During the beta-phase (1-10 days), however, both the platinum concentrations and the ratios were found to be similar for most tissues when cisplatin and Carboplatin were compared. The platinum concentrations and the tissue-to-plasma ratios of the spleen, brain, muscle, testes, ovary and bile, on the other hand, were consistently higher (two- to sixfold) after Carboplatin than after cisplatin. The highest ratios (greater than 20) were found in the kidney, liver, spleen (after Carboplatin only) and skin at 6 days after treatment. Comparison of the two compounds showed that the half-lives of platinum in the plasma and tissues during both the alpha- and beta-phases were similar, except for the spleen, in which a nine-fold greater t1/2 beta was recorded for Carboplatin than for cisplatin. The main route of excretion for the two complexes is via the kidneys, with 52% of cisplatin and 93% of Carboplatin being excreted during the first 3 days. The major part of this, however, is excreted within the 1st day. These results indicate that, although there are quantitative differences, the distribution and excretion profiles are similar for Carboplatin and cisplatin.

Animals↗
PubMed1988

Dinucleotide analogues as inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase.

P1-(Adenosine-5')-Pn-(thymidine-5') tri-, tetra-, penta-, and hexaphosphates (ApnT) plus the analogues with a methylene group alpha, beta to the thymidine residue (ApncpT) were synthesized by coupling the appropriate two nucleotides, having activated one by morpholine. These were tested as potential dinucleotide inhibitors of thymidine kinase, thymidylate kinase, and ribonucleotide reductase. All three enzymes bind ATP and thymidine or its nucleotides and therefore might be inhibited by dinucleotides containing adenosine and thymidine. Ap5T and Ap6T strongly inhibited all three enzymes (IC50 = 2.4-20 microM). Ap4cpT and Ap5cpT also strongly inhibited the two kinases (IC50 = 4-20 microM) but were much weaker inhibitors of the reductase (IC50 = 130 and 230 microM).

Adenine Nucleotides↗
PubMed1987

The comparative pharmacokinetics of carboplatin and cisplatin in mice and rats.

The plasma, urinary and biliary clearances of cisplatin and its non-nephrotoxic analogue, Carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II, CBDCA, JM8) have been determined in mice and rats following intravenous administration of the compounds. The plasma concentration-time curves were biphasic during the time period studied (0-60 min), with t1/2 alpha of 2-3 min for both platinum complexes and t1/2 beta of 10-15 min for cisplatin and 25-26 min for Carboplatin. The kinetic rate constants, k12 and k21, were similar for both Carboplatin and cisplatin, indicating that there was no appreciable net accumulation of the compounds in the peripheral tissues. Immediately after administration, Carboplatin became reversibly bound to plasma proteins in vivo to the extent of about 20%. Appreciable irreversible binding appeared after the first 60 min and increased steadily, so that by 4 hr only 34% of the compound was present in the plasma as the free drug. In comparison, binding of cisplatin to plasma was exclusively irreversible and, after the first 10 min, free drug disappeared rapidly, such that by 60 min free platinum was not detectable. The plasma clearance of free cisplatin (26.1 ml/min/kg) was significantly greater than that of either Carboplatin (10.3 ml/min/kg) or insulin (10.1 ml/min/kg). The main route of excretion of the two platinum complexes was via the urine, with 80-90% of Carboplatin and 43-48% of cisplatin being excreted within 4 hr. In the rat, the Carboplatin excreted in the urine was predominantly as the unchanged compound. The renal clearance of cisplatin (12.3 ml/min/kg) was significantly greater than that of either Carboplatin (9.3 ml/min/kg) or insulin (9.6 ml/min/kg), suggesting that cisplatin was excreted by an active renal secretory mechanism whilst Carboplatin was eliminated by glomerular filtration alone. Biliary excretion of the two compounds was only 0.4-1.2% of the administered dose in 6 hr, with biliary clearance of cisplatin (0.27 ml/min/kg) being fivefold greater than that of Carboplatin (0.053 ml/min/kg). The results indicate that the major pharmacokinetic differences between Carboplatin and cisplatin relate to their renal handling and their reactivity with macromolecules. These differences may well underline the substantial lack of Carboplatin nephrotoxicity in comparison with cisplatin.

Animals↗
PubMed1987

Flameless atomic absorption spectrophotometric determination of platinum in tissues solubilized in hyamine hydroxide.

Processing biological samples by solubilization in Hyamine hydroxide (methylbenzethonium hydroxide) as an alternative to wet ashing with concentrated nitric acid for atomic absorption determination of platinum has been explored. The concentrations of platinum in tissues removed from rats 2 h after they had received the antitumor drug Carboplatin (60 mg/kg, iv) were comparable using either of the procedures, indicating the utility of tissue solubilization. Limits of detection were also comparable between the Hyamine hydroxide (0.25 microgram platinum/g) and nitric acid (0.15 microgram/g) procedures. The solubilization method, however, has advantages over wet digestion because of its simplicity and greater safety.

Animals↗
PubMed1987

The effect of diethyldithiocarbamate on the haematological toxicity and antitumour activity of carboplatin.

Carboplatin has recently been established as an effective agent in cancer chemotherapy. The dose limiting toxicity of this platinum complex is myelosuppression and, in this study, we have shown that through the use of diethyldithiocarbamate (DDTC), a protective thiol compound, the toxicity in rodents can be ameliorated and lethality prevented. DDTC protected against carboplatin-induced leucopoenia and anaemia when administered as a single bolus or as a multiple schedule incorporating three injections. With the single bolus, the effectiveness of this protection decreased as the lag time between carboplatin and DDTC administrations increased. Thrombocytopoenia was unaffected by DDTC. The growth profile of ADJ/PC6A tumour in mice was dependent on the timing of DDTC administration when given in combination with the platinum complex. The tumour growth delay, however, was unaffected by DDTC at any schedule. Multiple injections of DDTC increased the ED90 for carboplatin from 5.0 to 7.5 mg/kg. The LD50 value was increased from 115 to 216 mg/kg with the same DDTC schedule. Thus, DDTC improved the therapeutic index of carboplatin by 25%. A clinical role for the use of DDTC as a protective agent for carboplatin-induced toxicities is suggested.

Anemia↗
PubMed1987

Haematological toxicity of carboplatin in rats.

In rats a maximal tolerated dose of carboplatin (60 mg kg-1, i.v.) caused severe anaemia, leucopenia and thrombocytopenia. These indices of haematological toxicity were also observed with a maximal tolerated dose of cis-platin (6.5 mg kg-1, i.v.), but reductions in blood cell counts were less than those observed with carboplatin. Anaemia was deduced to be the dose-limiting toxicity of carboplatin, since red cell transfusions afforded protection to rats receiving a lethal dose of this compound (80 mg kg-1, i.v.). Anaemia did not appear to be due to an increase in the susceptibility of cis-platin- or carboplatin-exposed red cells to lysis, as concluded from results of osmotic fragility tests. These red cells, when tagged with 51Cr, also did not exhibit reductions in survival time. Administration of 51Cr-labelled control red cells to rats, which had been treated with carboplatin 3 days earlier, resulted in substantial loss of the radiolabel from the circulation, indicating that internal haemorrhaging, as a result of thrombocytopenia, is probably the principle cause of drug-induced anaemia.

Anemia↗
PubMed1987

Recent preclinical and clinical studies with the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB 3717).

CB 3717, N10-propargyl-5,8-dideazafolic acid, is a tight-binding inhibitor of thymidylate synthase (TS) whose cytotoxicity is mediated solely through the inhibition of this enzyme. Recent preclinical studies have focused on the intracellular formation of CB 3717 polyglutamates. Following a 12-hour exposure of L1210 cells to 50 microM [3H]CB 3717, 30% of the extractable radioactivity could be accounted for as CB 3717 tetra- and pentaglutamate, as determined by high-pressure liquid chromatography (HPLC) analyses. As inhibitors of isolated L1210 TS, CB 3717 di-, tri-, tetra- and pentaglutamate are 26-, 87-, 119- and 114-fold more potent than CB 3717, respectively, and their formation may, therefore, be an important determinant of CB 3717 cytotoxicity. In early clinical studies with CB 3717, activity has been seen in breast cancer, ovarian cancer, hepatoma, and mesothelioma. Toxicities included hepatotoxicity, malaise, and dose-limiting nephrotoxicity. This latter effect is thought to be due to drug precipitation within the renal tubule as a result of the poor solubility of CB 3717 under acidic conditions. In an attempt to overcome this problem, a clinical trial of CB 3717 administered with alkaline diuresis is under way. Preliminary results at 400 and 500 mg/m2 suggest that a reduction in nephrotoxicity may have been achieved with only 1 instance of renal toxicity in 10 patients. Hepatotoxicity and malaise are again the most frequent side effects. Evidence of antitumor activity has been seen in 3 patients. Pharmacokinetic investigations have shown that alkaline diuresis does not alter CB 3717 plasma levels or urinary excretion and that satisfactory urinary alkalinization can be readily achieved.

Adult↗
PubMed1986

The effect of the nucleoside transport inhibitor dipyridamole on the incorporation of [3H]thymidine in the rat.

Dipyridamole is a non-specific inhibitor of nucleoside transport into mammalian cells. It is currently undergoing clinical evaluation in combination with various antimetabolites in an attempt to enhance the activity of these anticancer drugs by blocking the salvage of extracellular nucleosides, an important determinant of their cytotoxicity. In the present study, the effect of i.v. infusions of dipyridamole on [3H]thymidine incorporation into DNA has been examined in the anaesthetized rat. The tissues studied were bone marrow, gastrointestinal tract epithelium and the ascitic form of the Walker carcinosarcoma. Dipyridamole at 10 mg/kg, given over 3 hr, led to plasma levels of less than 5 microM and did not reduce [3H]thymidine incorporation into any of the tissues studied. At 40 mg/kg dipyridamole (plasma levels 10-15 microM) [3H]thymidine incorporation into the DNA of bone marrow and gastrointestinal tract epithelium was reduced to 20-30% of control values. Increasing the dose to 100 mg/kg did not lead to a further suppression of incorporation. Measurement of [3H]thymidine plasma pharmacokinetics and the intracellular distribution of tritium suggested that the inhibition of [3H]thymidine incorporation was due to reduced cellular uptake. In contrast to the effects on normal tissues, even at a lethal dose (200 mg/kg) dipyridamole did not significantly inhibit [3H]thymidine incorporation into Walker tumour cells. The levels of dipyridamole found in the ascitic fluid, at 100 mg/kg approximately half those in plasma, argue against a pharmacokinetic basis for this difference. Dipyridamole was found to bind extensively (97%) to rat plasma proteins, which may explain the discrepancy between the concentrations of dipyridamole required to inhibit nucleoside incorporation in vitro, in serum-free media, and those needed in vivo. From a comparison of the plasma levels of dipyridamole which cause an inhibition of [3H]thymidine incorporation in the rat with those which can be achieved safely in patients, it is concluded that dipyridamole is unlikely to markedly reduce nucleoside salvage in man.

Animals↗