The clinical and pharmacokinetic evaluation of two-route chemotherapy with cisplatin and sodium thiosulfate in combination with angiotensin II]

Thirty-six courses of chemotherapy with cisplatin (CDDP) and sodium thiosulfate (STS) were performed in 31 patients with gynecologic cancer 2 weeks after operation under the hypertensive condition induced by angiotensin II (AT-II). One hundred-fifty mg of CDDP/body was intraperitoneally administered while the usual systolic blood pressure was increased to 130-140% by AT-II. The hypertension was maintained for 15 minutes after finishing CDDP infusion, then 8g of STS was intravenously infused immediately after the cessation of AT-II. The urinary Pt level measured 15 minutes after finishing CDDP infusion was extremely low at 1.37 +/- 0.47 micrograms/ml, in spite of the significantly high levels of plasma total Pt (7.83 +/- 0.85 micrograms/ml) and filtrable Pt (4.02 +/- 0.55 micrograms/ml). This suggests that, during renal vasoconstriction induced by AT-II, the renal blood flow as well as renal uptake of CDDP was decreased. Plasma filtrable Pt levels were measured at 15, 30, 60 and 120 minutes after intraperitoneal administration of CDDP. At 15 and 30 minutes a significantly higher blood concentration was found than in the control group (p less than 0.05). However, CDDP-induced toxicities of the bone marrow, liver, kidney and alimentary tract were not increased. The extreme vasoconstriction in the kidneys and other organs induced by AT-II might have protected these organs from the toxicities of CDDP despite the fact that STS infusion was delayed by 15 minutes after CDDP infusion. STS infused immediately after the cessation of AT-II could neutralize the CDDP preventing the occurrence of toxicities.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neutralizing effect of sodium thiosulfate on antitumor efficacy of cisplatin for human carcinoma xenografts in nude mice

The present study was designed to examine the antitumor efficacy of combination chemotherapy with sodium thiosulfate (STS) and cis-diamminedichloroplatinum (CDDP) using a murine model. Xenograft tumors of the endometrial adenocarcinoma cell line responded well to intraperitoneal chemotherapy with CDDP in nude mice. However, addition of STS to CDDP treatment canceled the antitumor effect of CDDP. Such a finding was obtained in mice injected subcutaneously with STS even 72 hr after treatment with CDDP. On the other hand, alleviation of CDDP-induced side effects by administration of STS was not observed in mice treated by several modalities of combination chemotherapy with STS and CDDP. Thus, addition of STS to CDDP treatment reduced CDDP's antitumor efficacy with only minimal alleviation of side effects, suggesting that it would provide no benefit in patients treated with CDDP.     

Quantitative evaluation for murine oocyte toxicity following intraperitoneal treatment with chemotherapeutic agents

The ovarian toxicity induced with 12 oncostatics was evaluated using syngeneic mice, 6-week-old C57BL/6. Each drug diluted with saline to 0.2ml was intraperitoneally infused twice at 6 and 7 weeks old. Mice were sacrificed 2 weeks after the second treatment, the ovaries removed and fixed for serial sectioning, and the small oocytes of Pedersen and Peters counted. Small oocytes were destroyed in a dose-dependent fashion, and ED50, an effective dose of which produced 50% destruction of small oocytes in each mice group, was significantly divided into 4 groups of statistical difference (F = 5.77, p less than 0.0213). The smallest dose of ED50 (mg/mouse) (the strongest in oocyte toxicity): Actinomycin D 0.0064, doxorubicin 0.0184, peplomycin 0.021; the second: Bleomycin 0.107, mitomycin 0.0707, CDDP 0.120; the third: Cyclophosphamide 0.427; and the largest (the weakest): Ifosphamide 3.01, 5FU 6.17, etoposide 6.11, methotrexate 2.0 much less than, vinblastine 0.1 much less than. The most toxic included those which could attack not only DNA, but also RNA biosynthesis and the least included those which could have an effect on enzymes or proteins with no direct action on DNA. The ratio of ED50 to HUD, the single usual dose for human cancer chemotherapy, were smallest for doxorubicin (2.23), cyclophosphamide (2.59) and CDDP (5.19). Although these three are very useful oncostatics for ovarian cancer, they might have serious potential toxicity for human ovarian oocytes.     

Renal toxicity by intraperitoneal administration of CDDP

Renal toxicity following intraperitoneal (ip) CDDP therapy after laparotomy in twenty patients with ovarian cancer was examined. Four patients had renal toxicity. Patients who received CDDP at a dose of 150 mg (2/2) had a statistically higher incidence of toxicity than those who received less than 100 mg (2/18) (p less than 0.05). Patients who underwent ip therapy on the same day as laparotomy had a statistically higher incidence of the toxicity (4/15) than those underwent it on the fourth day after (0/5) (p less than 0.05). Renal toxicity was revealed in the mean urine volume of 1,100 ml on the day of therapy, but the toxicity did not appeared in those with a mean urine volume of 2,131 ml, whose volume was statistically different (p less than 0.01). These data suggest maintenance of renal blood flow during CDDP treatment plays an important role in preventing renal toxicity even following ip therapy. By investigating preoperative laboratory data, it is seen that patients with FDP values higher than 32 micrograms/ml have a higher risk of renal toxicity.     

Clinical pharmacology of intraperitoneal cisplatin

The clinical pharmacology of cisplatin was determined in six patients with malignant ascites secondary to ovarian cancer, and in one patient with peritoneal mesothelioma, following intraperitoneal administration of cisplatin (25-60 mg/m2). The drug was administered in 1 liter of normal saline as a 15- to 30-min infusion. Total, and in some patients free (ultrafilterable), platinum concentrations were determined in plasma, urine, and ascitic fluid by flameless atomic absorption spectrometry. The peak total platinum concentrations in ascitic fluid at the end of infusion were related to dose, a 50 mg/m2 dose producing a 20 to 80 micrograms cisplatin/ml concentration. Filterable platinum represented between 3 and 59% of total platinum in the peritoneum at 4 to 6.5 hr following its administration. Plasma platinum concentrations ranged between 0.2 to 1.6 micrograms/ml 4 hr following administration, and reached a plateau for the next 24 to 48 hr largely in the form of protein-bound platinum. The urinary excretion of cisplatin was consistent with variation in absorption from the peritoneum. Minimal gastrointestinal, bone marrow, and renal toxicities during therapy suggest that sustained free platinum concentrations in ascites may be obtained without significant toxicity and support the intraperitoneal route of administration as an effective strategy for cisplatin therapy of intra-abdominal malignancies.     

Vital initiation of pregnancy (VIP) using human menopausal gonadotropin and human chorionic gonadotropin ovulation induction: Phase I--1981

Laparoscopies for oocyte aspiration in 31 cycles were performed on 25 patients receiving human menopausal gonadotropin and human chorionic gonadotropin. Sixty oocytes were aspirated, of which 48 were considered preovulatory. Ninety-seven percent (58 of 60) of the oocytes were found in the original aspirate, and the remaining oocytes were found in either the first or second follicle wash. The fertilization rate per preovulatory oocyte was 33% (16 of 48), whereas on a per cycle basis it was 39% (12 of 31). A total of 15 conceptuses (2-cell = 5; 3-cell = 3; 4-cell = 7) were transferred to 12 patients, and two pregnancies were established. These pregnancies were established by transfers of 3-cell and 4-cell conceptuses at approximately 47 hours after insemination. Both pregnancies resulted in term deliveries of normal infants.     

Intraperitoneal versus intravenous cisplatin in combination with intravenous cyclophosphamide and epidoxorubicin in optimally cytoreduced advanced epithelial ovarian cancer: a randomized trial of the Gruppo Oncologico Nord-Ovest

Intraperitoneal chemotherapy has a strong biological and pharmacological rationale in the treatment of ovarian cancer. From 1989 to 1996 the present study included 113 patients with FIGO stage II-IV ovarian cancer with residual disease less than 2 cm who were randomly allocated to receive 50 mg/m(2) intraperitoneal cisplatin (CDDP) plus 60 mg/m(2) intravenous epidoxorubicin (EPIDOX) and 600 mg/m(2) intravenous cyclophosphamide (CTX) (ipPEC arm) or 50 mg/m(2) intravenous CDDP plus 60 mg/m(2) intravenous EPIDOX and 600 mg/m(2) intravenous CTX (ivPEC arm). Chemotherapy was repeated every 4 weeks for six cycles. Treatment protocol was changed in 22 patients, 2 from the iv arm (who received single-agent carboplatin) and 20 from the ip arm (who were crossed to systemic chemotherapy, ivPEC, or single-agent carboplatin). At the end of chemotherapy, a second-look was performed in 33 of the 54 patients from the ip arm and in 34 of the 57 patients from the systemic arm. The pathologic complete response rate was 41% of all entered patients and 69% of patients submitted to second-look. No significant difference in pathologic response rate as well as in hematologic and nonhematologic toxicities was seen between the two arms. Up to September 1998, 72 patients showed a disease recurrence (33 treated with ipPEC and 39 treated with ivPEC), 55 died (22 ipPEC and 30 ivPEC), and 10 were lost to follow-up (6 ipPEC and 4 ivPEC). Median progression-free survival was 42 and 25 months for ipPEC and ivPEC, respectively (p = 0.13). Median overall survival was 67 and 51 months for ipPEC and ivPEC, respectively (p = 0.14). In conclusion, besides confirming that intraperitoneal chemotherapy is feasible with acceptable toxicity but with poor compliance in community hospitals, this trial showed that intraperitoneal CDDP compared with intravenous CDDP in combination with EPIDOX and CTX obtained a slight (not significant) improvement in progression-free survival and overall survival of optimally cytoreduced advanced ovarian cancer patients.     

Vasoactive intestinal polypeptide (VIP) selectively stimulates prolactin release in healthy women

The neuropeptide, vasoactive intestinal polypeptide (VIP), is released from the hypothalamus to the portal circulation, and experiments on animals provide evidence that it might modulate hormone secretion from the pituitary. Here we report the effects of VIP on the release of different pituitary hormones, including prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyrotropin-releasing hormone (TSH), in normal women. Seven healthy women (aged 27-32; body weight 53-60 kg), with normal menses and receiving no medication, were tested on days 20-23 of their cycle. Porcine VIP was injected i.v. as a bolus dose of 1 mcg/kg body weight. Blood samples were collected 10 minutes prior to VIP administration and 5, 15, 30, 45, 60 and 90 minutes after VIP injection. Blood pressure and heart rate were continuously monitored. Hormone levels were determined by RIA. Stress, which can stimulate PRL release, was assayed by measuring the effect of placebo on hormone release (5 controls). VIP injection induced a significant (p less than 0.01) increase in plasma PRL levels. Basal PRL was 20.25 +/- 9.14 ng/ml; 5 minutes after VIP injection PRL levels rose to 45.0 +/- 14.9 ng/ml (p less than 0.01). At 15 minutes a plateau was reached (46.0 +/- 14.5 ng/ml), then the levels slowly decreased. VIP administration did not modify the plasma concentration of LH, FSH or TSH at any time during the observation period. The present study indicates that VIP might play a physiological role as a RPL-releasing factor in human beings.     

The effect of cis-platinum (CDDP) on methotrexate-resistant choriocarcinoma cell line

Cis-platinum (CDDP) was investigated in vitro and in vivo for its ability to inhibit the growth of Methotrexate (MTX)-resistant choriocarcinoma cell line (BeWo) and was compared with the effect of MTX and Actinomycin D (ACD). Each drug was added into medium (RPMI 1640 containing 10% FBS) for 1 hr. at the concentration of peak plasma level in clinical use (CDDP 7 X 10(-6)M, MTX 10(-6)M, and ACD 8 X 10(-8)M), or for 48 hrs. at one-tenth of the level. CDDP inhibited the cell growth to 40% of control at 7 X 10(-6)M for 1 hr., and 25% at 7 X 10(-7) M for 48 hrs. And ACD suppressed the cell growth to 10% at both 8 X 10(-8)M for 1 hr. and 8 X 10(-9)M for 48 hrs. But MTX did not inhibit the cell growth at 10(-6)M for 1 hr., and inhibited to 60% of control at 10(-7)M for 48 hrs. On the other hand, BeWo transplanted to athymic nude mice (CD-1(ICR) nu/nu) was treated with intraperitoneal injections of CDDP (1.4 mg/kg/day for 4 consecutive days in a week and repeated for 2 and 4 weeks), MTX (2mg/kg/day for 4 consecutive days in a week and repeated for 2 weeks), and ACD (90 micrograms/kg/day for 4 consecutive days in a week and repeated for 2 and 4 weeks). The suppression of the tumor growth was seen in CDDP-treated group (TRW/CRW = 6.5%) and ACD-treated group (TRW/CRW = 29%) after 2 courses of treatment, but no apparent suppression was shown in the MTX-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Distribution of intraperitoneally injected microspheres labeled with the alpha-emitter astatine (211At) compared with phosphorus (32P) and yttrium (90Y) colloids in mice.

The alpha-emitter 211At was bound to polymer microspheres with a diameter of 1.8 microns. The distributions in mice of intraperitoneally injected 211At microspheres, 90Y silicate colloid, and 32P chromic phosphate colloid were compared. The microspheres with 211At spread rapidly in the peritoneal cavity and remained mainly on the intraperitoneal surfaces. Intraperitoneal injection of 90Y colloid resulted in high levels in intraperitoneal fat and the diaphragm, but 1 day after injection 8.5% of the injected dose per gram was found in blood and after 6 days 2.5% was observed in bone. The highest accumulation of 32P was found in liver and spleen. The injection of additional nonradioactive chromic phosphate colloid resulted in an even higher accumulation of 32P in spleen and liver. The same phenomenon was not observed with 211At microspheres. It is suggested that it is not only the particle size which is important in the distribution of intraperitoneally injected colloid, but the amount of colloid, the type of colloid, the addition or presence of other substances such as ascites, and the animal species might also influence the distribution. In conclusion, the intraperitoneal distribution of 211At-labeled microspheres in mice was favorable compared with 90Y and 32P colloid. These data must be viewed cautiously since the distribution might be different in other animal species or humans.     

Impact of a second insemination on the results of an in vitro fertilization-embryo transfer (IVF-ET) program

In an attempt to increase the fertilization and pregnancy rates in our program, a second insemination was carried out when the first insemination yielded fewer than two fertilized oocytes. One hundred eighty consecutive patients were studied retrospectively and thirty-four required second insemination, 35% of them by donor-semen. Fifty-five and nine-tenths percent of the patients had at least one fertilized oocyte for embryo transfer, but only 21.9% of the oocytes exposed to a second insemination were fertilized. No pregnancy resulted from the transfer of oocytes fertilized by the second insemination. There were no significant correlations between the success of fertilization after a second insemination and the number of oocytes retrieved, the protocol for the induction of superovulation, or the age of the female patient. Considering that the first insemination was done at a variable time after oocyte retrieval to allow oocyte maturation, we expected all oocytes to be mature at the time of first insemination and we considered the possibility of delayed fertilization as negligible since second insemination was done at least 24–30 hr after oocyte retrieval. Even though a second insemination provides further hope for the patient, by yielding additional fertilized oocytes for embryo transfer, its main value is that it may provide additional information about male fertility.     

CDDP-ACR treatment in patients with recurrent ovarian cancer with prior chemotherapy containing CDDP--a preliminary study of a 14-day continuous infusion of CDDP with ACR

Six patients with recurrent ovarian cancer who had prior chemotherapy were studied for the clinical efficacy of CDDP-ACR treatment. Five out of the 6 had received CDDP a total doses of 1,320, 780, 750, 475, and 340 mg. CDDP-ACR therapy consisted of continuous infusion of CDDP at a daily dose of 10 mg/m2 over 14 days (total CDDP doses; 140 mg/m2) and of intermittent infusion of ACR (aclarubicin) at a dose of 20 mg/body every other day (total ACR doses: 140 mg). There were one CR and five PR and a response rate up to 100% was noted. Toxicity was manifested in slight nausea or vomiting, but there was no nephrotoxicity. However bone marrow was severe. Thrombocytopenia less than 50,000/mcl in 4 pts (67%) and leukopenia less than 1,000 mcl in 3 pts (50%). The mean filterable platinum exposure measured by area under the concentration-time curve (AUC) was as high as 19.7 +/- 6/0 mg.hr/ml. In conclusion the bone marrow toxicity in this regimen was severe, but the therapeutic efficacy was promising. Further studies on the appropriate infusion time and the minimum effective dose of CDDP are needed.     

The effect of bismuth subnitrate on cisplatin toxicity

Bismuth subnitrate (BSN), a bismuth compound medically used for antidiarrheics, was orally administered to see whether it can reduce CDDP nephrotoxicity or not. Thirteen patients aged 19 approximately 60 with ovarian cancer entered this BSN-CDDP trial. A total of thirty three courses of BSN-CDDP treatment was undergone. BSN was administered orally at a dose of 50 mg/kg for five days before CDDP therapy. CDDP was infused for two hours. No vigorous hydration or diuresis was performed. Only 2,000 ml of saline with 20 mEq per liter of KCl was given for post-hydration. The median dose of CDDP was 100 mg/m2. The renal toxicity of BSN-CDDP treatment was minimum. 82% of the courses at the sixth day after the treatment had creatinine clearance levels which were more than 80% of those before the treatment. But twenty-four hour NAG and beta 2-microglobulin excretion were significantly increased. Bone marrow suppression and gastrointestinal disturbance were commonly observed. The results of our study indicate that BSN pretreatment reduces the renal toxicity of CDDP to some extent.     

Successful pregnancy after ICSI with strontium oocyte activation in low rates of fertilization

Fertilization failure (complete fertilization failure or low fertilization rates) after intracytoplasmic sperm injection (ICSI) can occur in rare cases. In the majority of these cases, the unfertilized oocytes are inactivated. Assisted oocyte activation was applied as a treatment option for a case of low fertilization rate as a clinical trial. A patient with a low fertilization rate (ranging from 0% to 33.3%; mean = 17.0%) after eight previous ICSI cycles at another hospital, was diagnosed with fertilization failure. The most likely cause of fertilization failure was failure of oocyte activation. Therefore, artificial oocyte activation by strontium treatment was combined with ICSI to achieve viable fertilized oocytes. Oocytes were stimulated with strontium (10 mM SrCl(2), 60 min) approximately 30 min after ICSl. Six injected oocytes were stimulated and all were then successfully fertilized. Two blastocysts were transferred into the uterus, resulting in a pregnancy and birth. A second pregnancy was achieved following implantation of two cryopreserved embryos (one blastocyst and one morula). In conclusion, strontium treatment was found to be an effective method for artificial oocyte activation in a case with a low fertilization rate after ICSI.     

Embryological indicators in cycles with HCG or different doses of GnRH-a for the final oocyte maturation in IVF–ICSI patients

Abstract

So far there is no consensus on the optimal dosage of GnRH-a when using it as a trigger for final oocyte maturation in in vitro fertilization (IVF) cycles. We compared embryological characteristics in IVF–intra-cytoplasmic sperm injection (ICSI) cycles when applying triptorelin at a dose of 0.2?mg (test group 2), 0.5?mg (test group 3) and human chorionic gonadotropin (HCG) at a dose of 10?000?IU (test group 1). In group 1, the average number of oocytes per oocyte retrieval (11.7?±?4.8) was lower in comparison with groups 2 and 3, which can be explained by the differences in the selection of the patients’. The number of oocytes per retrieval in group 3 (20.2?±?6.3) was significantly higher (p?=?0.02) compared to group 2 (17.0?±?6.2). The percentage of mature oocytes (MII) and fertilization rate did not differ between the groups. The rate of blastocyst formation in group 3 (71.9?±?17.1%) was significantly higher (p?=?0.02) in comparison with group 2 (57.9?±?24%). We conclude that the application of triptorelin at a dose of 0.5?mg may be more effective for triggering final oocyte maturation in IVF cycles in comparison with the dose of 0.2?mg, due to the increase in the number of retrieved oocytes and the improved rate of the blastocyst formation.     

Transient cooling to room temperature can cause irreversible disruption of the meiotic spindle in the human oocyte

The effect on the microtubule system of human oocytes of cooling to room temperature for either 10 or 30 minutes has been investigated. Changes in spindle organization were found in all oocytes cooled for 30 minutes compared with control oocytes kept at 37 degrees C throughout. These changes included reduction in spindle size, disorganization of microtubules within the spindle itself, and sometimes a complete lack of microtubules. In some oocytes, chromosome dispersal from the metaphase plate was associated with these changes. Cooling the oocyte to room temperature for only 10 minutes produced a similar pattern of disruption to spindle structure in many cases. The spindles in oocytes that were cooled for either 10 or 30 minutes and then allowed to recover at 37 degrees C for either 1 or 4 hours were found to resemble those in noncooled control oocytes in less than one half of the cases examined, although in only a few cases did the chromosomes remain dispersed. The significance of these findings for the handling of oocytes during gamete intrafallopian transfer and in vitro fertilization procedures is discussed in relation to the levels of aneuploidy detected in early human embryos.     

Effect of lactoferrin on lipopolysaccharide (LPS) induced preterm delivery in mice

BACKGROUND: The present study attempted to confirm the preventive effect of lactoferrin on lipopolysaccharide (LPS) induced preterm delivery in mice. METHODS: Female C3H/HeNCrj mice were pair-mated with male Crj: B6D2F1 mice. On day 15 of gestation, a 50 micron/kg intraperitoneal injection of LPS (LPS group) was administered twice with a 3-hour interval between injections (at 2:00 and 5:00 PM). The mice were also given an intraperitoneal injection of lactoferrin (0.2 or 1 mg/200 microl/body) 1 hour prior to each LPS injection) (at 1:00 and 4:00 PM). To determine the effect of LF on plasma IL-6 level, mother mice were sacrificed and blood samples were obtained at 6 hours after the second treatment of LPS. RESULTS: Preterm delivery was induced by LPS in all mice on day 16 of gestation. Lactoferrin administration to LPS-treated mice significantly prolonged (p<0.001) gestation when compared with the LPS group. Plasma levels of IL-6 in the LPS group (1.628+/-115 pg/ml) were significantly higher (p<0.001) than in the untreated group (497+/-39 pg/ml). On the other hand, administration of lactoferrin (1 mg/body) to LPS-treated mice significantly suppressed (p<0.001) IL-6 levels (1.060+/-154 pg/ml). CONCLUSIONS: Lactoferrin exerts a preventive effect on the incidence of preterm delivery in mice via a suppression of plasma IL-6 augmentation by LPS.     

Pituitary responsiveness to luteinizing hormone-releasing hormone (LH-RH) during pregnancy in the rat

Effects of LH-RH on serum LH levels were studied during pregnancy in rats. On days 10, 15, 18 or 21 of pregnancy, a catheter was placed at the jugular vein under light ether anesthesia. Sixty minutes after the surgery, LH-RH (1 microgram/300 microliters/300 g body weight) was injected through the catheter without anesthesia. Blood samples were collected through the catheter before, and 15 and 30 minutes after LH-RH injection. Basal serum LH levels were lower on days 15 and 18 than on days 10 and 21 of pregnancy. LH-RH injections caused significant increases in serum LH levels on any days of pregnancy, showing the maximum levels at 15 minutes after injection. The LH response was highest on day 10 and gradually decreased towards day 21. LH responses were significantly lower on days 18 and 21 than on days 10 or 15. These results suggested that the lowering of serum LH levels from days 10 to 15 might be due to the decrease in the responsiveness of the pituitary to LH-RH.     

Intraperitoneal cis-platinum as salvage therapy for refractory epithelial ovarian cancer

Eighteen patients with residual epithelial ovarian cancer at second-look laparotomy were treated with a combined total of 210 cycles of intraperitoneal cis-platinum. Sixteen patients had previously received cis-platinum containing combination chemotherapy systemically. Seven patients had microscopic residual disease at the start of intraperitoneal therapy, eight had macroscopic disease of 5 mm in diameter or less, and three had disease of 6-10 mm in diameter. The drug was administered weekly in 2 L of Ringer's lactate solution via an indwelling Tenckhoff catheter, and the dose ranged from 30-270 mg per cycle (median 120 mg). The dwell time was 20 minutes. After 12 cycles, response was assessed by open laparoscopy (six patients), laparotomy (eight patients), or peritoneal cytology (three patients). One patient developed distant metastases. Local and systemic toxicity was mild. Delays of therapy were necessary for eight of the 210 cycles because of hematologic toxicity. Of the 15 patients available for pathologic evaluation, four (26.6%) had a complete response and two (13.3%) had a partial response. Results of this pilot study suggest a possible role for intraperitoneal cis-platinum in the management of carefully selected patients with epithelial ovarian cancer.     

Preclinical in vivo activity of a combination gemcitabine/liposomal doxorubicin against cisplatin-resistant human ovarian cancer (A2780/CDDP)

Both gemcitabine and liposomal doxorubicin are antineoplastic drugs with clinical activity in platinum-refractory ovarian cancer. The purpose of this study was to evaluate the antitumor activity of a combination gemcitabine/liposomal doxorubicin administered to athymic mice bearing cisplatin-resistant human ovarian cancer (A2780/CDDP) xenografts. Emphasis was on the use of very low doses of each drug and of different dosing schedules. Data obtained showed that combined treatment with 80 mg/kg gemcitabine and 15 mg/kg liposomal doxorubicin produced a significant enhancement of antitumor activity compared with monotherapy at the same doses of these agents. Noteworthy is the fact that the majority of xenograft-bearing animals receiving the combination therapy demonstrated a complete tumor regression at the end of the study. A similar trend was observed when doses of both drugs were reduced to 20 mg/kg gemcitabine and to 6 mg/kg liposomal doxorubicin. Again, three out of ten mice receiving the combination were tumor free at the end of the study. No significant differences were observed in antitumor activity when comparing the simultaneous vs the consecutive dosing schedule. Remarkably, no additive toxicity was observed in any experimental trials. These data encourage clinical trials to prove the advantages of this combination treatment with respect to the single-agent chemotherapy in platinum-refractory ovarian cancer patients.