[Thalidomide. Clinical trials in cancer]. / Talidomida. Ensayos clínicos en cáncer.

The breakthrough discovery of the anti-angiogenic effects of thalidomide gave impetus to a series of clinical trials in patients with solid tumors and hematologic malignancies. Thalidomide has been shown to block the activity of angiogenic substances like bFGF, VEGF and interleukin 6. This drug also down-regulates TNF alpha. Thalidomide has shown clinical antitumor activity in single-agent, phase II clinical trials in AIDS-related Kaposi sarcoma, glioma, multiple myeloma refractory to chemotherapy, and hormone-refractory prostate cancer. In contrast, thalidomide was inactive in breast, lung and kidney cancer. The dose-limiting toxicity of thalidomide is sedation. Other adverse effects include skin rash, constipation, dry mouth and liver function abnormalities, along with peripheral neuropathy and the drug's well-known teratogenic potential. The advantages of thalidomide include the convenience of the oral route of administration, the drug's toxicity profile--substantially milder than that of chemotherapy--and its low cost. The potential role of thalidomide in the treatment of human neoplasia will be confirmed by means of randomized clinical trials.

Talidomida. Ensayos clínicos en cáncer. / [Thalidomide. Clinical trials in cancer]

The breakthrough discovery of the anti-angiogenic effects of thalidomide gave impetus to a series of clinical trials in patients with solid tumors and hematologic malignancies. Thalidomide has been shown to block the activity of angiogenic substances like bFGF, VEGF and interleukin 6. This drug also down-regulates TNF alpha. Thalidomide has shown clinical antitumor activity in single-agent, phase II clinical trials in AIDS-related Kaposi sarcoma, glioma, multiple myeloma refractory to chemotherapy, and hormone-refractory prostate cancer. In contrast, thalidomide was inactive in breast, lung and kidney cancer. The dose-limiting toxicity of thalidomide is sedation. Other adverse effects include skin rash, constipation, dry mouth and liver function abnormalities, along with peripheral neuropathy and the drugs well-known teratogenic potential. The advantages of thalidomide include the convenience of the oral route of administration, the drugs toxicity profile--substantially milder than that of chemotherapy--and its low cost. The potential role of thalidomide in the treatment of human neoplasia will be confirmed by means of randomized clinical trials.

Paclitaxel in platinum-resistant ovarian cancer patients. Argentine Multicenter Taxol Group.

Paclitaxel (Taxol; Bristol-Myers Squibb Company; Princeton, NJ) is an antineoplastic agent that inhibits microtubular function and has shown efficacy in several solid tumors, mainly ovarian tumors, in which 20% to 40% response rates in previously treated patients were observed. We conducted a study to assess survival, response rate, and toxicity associated with paclitaxel treatment in patients with advanced ovarian cancer resistant to platinum therapy. Between September 1994 and November 1996, 38 patients were admitted for study and 37 were evaluable. All had disease progression or relapse within 1 year of receiving platinum-containing first-line chemotherapy. Mean age was 59 years (range, 30 to 75 years), all had bulky disease, and 18 showed increased carbohydrate antigen-125 at admission. They were treated every 3 weeks with paclitaxel 175 mg/m2 as a 3-hour infusion, preceded by standard premedication. Response rate was 51.3%, with a median response duration of 10.0 months and a median survival rate of 16.8 months. Mild to moderate hematologic toxicity was observed with only one episode of grade 4 neutropenia, without fever. Gastrointestinal toxicity was moderate and peripheral neuropathy was mild, except for two patients who had concomitant pathologies or previous treatment, which might have caused some neuropathy. We concluded that paclitaxel given as a 3-hour infusion was easily administered for ambulatory treatment, with mild to moderate toxicity and promising results based on rate and duration of response as well as survival.

Cytotoxicity and DNA damage associated with pyrazoloacridine in MCF-7 breast cancer cells.

We examined the effects of pyrazoloacridine (PZA), an investigational anticancer agent in clinical trials, on cytotoxicity, DNA synthesis, and DNA damage in MCF-7 human breast carcinoma cells. With PZA concentrations ranging from 0.5 to 50 microM for durations of 3-72 hr, cytotoxicity increased in proportion to the total PZA exposure (concentration x time). Inhibition of DNA and RNA syntheses increased with increasing PZA concentration x time (microM.hr). A 24-hr exposure to 1 and 10 microM PZA reduced DNA synthesis to 62 and 5% of control, respectively, decreased the proportion of cells in S phase with accumulation of cells in G2 + M phase, and inhibited cell growth at 72 hr by 68 and 100%. Newly synthesized DNA was more susceptible to damage during PZA exposure, with subsequent induction of parental DNA damage. Significant damage to newly synthesized DNA as monitored by alkaline elution was evident after a 3-hr exposure to > or = 5 microM PZA. Longer PZA exposures (> or = 10 microM for 16 hr) were required to elicit damage to parental DNA. Induction of single-strand breaks in parental DNA correlated closely with induction of double-strand breaks and detachment of cells from the monolayer. PZA-mediated DNA fragmentation was not accompanied by the generation of oligonucleosomal laddering in MCF-7 cells, but induction of very high molecular weight DNA fragmentation (0.5 to 1 Mb) was detected by pulsed-field gel electrophoresis. In vitro binding of PZA to linear duplex DNA (1 kb DNA ladder) and closed, circular plasmid DNA was demonstrated by a shift in migration during agarose electrophoresis. PZA interfered with topoisomerase I- and II-mediated relaxation of plasmid DNA in a cell-free system, but the cytotoxic effects of PZA did not appear to involve a direct interaction with topoisomerase I or II (stabilization of the topoisomerase I- or II-DNA cleavable complex). PZA-mediated cytotoxicity correlated strongly with inhibition of DNA and RNA syntheses, and damage to both nascent and parental DNA. Neither the cytotoxicity of PZA nor induction of double-stranded DNA fragmentation was prevented by aphidicolin, indicating that PZA-mediated lethality occurred in the absence of DNA replication. Since free radical formation was not detected, induction of nascent and parental DNA damage appeared to be a consequence of the avid binding of PZA to DNA, presumably by interfering with the access of replication, repair, and transcription enzyme complexes.

Determinants of sensitivity to 1-beta-D-arabinofuranosylcytosine in HCT 116 and NCI-H630 human colon carcinoma cells.

The cytotoxicity and metabolism of 1-beta-D-arabinofuranosylcytosine (AraC) and its effects on DNA synthesis and integrity were studied in HCT 116 and NCI-H630 human colon cancer cells. In 116 cells, 0.1 microM AraC decreased colony formation by approximately 50%, whereas 1 microM was required in H630 cells. AraCTP levels after a 24-hr AraC exposure were 2.3- to 3.5-fold lower in H630 cells due to increased ability to deaminate AraCMP. AraC DNA levels increased in proportion to AraCTP pools (r = 0.99) and were 2-fold higher in 116 cells after a 24-hr exposure to 0.1 and 1 microM AraC. Although the half-life of AraCTP was < 1 hr in both lines, > 80% of AraC DNA was retained at 24 hr after drug removal. Clonogenic capacity was inversely related to the extent of AraC DNA incorporation. Interference with nascent DNA chain elongation increased with increasing AraC concentration x time. A 24-hr AraC exposure produced a dramatic shift in the elution profile of nascent DNA during a 15-hr elution at pH 12.1; these effects were greater in 116 cells (DNA retained on filter [percentage of control]): 78%, 23%, and 9% with 0.1, 1, and 10 microM AraC versus 84%, 42%, and 18% in H630 cells, respectively. The extent of nascent DNA damage was proportional to AraC DNA content. Net DNA synthesis was potently inhibited during AraC exposure in both lines. H630 cells had partial recovery of DNA synthesis at 24 hr after drug removal, whereas persistent inhibition was noted in 116 cells. A slight excess of double-strand breaks in parental DNA was detected after a 24-hr exposure to 10 microM AraC in 116 cells. The extent of DNA fragmentation was more pronounced 16 hr after drug removal and was greater in 116 cells: 8.5%, 19%, and 21% with 0.1, 1, and 10 microM AraC DNA content, magnitude of nascent DNA damage, duration of DNA synthetic inhibition, and induction of double-stranded DNA fragmentation appeared to be the crucial determinants of lethality.

Phase I clinical trial of continuous infusion cyclopentenyl cytosine.

Cyclopentenyl cytosine (CPE-C) is an investigational drug that is active against human solid tumor xenografts. The 5'-triphosphate of CPE-C inhibits CTP synthase, and depletes CTP and dCTP pools. We conducted a phase I clinical trial of CPE-C given as a 24-h continuous i.v. infusion every 3 weeks in 26 adults with solid tumors. The starting dose rate, 1 mg/m2 per h, was selected on the basis of both preclinical studies and pharmacokinetic data from two patients obtained after a test dose of 24 mg/m2 CPE-C as an i.v. bolus. Dose escalation was guided by clinical toxicity. A total of 87 cycles were given, and ten patients received four or more cycles. The mean CPE-C steady-state plasma levels (Cpss) increased linearly from 0.4 microM to 3.1 microM at dose levels ranging from 1 to 5.9 mg/m2 per h (actual body weight); the mean total body clearance was 146 +/- 38 ml/min per m2. CPE-C was eliminated by both renal excretion of intact drug and deamination to cyclopentenyl uracil in an apparent 2:1 ratio. CTP synthase activity in intact bone marrow mononuclear cells was inhibited by 58% to 100% at 22 h compared to matched pretreatment samples at all CPE-C dose levels. When all data were combined, flux through CTP synthase was decreased by 89.6% +/- 3.1% at 22 h (mean +/- SE, n = 16), and remained inhibited by 67.6% +/- 7.7% (n = 10) for at least 24 h post-CPE-C infusion. Granulocyte and platelet toxicities were dose-dependent, and dose-limiting myelosuppression occurred during the initial cycle in two of three patients treated with 5.9 mg/m2 per h. Four of 11 patients (4 of 20 cycles) who received 4.7 mg/m2 per h CPE-C experienced hypotension 24-48 h after completion of the CPE-C infusion during their first (n = 2), third (n = 1) and sixth cycles (n = 1), respectively. Two of these patients died with refractory hypotension despite aggressive hydration and cardiopulmonary resuscitation. One of 12 patients (28 total cycles) treated with 3.5 mg/m2 per h CPE-C experienced orthostatic hypotension during cycle 1, and this patient had a second episode of orthostatic hypotension at a lower dose (3.0 mg/m2 per h). Hypotension was not seen in patients receiving < or = 2.5 mg/m2 per h CPE-C.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparison of acute effects of mitoxantrone and doxorubicin in guinea-pig atria.

1. The acute effects of doxorubicin (DOX) and mitoxantrone (MTX) on basal rate and on positive chronotropic activity induced by 1-noradrenaline (1-NA) were investigated in isolated guinea-pig atria. 2. DOX (10(-5)-10(-4)M) progressively depressed atrial rate after a short latency period. Only 10(-4) M MTX reduced the spontaneous frequency after 120 and 180 min incubation. This effect was significantly lower to that elicited by DOX (10(-4)M). 3. Atropine (1.5 x 10(-6) M) and reserpine pretreatment did not affect the negative chronotropic action induced by DOX or MTX. 4. DOX (10(-5)-10(-4) M) produced a significant reduction of the maximal chronotropic response (Emax) to 1-noradrenaline (1-NA) after 60, 120 and 180 min of exposure. 5. MTX (10(-5)-10(-4) M) after 60 and 120 min incubation induced a beta-adrenergic, concentration- and time-dependent, competitive blocking effect. After 180 min of exposure, MTX (10(-4) M) reduced the Emax to 1-NA which was of less magnitude to that produced by DOX (10(-4) M). 6. Although both DOX and MTX depressed spontaneous and 1-NA induced chronotropic activity, MTX effects were of a slower onset and development compared to those exerted by DOX.

P-glycoprotein-independent mechanism of resistance to VP-16 in multidrug-resistant tumor cell lines: pharmacokinetic and photoaffinity labeling studies.

The interaction of etoposide (VP-16), Vinca alkaloids, and verapamil with the P-glycoprotein (P-gp) was studied in human breast (MCF-7) and Chinese hamster lung (DC3F) cell lines and the corresponding multidrug-resistant MCF-7/ADR and DC3F/ADX tumor cell lines, selected for resistance to Adriamycin and actinomycin D, respectively, and overexpressing P-gp. Verapamil (10 microM) markedly reversed resistance to vincristine (11-fold in DC3F/ADX and 125-fold in MCF-7/ADR; 1-hr exposure), but it had a very modest effect on resistance to VP-16 (3- to 4-fold; 1-hr exposure). Resistant cells accumulated 2- to 4-fold less VP-16 and vincristine than the parental cell lines. Verapamil (10 microM) significantly increased accumulation and retention of vincristine, but not of VP-16, in resistant cell lines. Photoaffinity labeling of resistant cell lines with radioactive analogs of verapamil [N(p-azido-3-125I-salicyl)-N'-beta-aminoethylverapamil (NASVP)] and vinblastine[N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine (NASV)] showed distinctly labeled P-gp bands in both resistant cell lines, compared with wild-type cells. Excess nonradioactive vinblastine or verapamil effectively competed with the P-gp photolabeling by either NASVP or NASV, with IC50 levels of 0.6 and 10 microM, respectively. In contrast, nonradioactive VP-16 was 100- to 500-fold less potent than vinblastine in competing with P-gp photolabeling, suggesting that VP-16 has significantly lower affinity for P-gp than Vinca alkaloids have. Taken together, our data indicate that P-gp glycoprotein by itself may not be important in the transport/efflux of VP-16 and, thus, in the mechanism of resistance to VP-16 in these cells.

Role of oxygen free radical formation in the mechanism of menogaril resistance in multidrug resistant tumor cells.

The mechanisms of action and resistance to menogaril, a clinically active anthracycline antitumor drug, were evaluated in sensitive and doxorubicin-selected multidrug resistant human breast tumor (MCF-7) cell lines. While MCF-7/ADRR cells were highly resistant (250-500-fold) to doxorubicin, they displayed only marginal resistance (10-fold) to menogaril. In contrast to doxorubicin, the mechanism of resistance to menogaril in these cells does not involve differential inhibition of DNA synthesis as measured by thymidine incorporation. P-170-glycoprotein-dependent drug transport did not contribute to resistance as there was no difference in the accumulation and retention of menogaril by sensitive and resistant cell lines. However, there was a 2-fold decrease in oxygen free radical formation in the resistant cells, compared to sensitive cells, in the presence of menogaril. Since resistant cells contain 12-fold higher glutathione peroxidase activity than the parental sensitive cells, the detoxification of hydrogen peroxide may be responsible for the decreased free radical formation and thus, may play a role in the resistance to menogaril.

Structure-activity relations, cytotoxicity and topoisomerase II dependent cleavage induced by pendulum ring analogues of etoposide.

The cytotoxicity of etoposide and its analogues, dihydroxy (DHVP), o-quinone (VP-Q) and o-methyl (VP-OMe), was evaluated in human breast (MCF-7) and HL60 tumour cells. Although less potent than etoposide, both DHVP and VP-Q were cytotoxic to these cells. However, VP-OMe was inactive. Studies with purified topoisomerase II showed that the intensity of DNA cleavage and the pattern of cleavage were similar for DHVP, VP-Q and etoposide. In contrast, the VP-OMe failed to induce DNA cleavage, indicating that the presence of 4'-OH is essential for metabolism, induction of topoisomerase II-mediated DNA cleavage and cytotoxicity of etoposide and its analogues.

Anthracyclines.

After twenty years, understanding the mechanisms of tumor cells kill by anthracyclines still remains an active area of research. Of many mechanisms described for this class of drugs, efforts in the last year have focused on defining the role of free radical formation, topoisomerase II-induced DNA breakage, and P-170-dependent cellular accumulation of anthracyclines in tumor cell kill and resistance. First, in a number of tumor cell lines, the formation of free radical species from anthracyclines has been implicated in the cell killing. Modulation of detoxification pathways in a drug-resistant cell line e.g depletion of GSH, a substrate for peroxidase and transferase, enhanced both the formation of oxy-radicals and adriamycin cytotoxicity. It should be noted, however, that these findings are not true for every cell line examined, and free radical-mediated tumor kill may be cell- or tissue-specific. Second, anthracyclines-mediated topo II-dependent DNA cleavage was observed in most cell lines and reduced breaks were found in resistant cells. The decrease in single-strand breaks, however, neither correlated with the degree of resistance nor with differences in the relative topo II activity, which was in most cases only two-fold less in resistant cells than in sensitive cells. Finally, the reduced accumulation of the drug does not appear to be the only contributing factor in multidrug resistant cells and P-170 is not the only protein overexpressed in certain cells, e.g., an 85,000 Da protein may also be linked to adriamycin resistance. Although GST protein is overexpressed in most adriamycin resistant cells along with mdr1 gene, current evidence suggests that this protein may not be directly involved in adriamycin resistance. Taken together, both the mechanism of action and resistance to this class of drug likely vary among cell lines. Clinical studies in the past year have brought about interesting refinements in anthracycline-containing chemotherapy; ICRF-187 (by itself also cytotoxic) seems to offer protection against cardiac toxicity, while implicating iron in the mediation of cardiac damage. Out of a large number of newer anthracycline derivatives, clinical evidence indicates only a modest increase in therapeutic index with a few analogs, perhaps idarubicin and epirubicin. It is not yet clear that being able to receive more milligrams (or more cycles) of anthracycline eventually translates into a significantly better response rate or in a survival advantage. Much less clear is whether patients refractory to adriamycin may derive any benefit from newer anthracyclines.(ABSTRACT TRUNCATED AT 400 WORDS)

Free-radical formation by mitomycin C and its novel analogs in cardiac microsomes and the perfused rat heart.

Using a spin-trapping technique, we have examined free-radical formation by mitomycin C and its analogs, BMY 25282 and BMY 25067, in rat cardiac microsomes and isolated perfused rat hearts. All three drugs stimulated 2--4-fold OH radical formation in cardiac microsomes which was inhibited by SOD and catalase. Superoxide anion radical was also detected in the presence of diethylenetetraaminopentaacetic acid. Addition of DMSO yielded methyl radicals, thus indicating the production of free OH under these conditions. Similar stimulation of OH formation (2--3-fold) in the perfusates from rat hearts was detected with all three drugs. Perfusion with catalase (550 U/ml) completely suppressed the OH signal both in the presence and absence of the drugs, thus suggesting the intermediacy of hydrogen peroxide. However, BMY 25067-induced OH formation was more sensitive to inhibition by superoxide dismutase (SOD) and the iron chelator ICRF-187. Perfusion with DMSO produced methyl radicals at the expense of OH in the presence of all three drugs. SOD and catalase inhibited DMPO-OH signals, indicating that most of the OH formation was extracellular in this setting. While mitomycin C and BMY 25067 (up to 10 microM) did not affect the heart rate, perfusion with 10 microM BMY 25282 caused acute arrhythmia and cardiac standstill within 20 min. An initial surge in OH formation (2-fold) accompanied this cardiotoxic effect. Both the arrhythmia and the free radical signal were partially blocked by SOD, catalase and ICRF-187, indicating that iron-dependent oxygen radical formation from BMY-25282 (and possibly other compounds) is involved, in part, in inducing toxic manifestations in the rat heart and possibly in clinic.

Role of differential drug uptake, efflux, and binding of etoposide in sensitive and resistant human tumor cell lines: implications for the mechanisms of drug resistance.

In order to study the mechanism of etoposide (VP-16) resistance in human tumor cells and to assess the role of P-170 glycoprotein in VP-16 accumulation, we have examined the uptake and efflux of VP-16 in both sensitive and multidrug-resistant MCF-7 human breast and HL60 human promyelocytic leukemia cells. The drug-resistant cells, MCF-7/ADR and HL60/ADR, were selected for resistance to adriamycin and were 200- to 250-fold resistant to VP-16. Whereas MCF-7/ADR cells overexpress the P-170 glycoprotein and show the multidrug-resistant phenotype, HL60/ADR cells do not overexpress the P-170 glycoprotein. Although there was a 2-fold decrease in accumulation of VP-16 in MCF-7/ADR cells, this decrease did not correlate with a 250-fold resistance to the drug. VP-16 efflux was rapid and almost complete from MCF-7 cell lines and it was decreased at 4 degrees. Further, there was a significant increase in VP-16 accumulation in the MCF-7/ADR cells in the presence of glucose-free medium supplemented with sodium azide. However, no change in the pattern of VP-16 efflux was observed. Under these conditions, addition of glucose caused release of VP-16 from MCF-7/ADR cells, suggesting energy-dependent modifications in the drug binding. Coincubation of vincristine with VP-16 also increased the drug accumulation and decreased the rate of efflux of VP-16 in both sensitive and resistant MCF-7 cells, suggesting that vincristine and VP-16 may compete for similar binding and efflux mechanisms in these cell lines. In contrast, daunorubicin increased VP-16 accumulation only in the sensitive MCF-7 cell line, whereas the efflux rate of VP-16 was not significantly changed in either cell line. HL60 sensitive cells accumulated 4- to 5-fold more VP-16 than the resistant subline. Both sensitive and resistant cells showed an important noneffluxable pool of the drug, 3-fold larger for sensitive cells (79 +/- 12 versus 25 +/- 2 pmol of VP-16/mg of protein, for sensitive and resistant cells, respectively). The efflux of VP-16 was temperature dependent only in sensitive cells. VP-16 accumulation in HL60/ADR cells was increased in glucose-free medium supplemented with sodium azide; however, the noneffluxable pool of VP-16 was not significantly changed. In contrast, although these conditions had no effect on the drug accumulation in the parental line, they caused a decrease in the noneffluxable pool of VP-16, suggesting an energy-dependent binding and retention of VP-16.(ABSTRACT TRUNCATED AT 400 WORDS)

Adriamycin-induced free radical formation in the perfused rat heart: implications for cardiotoxicity.

Adriamycin is an anthracycline drug with a wide spectrum of clinical antineoplastic activity. However, the usefulness of the drug is limited by its dose-dependent cardiotoxicity. Adriamycin-stimulated free radical formation has been suggested as one of the mechanisms for its cardiotoxic effects. In order to evaluate this underlying mechanism, we have perfused rat hearts with Adriamycin, using a modified Langendorf technique, and the free radicals formed were analyzed by electron spin resonance spectroscopy using spin-trapping techniques. Our studies show that Adriamycin stimulated the formation of .OH in the heart, and the maximum .OH was formed with 1 microM of the drug. The addition of superoxide dismutase (600 units/ml) inhibited the hydroxyl radical formation by 2- to 3-fold, while catalase (550 units/ml) abolished it completely, showing the intermediacy of superoxide and H2O2. Furthermore, ICRF-187, an iron chelator and a cytotoxic drug, was also an effective inhibitor of .OH formation in the rat heart. The heart rate was not significantly modified by all the above experiments. This study demonstrates that Adriamycin stimulates the formation of .OH in the isolated rat heart and suggests that this mechanism may be significant in Adriamycin-induced cardiotoxicity.

Effects of doxorubicin on the release of catecholamines from the bovine adrenal medulla.

We have studied the effects of the anthracycline doxorubicin on the release of catecholamines from the perfused bovine adrenal gland. Doxorubicin produced different concentration-dependent effects on adrenomedullary catecholamine secretion. At a 3 x 10(-6) M concentration, doxorubicin facilitated the secretory response induced by acetylcholine and 56 mM K+ but did not affect the spontaneous catecholamine output or that evoked by NaCl deprivation. Conversely, a higher concentration of doxorubicin (10(-4) M) resulted in a significant and irreversible inhibition of the spontaneous secretion of catecholamines, as well as of that caused by acetylcholine or high K+. Doxorubicin at this high concentration did not modify the catecholamine release induced by NaCl deprivation. These results suggest that doxorubicin effects could be mediated at the plasma membrane of the chromaffin cells. The present study is compatible with the idea that increased adrenomedullary catecholamine release is involved in the cardiotoxic action of relatively low doses of doxorubicin.

Cardiotoxicidad de la adriamicina: estudio farmacológico e histopatológico en ratas / Cardiotoxicity of adriamycin: pharmacological and histopathological study in rats

Trabajos recientes mostraron una disminución en la respuesta adrenérgica miocárdica en la insuficiencia cardíaca. Por ello evaluamos los efectos de un tratamiento subagudo con ADM sobre la actividad cardíaca de noradrenalina (NA) e ISOproterenol (ISO). Ratas Wistar de ambos sexos (300-400 g) recibieron ADM 4 mg/kg i.v. en los días 1 y 8. Los controles fueron inyectados con solución fisiológica. El día 21 se sacrificaron los animales y se estudió la histopatología cardíaca. Mediante curvas concentración-respuesta, se evaluó la actividad cronotrópica (CRONO) de NA en la aurícula dreecha aislada (Krebs-carbogeno, 37 grados centígrados). El efecto inotrópico (INO) de NA e ISO fue estudiado en aurícula izquierda, estimulada a 3 Hz. Cada grupo experimental incluyó 4-6 ratas. Las curvas concentración-respuesta a NA revelaron: 1) Desplazamiento a la derecha para CRONO en el grupo ADM (ED 50:7,1 + ou - 1,7. 10-7M versus 3,0 + ou - 1,4.10-8 M en controles; p<0,01).2) Un fenómeno similar para INO (ED 50:2,8 + ou - 0,2.10-7 M con ADM versus 2,3 + ou - 0,7.10-8 en controles; p<0,01). Con ISO, se obtuvieron resutados similares en INO (ED 50:1,8 + ou - 0,7.10-8 M con ADM, versus 3,6 + ou - 1,7.10-10 M en controles; p<0,001). Las ratas tratadas con ADM presentaron ascitis, derrame pleural y lesiones miocárdicas (miocitolisis, vacuolización, infiltración linfocitaria), no así las ratas control. El tratamiento subagudo con ADM deprime la respuesta beta-adrenérgica miocárdica en ratas. Este fenómeno se acompaña de signos histopatológicos de daño cardíaco. El presente modelo puede ser útil para evaluar posibles agentes protectores de la cardiotoxicidad promovida por la ADM

Cardiotoxicidad de la adriamicina: estudio farmacológico e histopatológico en ratas / Cardiotoxicity of adriamycin: pharmacological and histopathological study in rats

Trabajos recientes mostraron una disminución en la respuesta adrenérgica miocárdica en la insuficiencia cardíaca. Por ello evaluamos los efectos de un tratamiento subagudo con ADM sobre la actividad cardíaca de noradrenalina (NA) e ISOproterenol (ISO). Ratas Wistar de ambos sexos (300-400 g) recibieron ADM 4 mg/kg i.v. en los días 1 y 8. Los controles fueron inyectados con solución fisiológica. El día 21 se sacrificaron los animales y se estudió la histopatología cardíaca. Mediante curvas concentración-respuesta, se evaluó la actividad cronotrópica (CRONO) de NA en la aurícula dreecha aislada (Krebs-carbogeno, 37 grados centígrados). El efecto inotrópico (INO) de NA e ISO fue estudiado en aurícula izquierda, estimulada a 3 Hz. Cada grupo experimental incluyó 4-6 ratas. Las curvas concentración-respuesta a NA revelaron: 1) Desplazamiento a la derecha para CRONO en el grupo ADM (ED 50:7,1 + ou - 1,7. 10-7M versus 3,0 + ou - 1,4.10-8 M en controles; p<0,01).2) Un fenómeno similar para INO (ED 50:2,8 + ou - 0,2.10-7 M con ADM versus 2,3 + ou - 0,7.10-8 en controles; p<0,01). Con ISO, se obtuvieron resutados similares en INO (ED 50:1,8 + ou - 0,7.10-8 M con ADM, versus 3,6 + ou - 1,7.10-10 M en controles; p<0,001). Las ratas tratadas con ADM presentaron ascitis, derrame pleural y lesiones miocárdicas (miocitolisis, vacuolización, infiltración linfocitaria), no así las ratas control. El tratamiento subagudo con ADM deprime la respuesta beta-adrenérgica miocárdica en ratas. Este fenómeno se acompaña de signos histopatológicos de daño cardíaco. El presente modelo puede ser útil para evaluar posibles agentes protectores de la cardiotoxicidad promovida por la ADM (AU)