Protective effect of sodium-2-mercaptoethanesulfonate on the gastrointestinal toxicity and lethality of cis-diamminedichloroplatinum

cis-Diamminedichloroplatinum (cis-platinum) is an effective and widely used antitumor drug. Patients receiving cis-platinum, however, experience very profound and long lasting gastrointestinal symptoms. The role of intestinal mucosal toxicity in the pathogenesis of these symptoms is unclear. In this study we have investigated the thiol-containing compound mesna (sodium-2-mercaptoethanesulfonate) as a potential antidote to cis-platinum-induced gastrointestinal tract damage. In mice, mesna caused a significant reduction in the gastrointestinal toxicity of cis-platinum assessed by electron microscopy, villus recovery rate, and by disaccharidase estimations. Mesna also significantly reduced serum creatinine levels following cis-platinum. Administration of mesna prior (or immediately following) a 67% lethal dose of cis-platinum protected 87-100% of the animals from the lethal effects. The antitumor efficacy of cis-platinum in L1210 leukemia bearing mice was not affected by coadministration of mesna indicating that the protective effect may be tissue specific. In addition this finding indicates that mesna has potential as an agent which may improve the therapeutic index of cis-platinum in clinical practice.     

Gastrointestinal toxicity of chemotherapy and the influence of hyperalimentation

The effect of combination chemotherapy on human small intestinal morphology and disaccharidase activities and their relation with clinical and chemical (fecal wet weight and K-excretion) parameters for gastrointestinal toxicity were evaluated in patients with disseminated malignant melanoma receiving enteral normoalimentation (NA). Also evaluated were the supposed protective effects on gastrointestinal toxicity of enteral hyperalimentation (HA) with an elemental diet. After chemotherapy, a comparable decrease in villus height, total mucosal height, and mitotic index was found in jejunal biopsy specimens of both groups. However, in the NA group, the crypt depth decreased (in contrast to the HA group), whereas the disaccharidase activities in the HA group deteriorated to lower values than in the NA group. The authors found no correlation between disaccharidase levels and mucosal morphology, nor was there a correlation between these variables, fecal parameters and clinical diarrhea, suggesting that diarrhea occurring after chemotherapy was not due to loss of mucosal tissue or decrease in enzyme activities. A protective effect of HA with an elemental diet on gastrointestinal toxicity could not be established.     

Comparison of intestinal toxic effects of platinum complexes: cisplatin (CDDP), carboplatin (CBDCA), and iproplatin (CHIP)

Summary The biochemical background of the intestinal side effects of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (CBDCA) and cis-diisopropylammine-trans-dihydroxy-dichloro platinum (IV) (CHIP) was compared with those of cis-diamminedichloroplatinum (II) (CDDP). Biochemical investigations were carried out on mucosal cells isolated by a combined chemical-mechanical method from the total length of the small intestine. After treatment with single, equitoxic doses of Pt analogues, the activities of thymidine kinase (TK) EC 2.7.1.21, sucrase (SUC) EC 3.2.1.26, maltase (MAL) EC 3.2.1.20, and protein content showed dose-dependent decreases, whereas the activity of alkaline phosphatase (AP) EC 3.2.1.20 increased slightly. The nadir of enzyme activity changes occurred 24–48 h after treatment. For the regeneration of the mucosa more than 96 h was necessary. Of the platinum analogues studied, CHIP proved to be the most toxic to the small intestine. While the highest doses of CDDP and CBDCA (0.66xLD₅₀) caused significant but less than 50% decreases in TK, SUC, MAL, and protein content (PROT), the CHIP doses needed for 50% reduction were between 0.44–0.66xLD₅₀.     

High-dose dexamethasone for prevention of cis-platin-induced vomiting

Summary Severe, debilitating nausea and vomiting are seen in almost 100% of patients treated with cis-platinum. These side-effects can be so severe and prolonged as to preclude therapy in a large number of patients. Commonly used antiemetics have had only limited success in controlling cis-platinum-induced nausea and vomiting. Various reports have indicated benefits from steroids in this setting.We have tested a high-dose dexamethasone regimen with or without neuroleptics, which inhibits chemotherapy-induced vomiting in 50% of patients failing with prior antiemetics and in 71% of those who had not received prior antiemetics. This treatment was administered on an out-patient basis as it involved oral administration of the antiemetic.Neuroleptic therapy was not randomly assigned, but the results of this pilot study suggest that it did not enhance dexamethasone's efficacy. There were no significant side-effects due to the steroids. The antiemetic effectiveness of dexamethasone was retained through repeated courses of chemotherapy.     

Enhancement of radiation-induced cell kill by platinum complexes (carboplatin and iproplatin) in V79 cells

Two second generation platinum complexes currently undergoing clinical chemotherapeutic trials, carboplatin (CBDCA) and iproplatin (CHIP), were evaluated for their ability to alter the survival of cultured Chinese hamster V79 cells following irradiation. Two protocols were employed. In the first, the drug was added to preplated cells, some of which were subsequently made hypoxic with nitrogen gas. These hypoxic cells were irradiated following 1 hour exposure to drug and survival was assessed by standard colony forming unit (CFU) methods. Enhancement ratios (ER) of approximately 1.4 were obtained for irradiation under hypoxic conditions, if the cells were exposed to equitoxic doses of CBDCA (500 microM) CHIP (50 microM). In the second series of experiments, cells were treated with 10 Gy in air and then incubated for various times prior to trypsinization and serial dilution of single cell suspensions. Six hours after irradiation, cells treated with X rays alone had recovered to produce a surviving fraction twice that of cells trypsinized immediately after irradiation (not held). Post-irradiation administration of CBDCA (50 microM) or CHIP (20 microM), at a time when free radical-mediated radiosensitization would not be possible, operationally inhibited this recovery from radiation-induced potentially lethal damage (PLD). Inhibition, expressed as recovery inhibition factor (RIF) after 6 hr with drug, was 2.0 for CBDCA and 1.2 for CHIP. These results suggest that the rationale for designing clinical trials to exploit interactions between cisplatin and radiation might also extend to include combined modality therapy using radiation with either of these two platinum complexes.     

Transforming Growth Factor-beta2 protects the small intestine during methotrexate treatment in rats possibly by reducing stem cell cycling

During chemo- and radiation therapy, the balance between epithelial cell proliferation, differentiation, and cell death at the villus tip is disrupted by premature death of dividing epithelial cells. This will subsequently lead to the onset of mucosal barrier injury in the whole gastrointestinal tract. Up till now there is no validated method to treat side effects occurring due to therapy. An approach to manage this side effect might be to reversibly arrest growth of epithelial stem cells during therapy using Transforming Growth Factor-beta2. A Transforming Growth Factor-beta2 enriched fraction prepared from bovine milk was shown to protect small intestinal epithelial cells against cell cycle specific chemotherapeutic agents by arresting the cells in G1-phase. Secondly, in a rat model for induced small intestinal damage, oral supplementation of rats exposed to methotrexate with the Transforming Growth Factor-beta2 enriched fraction significantly reduced the chemotherapy-associated weight loss and ileal villus atrophy by reducing cell proliferation in the normal stem cell population. Thus oral supplementation with a bovine milk fraction enriched for Transforming Growth Factor-beta2 attenuated the side effects of chemotherapy in the small intestine in rats.     

Phase II trial of carboplatin or iproplatin in cervical cancer

Summary From July 1984 to November 1987, 89 patients with recurrent measurable squamous-cell cancer of the uterine cervix were randomized in a single institution to receive treatment with either carboplatin (CBDCA) or iproplatin (CHIP). Objective response rates were similar: 2 complete regressions (CRs) and 10 partial regressions (PRs) were recorded both in the 46 evaluable patients treated with CBDCA (response rate, 26.1%; 95% confidence interval, 15–41%) and in the 40 evaluable patients treated with CHIP (response rate, 30%; 95% confidence interval, 17–47%). The median duration of response was 5.5 months for CBDCA and 6 months for CHIP; the median survival was 7.5 and 7.6 months, respectively. Both drugs were given in an outpatient setting and myelosuppression (thrombocytopenia) was the predominant toxicity. Analysis of all toxic events yielded additional interesting observations: the occurrence of moderate to severe platelet nadirs beyond cycle 1 was confined to CHIP, a higher incidence of gastrointestinal toxicity during treatment with CHIP, and five moderate to severe complaints of asthenia (recorded as neurologic events) during CHIP therapy versus only one during treatment with CBDCA. Because of its antitumor activity and its toxicologic advantage, a future role for CBDCA in the treatment of cervical cancer appears likely.     

Anguidine potentiates cis-platinum in human brain tumor cells

Summary Anguidine pretreatment was previously shown to potentiate cis-platinum in Chinese hamster ovary cells by 100-fold, probably by enhancing cellular cis-platinum. uptake. Since both cis-platinum and anguidine have been reported to have clinical efficacy in human brain tumors, the present study was initiated to investigate whether anguidine's potentiation of cis-platinum was applicable to human brain tumor cells in culture. Using the colony formation assay, it was found that anguidine enhanced cis-platinum's cytotoxicity by ten-fold, producing a dose modification factor of 1.74. Alkaline elution analysis of cis-platinum-induced DNA crosslinks found that anguidine enhanced cross-linking by a factor of 1.55, 1.76, 1.63, and 1.48 at 0, 6, 24, and 48 hr, respectively, after cis-platinum treatment. This enhancement of cross-linking is evidence for anguidine increasing cis-platinum uptake. Thus, anguidine enhances cis-platinum-induced DNA cross-linking and subsequent cytotoxicity in human brain tumor cells, and may be clinically useful in combination with cis-platinum in those tumors.     

Modification of the bone marrow toxicity of cis-diamminedichloroplatinum(II) in mice by diethyldithiocarbamate

It has been shown that cis-platinum-induced nephrotoxicity in rats can be inhibited by diethyldithiocarbamate (DDC). We report here the bone marrow protective properties of DDC in hybrid (C57BL X BALB/c) mice exposed to single and fractionated doses of cis-platinum. Relatively nontoxic doses of DDC afford maximum protection, using that dose of cis-platinum that would result in the death of 50% of the mice within 9 days as an end point (dose-limiting gut toxicity in mice), when injected 0.5 to 2 hr following i.p. cis-platinum treatment. Survivals of colony-forming units in spleen, nucleated bone marrow cells, and peripheral white blood cell were used to assess the bone marrow protective properties of DDC following both single and fractionated doses of cis-platinum. A dose modification factor of 3.2 (based on colony-forming units in spleen survival) was obtained when DDC (1000 mg/kg) was injected into mice 0.5 hr after graded doses of cis-platinum. When fractionated doses of cis-platinum were used (6 mg/kg on Days 0, 10, 20, and 30), the survival of colony-forming units in spleen was markedly enhanced if the animals were rescued with DDC 0.5 hr following each cis-platinum dose. When bone marrow cellularity was measured immediately before and 2 days after each dose of cis-platinum, a similar pattern of depression and recovery was noted whether DDC was present or not; however, the depression was less marked in mice rescued with DDC. When peripheral white blood cell counts were monitored, the nadir and recovery were similar in the presence or absence of DDC; however, recovery occurred sooner in the animals that had received DDC. Our data support the ability of DDC to modify the bone marrow toxicity of cis-platinum in normal mice. Experiments are in progress in tumor-bearing animals exploring the differential protection afforded by DDC between bone marrow and tumor.     

High-dose carboplatin with diethyldithiocarbamate chemoprotection in treatment of women with relapsed ovarian cancer

Diethyldithiocarbamate (DDTC) has been found to protect the bone marrow, kidneys, and gastrointestinal tract from the toxic effects of cisplatin and carboplatin (CBDCA) in animal models. In an attempt to minimize the toxic effects of high-dose CBDCA (800 mg/m2), a pilot study was undertaken in which women with relapsed or refractory epithelial ovarian cancer were treated with high-dose CBDCA, which was followed 3 hours later with DDTC (4 g/m2). There were four partial responses and no complete response in 21 patients who could be evaluated (overall response rate, 19%). Significant toxic effects, including three treatment-related deaths, were associated with the regimen. This study suggests that while high-dose CBDCA plus DDTC may be active in relapsed or refractory ovarian cancer, it is associated with clinically significant hematologic and autonomic toxic effects.     

Acquisition of platinum drug resistance and platinum cross resistance patterns in a panel of human ovarian carcinoma xenografts.

In vivo models of acquired resistance to the platinum-based agents cisplatin (CDDP), carboplatin (CBDCA), iproplatin (CHIP) and tetraplatin have been established using a panel of six parent human ovarian carcinoma lines, two (HX/110 and PXN/87) being derived from previously untreated patients. Resistance has been generated to CDDP (three lines), CBDCA (one line), CHIP (three lines) and tetraplatin (one line) either by treatment in vivo or (for one line to CDDP) through exposure in vitro and subsequent transfer to mice. With the four tumours where resistance was generated using CDDP or CBDCA, a complete cross-resistance to the remaining platinum agents studied was observed. In contrast, in one of three lines with derived resistance to the platinum (IV) agent, CHIP, (PXN/951) a retention in sensitivity was observed with CDDP and CBDCA. Only one of the six parent tumour lines (PXN/100) was markedly sensitive to tetraplatin. Where resistance was generated to tetraplatin (PXN/100T) there was some retention of activity by CDDP. For the CDDP-resistant line established in vitro, there was a close agreement between the cross-resistance profile obtained in vitro vs that obtained in vivo. This tumour panel may be useful in the elucidation of cellular and molecular resistance mechanisms to platinum drugs operative in vivo. Moreover, as they appear to mimic the clinical observations of shared cross-resistance between CDDP, CBDCA and CHIP, they may represent valuable preclinical evaluation models for the discovery of drugs capable of conferring responses in CDDP-refractory ovarian cancer.     

Droperidol as an antiemetic in cis-platinum-induced nausea and vomiting

23 patients received cis-platinum, doxorubicin and cyclophosphamide for gynecologic malignancy between December 1, 1980 and December 1, 1982. Each patient was randomized with each course of chemotherapy to receive intravenous droperidol or the combination of promethazine and chlorpromazine rectal suppositories as an antiemetic regimen. Both the rate and duration of emesis were significantly lower when droperidol was used as the antiemetic regimen. There were no major side effects with either regimen. Droperidol seems to be superior to the combination of promethazine and chlorpromazine rectal suppositories in alleviating cis-platinum-induced nausea and vomiting.     

Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses

Carboplatin (CBDCA) is a second-generation platinum analog with prominent myelotoxicity and modest extramedullary toxicity. We performed a phase I study of CBDCA in adult patients with relapsed acute leukemia. Therapy was administered as a five-day continuous infusion. The initial dose of 875 mg/m2 over five days was escalated in 15% increments to a final dose of 2,100 mg/m2 over five days. Twenty-eight patients received 35 induction courses of CBDCA, including two patients who achieved a complete remission (CR) following the first course, and received a second induction course at the time of relapse. Therapy was well tolerated. No grade 3 or 4 extramedullary toxicity was seen. Myelosuppression was regularly observed, with prolonged myelosuppression at 2,100 mg/m2 over five days being the indication to cease dose escalation. Eight of 28 patients (28.5%) responded to CBDCA therapy (six CR, two partial remission [PR]) or ten of 30 initial induction courses (33.3%). Continuous-infusion CBDCA has an advantage over other therapy for acute leukemia because of its highly selective myelotoxicity and minimal gastrointestinal and renal toxicity. A standard phase II study should be undertaken to establish a more accurate response rate.     

Treatment of gynecological cancer with cis-platinum

Seven patients with gynecological cancer were treated with cis-platinum. Cis-platinum at 50 mg/m2 was administered by intravenous infusion for 2 hours, followed by 2,000 ml of intravenous fluid. This treatment was repeated every three weeks. Five of the seven patients were evaluable. These patients included those with ovarian cancer (3 cases), metastatic ovarian cancer (1 case), and endometrial cancer (1 case). One patient attained a complete response, two a partial response, and two showed progressive disease. The response rate for both complete and partial response was 60%. Gastrointestinal symptoms were most frequently found. Nephrotoxicity was generally mild, but one patient had to discontinue cis-platinum treatment due to severe nephrotoxicity. Cis-platinum treatment is considered to be effective and useful for gynecological cancer. Second-look operation and two-channel chemotherapy were also discussed in this paper.     

Effect of intra-arterially injected cisplatinum and lipiodol on the rat liver

The purpose of this study was to elucidate the availability of cis-platinum powder suspended in lipiodol as a means for the treatment of liver cancer. The effects of cis-platinum powder (1.0 mg), suspended in lipiodol or saline (0.1 ml), as well as that of lipiodol (0.1 ml, 0.3 ml) alone, on the liver, was investigated by intra-arterially administration to 72 normal Wistar rats. It was found that injection of Cis-platinum powder suspended in Lipiodol, is compared to the suspension in saline, resulted in higher concentrations of platinum in the liver Severe histological degenerative and necrotic changes were also found. The liver cells were only moderately affected by lipiodol alone, but large amounts of lipiodol multiple anemic infarctions in the peripheral area 24 hours later. These results suggest that cis-platinum itself affects liver cells only slightly and therefore can be used for the treatment of liver cancer.     

Acute leukemia arising from a myelodysplastic syndrome after long-term administration of iproplatin.

BACKGROUND. Iproplatin (cis-dichloro-transdihydroxybis-isopropylamine platinum IV; CHIP) is a second generation cisplatin derivative that was developed to retain the antineoplastic effect of cisplatin with fewer toxic effects. Early clinical studies showed moderate activity in some neoplasms, with disappointing results in tumors of the lower gastrointestinal tract. Myelosuppression was the dose-limiting toxic effect in the acute setting. METHODS. The authors report a patient with metastatic adenocarcinoma of the colon who received long-term therapy with CHIP. RESULTS. The patient achieved complete remission of disease after prolonged treatment with CHIP. The patient subsequently had a myelodysplastic syndrome that rapidly transformed to acute myelogenous leukemia. CONCLUSIONS. Acute leukemia may represent a late complication of CHIP therapy.     

The effects of intracolonic EGF on mucosal growth and experimental carcinogenesis

Although intra-luminal epidermal growth factor (EGF) may stimulate cell proliferation in the upper gastrointestinal tract, its role in the large bowel has not been established. We have therefore studied the effect of intra-rectal EGF administration on both normal growth and carcinogenesis in the rat colon. Colonic cancer was induced in rats with azoxymethane (10 mg kg-1 week-1 for 12 weeks s.c.) and controls dosed with saline. In each group, animals were randomised to receive EGF (12 nM, 0.8 nM or saline control) in 0.5 ml saline via a rectal tube daily for 24 weeks. At this time, crypt cell production rates (CCPRs) were determined at two sites in the colon: one of maximal and another of minimal exposure to EGF (5 cm and 10 cm from the anal margin respectively). No effects of EGF were seen at 10 cm. The lower dose of EGF gave CCPRs that mirrored the control values. The higher dose of EGF in the animals not treated with azoxymethane stimulated mucosal growth. Azoxymethane increased in CCPR, but this was suppressed by the high dose of EGF. These results suggest that (1) luminal EGF and azoxymethane independently increase the colonic CCPR and their combined effect is not synergistic but antagonistic; (2) EGF may have a role in normal epithelial growth, but does not potentiate colonic carcinogenesis in this model.     

The effect of calcium supplements on rectal mucosal proliferation.

Seventy-nine patients with colorectal adenomata were randomised to receive calcium carbonate (3,000 mg) or placebo in a double-blind randomised trial to assess the short- and long-term effects on rectal mucosal proliferation measured by the in vitro metaphase arrest technique crypt cell production rate (CCPR). There was no significant difference in mean CCPR between the groups before treatment or after 3 or 12 months. In those patients randomised to calcium, CCPR fell at both 3 months [9.0 (2.8) cc c-1 h-1, t = 3.15, d.f = 76, P = 0.002] and 12 months [9.2 (3.3) cc c-1 h-1 t = 2.7, d.f. = 74, P = 0.009] compared with pretreatment CCPR [12.2 (5.5) cc c-1 h-1]. We have demonstrated that calcium had no effect on mucosal proliferation compared with placebo. The results on adenoma formation are awaited.     

Effect of combination chemotherapy on murine bladder cancer

A murine bladder tumor model was evaluated for tumor growth retardation while receiving combination chemotherapy, either 40 mg/m2 methotrexate and 35 mg/m2 cis-platinum or 500 mg/m2 cytoxan and 35 mg/m2 cis-platinum at 3-week intervals. Tumor growth was observed in the control and treated groups. A significant decrease (p less than 0.001) in tumor growth and lung metastasis was noted in the cytoxan and cis-platinum group. Although the 40 mg/m2 group treated with methotrexate and 35 mg/m2 cis-platinum showed a decrease in tumor growth, it was not significant (p greater than 0.1), and lung metastasis was greater than in the control group. Cis-platinum with cytoxan was clearly effective in retarding tumor growth and metastatic spread.     

Current clinical status of new anticancer drugs

4'-Epiadriamycin demonstrated considerable efficacies in lymphomas, breast cancer and soft part sarcomas with reduced gastrointestinal, hematologic and probably cardiac toxicities. Mitoxantrone appears to be established the clinical role in lymphomas, acute leukemia and breast cancer with mild clinical toxicities. A new analogous compound of cisplatinum CBDCA concluded phase I study and the dose limiting factor was thrombocytopenia. It is of interest that the drug had responders in ovarian cancer during phase I study. The results reported in new anthracyclines; marcellomycin, carminomycin and 4-demethoxydaunorubicin, anthraquinones; ametantrone and bisantrene, new cisplatinums; CHIP, DACCP and TNO-6, and various other drugs including mAMSA, 5'-DFUR, spirogermanium, VP-16-213 and AZQ were reviewed.