Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients

Background: Experimental studies have demonstrated that 5-fluorouracil(5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity.Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZTis 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU +l-leucovorin (LV), and that this combination has promising antitumor activity.The purpose of this study was therefore to evaluate the antitumor activity ofweekly bolus 5-FU + LV + AZT, administered at its MTD, and to determinewhether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.Patients and methods: Twenty-nine chemotherapy-naïve metastaticcolorectalcancer patients with measurable disease entered the study to evaluate theactivity of a weekly 5-FU 500 mg/m² i.v. bolus + LV 250mg/m² i.v. two-hour infusion + AZT 8000mg/m² i.v. two-hour infusion. In 10 different patients, whoduring three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNAstrand breaks in blood nuclear cells were determined by a fluorescent analysisof DNA unwinding.Results: Treatment was generally well tolerated and WHO grades III–IVtoxicities, consisting mostly of diarrhea (17%), were uncommon. Onepatient died of severe diarrhea with consequent hypokalemia and cardiacarrhythmia. All patients were considered evaluable for response, and 3(10%) complete and 10 (35%) partial responses were observed, foran objective response rate of 45% (95% confidence limit interval26%–64%). Both 5-FU + LV and AZT decreased the percentageof double stranded DNA in nuclear blood cells. The greatest effect wasobserved with 5-FU + LV + AZT, which reduced the percentage of double strandedDNA to 50% and 36% after 24 and 48 hours, respectively, and thisinteraction between 5-FU + LV and AZT was found to be cumulative.Conclusions: These studies demonstrate that the present dose and scheduleof AZT in combination with 5-FU + LV has significant activity in metastaticcolorectal cancer and that the combination of 5-FU + LV with AZT increases theamount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrantsfurther study in colorectal cancer.     

A registry-based study of follow-up failures in the screening experience of cervical cancer patients

Amadori A, Gentilini P, Bucchi L, Innocenti MP, Falcini F, Martini F, Fabbri M, Liverani M, Danesi S, Piantini B, Milandri C, Saragoni L, Amadori D. A registry-based study of follow-up failures in the screening experience of cervical cancer patients. Int J Gynecol Cancer 1998; 8 : 251–256.
Although all components of cervical screening are at risk of error, most studies of the previous screening experience of cervical cancer patients addressed only the false negative cytology results. Other reports showed the importance of screening failures not attributable to the Pap smear. We studied the relative frequency of all types of error observed in the screening history of 115 cervical cancer cases (median age, 60; range, 23–89) registered with the population-based Romagna Cancer Registry in Forlì (northern Italy) between 1986 and 1993. For each case, a search was made for all cytology, colposcopy, biopsy, and treatment reports issued prior to diagnosis. Eighty-one (70.4%) patients had never had a Pap smear. Eight (7.0%) were diagnosed at their first test. Twenty-six patients (22.6%) had had at least one previous smear. Among these, 10 were screened during the five years prior to diagnosis: three patients had false negative cytology results, one patient did not comply with the recommendation for an early repeat smear, two patients with positive cytology results underwent colposcopy with considerable delay (7 and 9 months), one patient had a negative colposcopy (without biopsy), and three patients had biopsies histologically reported as negative. An overview of the registry-based studies of screening histories reported so far from Italy (total number of cases 262) demonstrated that patients with serious shortcomings in follow-up after smear test, colposcopy, biopsy, clinical assessment, and treatment accounted for a substantial proportion of screening failures.     

Enhancement of Radiation Response by Paclitaxel in Mice According to Different Treatment Schedules

Purpose: The aim of our study was to determine if paclitaxel could be used as a radiosensitizer in vivo.

Materials and methods: Paclitaxel was tested as a single agent and combined with an X-ray treatment. Paclitaxel was administered i.p. in doses from 30 to 120 mg/kg b.w. to (C3D2F1) mice bearing spontaneous mammary carcinoma. Tumor growth delay (TGD) or tumor control dose (TCD₅₀, radiation dose needed to induce local tumor control in 50% of irradiated animals) and moist desquamation dose (MDD₅₀, radiation dose needed to induce serious moist desquamation in 50% of the non-tumor-bearing feet) were the endpoints. DNA flow cytometric analysis was performed.

Results: DNA analysis demonstrated a G2/M block of tumor cells and a depletion of cells in S phase, with a maximum at 24 h from paclitaxel administration. Administering paclitaxel, in graded doses, 15 min before a 10-Gy X-ray treatment resulted in a linear regression line, almost parallel to that with paclitaxel alone, with a growth delay of about 6 days. In contrast, varying the X-ray dose with a constant paclitaxel injection (45 mg/kg b.w.) treatment showed some degree of synergism as the linear regression curves diverged. Interval time and sequence between paclitaxel administration and a 10 Gy X-ray treatment did not influence TGD. Protocols with paclitaxel at 30, 45, or 60 mg/kg were combined with radiation treatments at various doses (from 10 to 65 Gy). Values of TCD50 varied from 50.8 Gy for X-ray alone to 31.8 Gy for paclitaxel 60 mg/kg + X-ray. No differences were observed among MDD of different protocols.

Conclusions: These results suggest that, under some conditions, paclitaxel combined with radiation can show superadditive effects and this result combined with the lack of severe normal tissue damage indicate that a favorable therapeutic gain can be obtained.     

Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule

PURPOSE: The aim of our study was to investigate if oxaliplatin (1-OHP) could be used as a radiosensitizer in vivo. MATERIALS AND METHODS: Experiments were performed in mice (C3D2F1) bearing a transplanted mammary carcinoma in a foot. Drugs, 1-OHP and cis-diammine-dichloro-platinum (CDDP), were administered i.p. Results were analyzed in terms of tumor growth delay (TGD). RESULTS: 1-OHP and CDDP were tested in single doses of 6 and 10 mg/kg body weight. Administration of either 1-OHP or CDDP produced a significant TGD but only with the dose of 10 mg/kg. Single dose combined X-ray (10 Gy) and 1-OHP (6 and 10 mg/kg) treatments were performed with different sequences and time intervals (1 h, 4 h, and 24 h). All TGDs of these combined treatments were uniform among themselves (indicating that sequence and time interval did not influence the results), and did not depend on the drug dose. In X-ray (10 and 20 Gy) and 1-OHP (6 and 10 mg/kg) combined treatment, the TGDs increased only with X-ray dose. Different 1-OHP administration schedules were performed for fractionated experiments: two treatments every 4 days. The least toxic protocol (1-OHP total dose from 6 to 14 mg/kg) was selected for combined treatments with 10 daily X-ray treatments of 2 Gy. A clear drug dose-effect relationship was observed in those treatments with 1-OHP doses from 10 to 14 mg/kg. CONCLUSION: Although low-dose 1-OHP did not induce a TGD when administered alone, in combined protocols it increased X-ray efficacy.     

Influence of time interval between surgery and radiotherapy on tumor regrowth

In order to evaluate the influence of time intervals between tumor cell injection and radiotherapy on tumor control and regrowth after surgery, we performed two kinds of experiments on C3D2F1 mice bearing a mammary carcinoma inoculated in the foot or leg. 1st experiment: tumor in foot. End point: Tumor Control Probability (TCP). Single dose radiation treatments (RT) were administered at different period times from injection time of tumor cells (day 1). 1st group: unirradiated control, 2nd group: RT on day 2 (TCP50 29 +/- 2.1 Gy), 3rd group: RT on day 7 (TCP 52.5 +/- 2.9 Gy), 4th group: RT on day 12 (TCP50 61.9 + 2.4 Gy). 2nd experiment: tumor in leg. End point: percentage of tumor regrowth. Mice were randomly assigned to three groups: 1st control group (tumor growth in all mice), 2nd surgical excision of macroscopically evident tumor on day 7-9 from injection (tumor regrowth in 85% of mice), 3rd as the previous group plus 30 Gy radiation treatment within 24 hours from excision (tumor regrowth in 33% of cases). The radiation dose was selected on the basis of TCP50 observed in the 1st experiment for mice with sub-clinical disease. These data indicate that the radiation dose able to control 50% of tumors increases with the time interval between tumor cells injection and RT. A short time interval between surgery and RT should increase the probability of local control, supporting the rationale of intraoperative radiation therapy (IORT) as adjuvant therapy after surgical resection, when subclinical residual cells are suspected.     

An exploratory study on pharmacogenetics of inosine-monophosphate dehydrogenase II in peripheral mononuclear cells from liver-transplant recipients

Mycophenolate mofetil (MMF) is an immunosuppressant used for the prophylaxis of rejection in renal, pancreas, and liver transplantation. It inhibits the inducible isoform of the enzyme inosine-monophosphate dehydrogenase (IMPDH II) via its active metabolite mycophenolic acid (MPA). IMPDH II is necessary for de novo purine synthesis in activated lymphocytes. The aims of the present study were to evaluate the feasibility of a real-time polymerase chain reaction (PCR) quantitative assessment of IMPDH II gene expression in liver transplant recipients as well as to provide a preliminary evaluation of possible correlations with drug tolerability. RNA was extracted from peripheral blood mononuclear cells of liver recipients after at least 6 months of MMF administration. IMPDH II gene expression was assessed using quantitative, real-time PCR and normalized using glyceraldheyde-3-phosphate dehydrogenase (GAPDH). Finally, adverse events associated with MMF administration were recorded. Real-time PCR quantitation of IMPDH II gene expression was reliable, sensitive, and specific. The intrapatient variability for both IMPDH II and GAPDH assays was lower than 0.6% in all patients. The results demonstrated a wide interpatient variability, with the mean value +/- standard deviation of 0.949 +/- 0.525 (95% confidence interval, 0.669-1.229) and a median value of 0.797. Patients with treatment-related toxicities displayed a trend to a higher level of IMPDH II expression than those without toxicity (mean, 1.126 vs 0.771). In conclusion, pharmacogenetic analysis of IMPDH II may represent a novel approach to MMF therapeutic monitoring.