Phase II study of the oxygen saturation curve left shifting agent BW12C in combination with the hypoxia activated drug mitomycin C in advanced colorectal cancer

BW12C (5-[2-formyl-3-hydroxypenoxyl] pentanoic acid) stabilizes oxyhaemoglobin, causing a reversible left-shift of the oxygen saturation curve (OSC) and tissue hypoxia. The activity of mitomycin C (MMC) is enhanced by hypoxia. In this phase II study, 17 patients with metastatic colorectal cancer resistant to 5-fluorouracil (5-FU) received BW12C and MMC. BW12C was given as a bolus loading dose of 45 mg kg(-1) over 1 h, followed by a maintenance infusion of 4 mg kg(-1) h(-1) for 5 h. MMC 6 mg m(-2) was administered over 15 min immediately after the BW12C bolus. The 15 evaluable patients had progressive disease after a median of 2 (range 1-4) cycles of chemotherapy. Haemoglobin electrophoresis 3 and 5 h after the BW12C bolus dose showed a fast moving band consistent with the BW12C-oxyhaemoglobin complex, accounting for approximately 50% of total haemoglobin. The predominant toxicities--nausea/vomiting and vein pain--were mild and did not exceed CTC grade 2. Liver 31P magnetic resonance spectroscopy of patients with hepatic metastases showed no changes consistent with tissue hypoxia. The principle of combining a hypoxically activated drug with an agent that increases tissue hypoxia is clinically feasible, producing an effect equivalent to reducing tumour oxygen delivery by at least 50%. However, BW12C in combination with MMC for 5-FU-resistant colorectal cancer is not an effective regimen. This could be related to drug resistance rather than a failure to enhance cytotoxicity.     

Loss of fragile histidine triad expression in colorectal carcinomas and premalignant lesions

Abnormal expression of the fragile histidine triad (FHIT) candidate tumor suppressor gene has been observed in a variety of human tumors, but little is known about its expression during colorectal tumorigenesis. Sections of 70 aberrant crypt foci (ACF), 55 adenomas, 84 primary colorectal carcinomas, and 13 metastatic lesions were evaluated immunohistochemically for Fhit expression. All normal colonic epithelium showed a strong expression of Fhit; 44% of carcinomas showed a marked loss or absence of Fhit expression. The proportion of carcinomas with reduced expression showed an increasing trend (a) with decreasing differentiation and (b) in tumors with metastases (62%) compared with tumors without metastases (38%). The proportion of metastatic lesions (12 of 13) with reduced expression of Fhit was even greater. Although only a small proportion of ACF and adenomas showed a reduction of Fhit expression, the reduced expression of Fhit was strongly associated with the degree of dysplasia in both ACF (P = 0.0002) and adenomas (P = 0.0085). The findings of reduced expression of Fhit in a small proportion of colonic precancerous lesions and in increased proportions of primary and metastatic colorectal cancers suggest that Fhit plays a role in the development and progression of some colon carcinomas.     

Can flexible sigmoidoscopy predict need for colorectal surgery in ovarian carcinoma?

INTRODUCTION: It is difficult to predict which patients with ovarian cancer will require bowel surgery. We propose that sigmoidoscopy performed by an experienced colorectal surgeon could predict the need for bowel resection as part of optimum cytoreduction by assessment of rigidity and encasement of the rectosigmoid colon or mucosal involvement. Laparotomy may then be performed electively in collaboration with a colorectal surgeon after administration of bowel preparation. METHODS: In a prospective study 30 patients undergoing surgery for a high suspicion of ovarian malignancy and with at least two of either a complex pelvic mass on ultrasound, elevated CA125 or ascites were studied. Flexible sigmoidoscopy performed at time of admission was reported as "clear bowel", "external compression only" or "mucosal involvement" with the recommendation to "avoid resection" or "may need resection". RESULTS: Sigmoidoscopy was completed in all patients and was well tolerated. Satisfactory preparation and evaluation was possible in 70% and did not delay definitive surgery. 67% (20/30) of cases proved to have ovarian carcinoma. Overall prediction to avoid resection was correct in 21/25 and to resect in 5/9 with accurate prediction in those with ovarian cancer of 17/20 cases. This included 3/4 sigmoid colectomies for ovarian malignancy as part of an optimum debulking procedure. Sigmoidoscopy was more accurate than relying on a history of change in bowel habit alone in predicting the need for bowel resection. CONCLUSIONS: Sigmoidoscopy was shown to be a practical procedure, causing no significant morbidity in patients with ovarian carcinoma. In evaluating a pelvic mass it can exclude primary colorectal pathology and impending obstruction. Flexible sigmoidoscopy correctly identified the majority of cases which required colorectal surgery and allowed an optimal resection to take place as a planned procedure.     

Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

Purpose: Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein α₁-acid glycoprotein (AAG), which may limit tissue availability. In this phase I–II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo. Methods: Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m² i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined. Results: Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 μM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 μM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123. Conclusions: We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo. Received: 7 July 1999 / Accepted: 15 November 1999     

Steroidogenic relationships of gonadotrophin hormones in the ovary of the hen (Gallus domesticus)

The effects of chicken luteinizing hormone (cLH: IRC-2 and PRC AE1-1), turkey LH (B221B and HS-5-18), bovine follicle-stimulating hormone (bFSH: HS-2-17), chicken FSH (cFSH: PRC DC3(2) and AGCQSQ113445C), and turkey FSH (B150A and HS-1-153) on steroid output were evaluated by in vitro incubation of various ovarian tissues with the gonadotrophins. Output of androstenedione and estradiol was determined by 3-hr incubations of individual whole small follicles, classified by size and color as follows: small white (SWF, less than 1 mm), large white (LWF, 2-3 mm), and small yellow follicles (SYF, 5-10 mm). The effects of gonadotrophin preparations were also evaluated in large preovulatory follicles (F1-F5). Androstenedione and estradiol output was measured in incubation media from 100,000 theca cells and progesterone content was determined in the incubation media of 100,000 granulosa cells. All incubations were conducted in 1 ml of Medium 199 at 37 degrees. Steroid output was quantitated by radioimmunoassay of incubation media. Potency estimates were derived by calculation of a peak stimulation index. The standard reference preparation was bLH (NIAMDD-LH-B4). Steroidogenesis was stimulated by three avian LH preparations. preparations. PRC AE1-1 was the most potent, with IRC-2 and B150A showing approximately 50% of the biological activity of PRC AE1-1 in most tissues. Turkey LH HS-5-18 was generally not potent. The presence of multiple isohormones of LH was implied, as various LH preparations exhibited different potency estimates in different tissues. The effects of FSH on steroidogenesis were not significant in most cases. Although the addition of cFSH AGCQSQ113445C failed to significantly increase output of estradiol from small follicles, potency estimates of this preparation were 0.15, 0.20, and 0.13 relative to NIAMDD-LH-B4 follicles was more highly stimulated by LH than by FSH, and thus it would seem that FSH does not play a significant role in steroidogenesis in the hen's ovary. The results of this study suggest that steroid biosynthesis in the hen's ovary may be regulated by multiple forms of LH.     

Long-term treatment of ventricular arrhythmias with oral mexiletine.

Twenty-four patients with ventricular arrhythmias were treated with oral mexiletine for periods of from one to 16 months (total 10.4 patient-years). In 19 patients arrhythmias were satisfactorily controlled and plasma levels previously shown to be within the therapeutic range were maintained on an 8 hourly regimen. The drug was well tolerated in most patients and regular hematological and biochemical screening revealed no problems of toxicity.     

Electrical axis and voltage criteria on left ventricular hypertrophy.

The voltage criteria of left ventricular hypertrophy were studied in 229 hypertensive patients undergoing treatment and 62 patients who were not treated. The limb-lead voltage criterion (R Lead aVL greater than or equal 11 mm.) was found more frequently in patients with radiographic evidence of cardiomegaly than other voltage criteria. This may have been due to a more negative axis in patients with cardiomegaly than in patients without cardiomegaly. It is possible that dilatation of the left ventricle to the left and posteriorly accentuates limb-lead criteria at the expense of V-lead criteria. Left anterior hemiblock occured in less than 10 per cent of the hypertensive patients. In 10 out of 16 patients with left anterior hemiblock, the hemiblock disappeared after treatment of the hypertension for 4 years whereas all five hemiblocks in untreated hypertensives persisted. Development of left anterior hemiblock subsequently occurred in only one patient with treatment and one without treatment over a 4-year period.     

Calcium fluxes in frog heart ventricles

Summary Calcium fluxes in frog heart ventricles are determined both during quiescence and during periods of activity. The two main results: (a) calcium influx is much increased by activity; (b) a net release of calcium from the cells occurs immediately after activity, in parallel with, and probably related to, the decline in tension of the downward staircase.