Journal of Chemotherapy

ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20

Multimodal Biochemical Modulation of 5Fluorouracil Activity in Advanced Colorectal Cancer with Allopurinol, Folinic Acid and Dipyridamol N. Tsavaris, A. Zinelis, N. Karvounis, D. Beldecos, N. Mylonacis, N. Zamanis, Ch. Bacoyannis, P. Valilis, A. Antonopoulos & P. Kosmidis To cite this article: N. Tsavaris, A. Zinelis, N. Karvounis, D. Beldecos, N. Mylonacis, N. Zamanis, Ch. Bacoyannis, P. Valilis, A. Antonopoulos & P. Kosmidis (1990) Multimodal Biochemical Modulation of 5-Fluorouracil Activity in Advanced Colorectal Cancer with Allopurinol, Folinic Acid and Dipyridamol, Journal of Chemotherapy, 2:2, 123-126, DOI: 10.1080/1120009X.1990.11738995 To link to this article: http://dx.doi.org/10.1080/1120009X.1990.11738995

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Journal of Chemotherapy

Multimodal Biochemical Modulation of 5-Fluorouracil Activity in Advanced Colorectal Cancer with Allopurinol, Folinic Acid and Dipyridamol N. D. N. A.

TSAVARIS - A. ZINELIS - N. KARVOUNIS BELDECOS - N. MYLONACIS ZAMANIS - CH. BACOYANNIS - P. VALILIS ANTONOPOULOS - P. KOSMIDIS

Summary --------------------------------

It is now commonly accepted that the activity of 5fluorouracil (5FU) may be potentiated by folinic acid (FA). Moreover dipyridamol (DIP) interacts with the pyrimidine salvage pathway of 5FU. In 28 patients with advanced colorectal cancer, in progression under FA-5FU, we continued treatment with FA-5FU plus DIP. FA 200 mg/m'Jday. i.v. push was given before 5FU 766.52 mg/m'Jday (mean dose), in 60 min infusion for 5 subsequent days. Cycle was repeated every 21 days. We noticed greater but not seriously increased toxicity by the addition of DIP. The addition of DIP did not change response rates; it seemed to increase response but not significantly. Key words: folinic acid, fluorouracil, colorectal cancer, allopurinol, dipyridamol.

Second Department of Medical Oncology, «Metaxas» Cancer Hospital, Piraeus 18537, Greece. © Edizioni Riviste Scientifiche - Firenze

Vol. 2 - n. 2 (123-126) - 1990

INTRODUCTION

It is now commonly accepted that the activity of 5-fluorouracil (5FU) may be potentiated by folinic acid (FA), both in experimental and clinical studies 1- 3 • 5FU and allopurinol (AL) were combined because metabolites of AL were expected to inhibit 5FU metabolism in normal tissues but not in tumor tissues. This combination may require further evaluation 3-5. Moreover, dipyridamol (DIP), a coronary vasodilator, is a potent inhibitor of facilitated nucleoside transport and potentiates the toxicity of various antimetabolites, such as 5FU 6-11. We examined the ability of DIP to potentiate 5FU antitumor activity. For this purpose patients with no response or with progressive disease after two or three cycles with the combination AL-FA-5FU continued with the addition of DIP to examine the potentiation of response and toxicity.

PATIENTS AND METHODS

Patients A total of 26 patients with advanced colorectal cancer, who received prior chemotherapy with the combination of AL-FA-5FU were entered in this study and received 53 cycles of chemotherapy. They included 14 women and 12 men, all stage 4. Twenty-one patients were Grade II and 5 were Grade III. The primary sites were ortho 6, sigmoid 14, colon 5. The average Performance Status (Karnofsky) was 70-80% (Table 1). ISSN 1120-009X

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N. TSAVARIS - A. ZINEUS - N. KARVOUNIS ET AU!

TABLE 1 -

Patients' characteristics

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No. Patients Number of patients Number of cycles Sex: Men Women Stage 4 Grade II III Primary Site: Ortho Orthosigmoid Colon Performance Status 100 [Karnovsky] 90 80 70

60

26 53 12 14 26 21 5 6 7 5 1 3 9 8 5

Study design and treatment plan:

The purpose of our study was to evaluate the response and toxicity of the combination of ALFA and 5FU with the addition of DIP. All 26 patients had received in the past AL-FA-5FU combination chemotherapy. Twelve patients had stable disease, whereas 14 developed progressive disease. DIP was administered to all 26 patients. Patients received AL (Wellcome) 300 mg X 3/days p.o., 2 days before, 5 days during therapy, and 10 days after therapy. DIP (Boehringer) was given continuously 75 mg X 2/day p.o. FA (Pharmachemie Holland) was given 200 mgfm 2/day i.v. push before the infusion of 5FU (Roche) in the dose of 700 mg/m 2/day, in 500 cc 5 % distilled water in 60 min infusion for 5 continuous days. Cycles were repeated every 21 days. We delayed starting each cycle until correction in case of liver dysfunction (bilirubin > 3 mgf100 cc, SGOT, SGPT, elevated more than threefold) significant toxicity such as myelosuppression (absolute number of neutrophils < 1000 mm 3 , platelet count < 100,000 mm 3), mucositis > Grade III. If no correction was noticed then treatment was discontinued. In patients with disease progression the treatment was also discontinued. Evaluation

Patients had complete blood cell counts [CBCs] drawn weekly and were followed at 3-

week intervals with physical examinations and serum chemistries; carcinoembryonic antigen [CEA] levels were drawn at 3-week intervals but were not used to assess response. Computerized Tomography [CT], or ultrasonic scans were repeated at 6-week intervals in order to observe bidimensionally measurable lesions. Lesions visible on chest X-ray were evaluated every 3 weeks. A 0-25% decrease in the sum of the product of the perpendicular diameters of measurable lesions was defined as stable disease (SD), 25-50% as a minor response (MR) , and greater than 50% as partial response (PR), whereas the complete disappearance of all clinically and laboratory evaluable disease constitutued a complete response (CR) to therapy. The eligible patients' characteristics are shown in Table 1. Toxicity was evaluated according to the WHO 12.

RESULTS

Twenty-six patients received 53 courses with the addition of DIP to their previous schedule of therapy which consisted of AL-FA-5FU. The mean dose without DIP was 735.15 mg/m 2 (715-780 mg/m 2 ) and 768.52 mg/m 2 (715-840 mgfm 2 ) with the addition of DIP. Table 2 lists the distribution of response and toxicities. Only 4 patients with no response showed stable disease with the addition of DIP. The rest showed no response (6 patients) or progressive disease (16 patients). Toxicity was mildly well tolerated. We did not have any toxic death or hospitalization because of toxicity. Myelosuppression was slightly increased by the addition of DIP, so 21 patients

TABLE 2 -

Response rate and doses Patients Without DIP

With DIP

Patients

Patients

12 14 735.15 [715-780]

10 16 768.52 [715-840]

Response Complete Response Partial Response Minor Response Stable Disease Progressive Disease Mean Dose of 5FU [mg/m2]

o o o

o o o

MULTIMODAL BIOCHEMICAL MODULATION OF 5-FLUOROURACIL ACTIVITY IN ADVANCED COLORECTAL CANCER ETC.

TABLE 3 - Patients according to the grading of toxicity Toxicity (WHO)

Patients

%

Patients

%

21 3 0 2

80.76 11.53

17 5 2 2

65.38 19.23 7.69 7.69

Granulocyte Count Grade 0 Grade 1 Grade 2 Grade 3

19 6 0 1

73.07 23.07

13 6 3 4

50.00 23.07 11.53 15.38

Platelet Count Grade 0

26

Mucositis Grade Grade Grade Grade

0 1 2 3

17 6 2 1

65.38 23.07 7.69 3.84

15 5 4 2

57.69 19.23 15.38 7.69

Diarrhea Grade Grade Grade Grade

0 1 2 3

18 5 2 1

69.23 19.23 7.69 3.84

10 4 9 3

38.46 15.38 34.61 11.53

Weakness Grade Grade Grade Grade

0 1 2 3

12 12 2 0

46.15 46.15 7.69

11 4 8 3

42.30 15.38 30.76 11.53

Anorexia Grade Grade Grade Grade

0 1 2 3

14 11 1 0

53.84 42.30 3.84

12 4 8 2

46.15 15.38 30.76 7.69

Nausea-Vomiting Grade 0 Grade 1 Grade 2

18 8 0

69.23 30.76

16 8 2

61.53 30.76 7.69

Anorexia Grade Grade Grade Grade

14 11 1 0

53.84 42.30 3.84

12 4 8 2

46.15 15.38 30.76 7.69

18 8 0 3

69.23 30.76 11.53

16 8 2 4

61.53 30.76 7.69 15.38

2

7.69

3

11.53

5

19.23

5

19.23

Skin Vein Pigmentation

17

65.38

16

61.53

Alopecia Grade 0 Grade 1

24 2

92.30. 7.69

21 5

80.76 19.23

Neurotoxicity

3

11.53

3

12.96

WBC Grade Grade Grade Grade

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With DIP

Without DIP

Toxicity & Grading

0 1 2 3

0 1 2 3

Nausea-Vomiting Grade 0 Grade 1 Grade 2 Neurotoxicity Skin Hyperpigmentation Dermatitis

7.69

3.84 100

26

100

125

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N. TSAVARlS - A. ZINEUS - N. KARVOUNIS ET AU!

(80.76%) without DIP and 17 patients (65.38%) with D had WBe Grade 0; 10 patients (73.07%) without DIP and 13 patients (50.00%) with DIP had a Grade 0 granulocyte count and no patients presented thrombocytopenia. Grade 0 diarrhea was found in 18 patients (69.23%) without DIP, and 10 patients (38.46%) with DIP. Grade 0 anorexia was found in 14 patients (53.84%) without DIP, and 12 patients (46.15%) with DIP. Grade 0 nausea and vomiting occurred in 18 patients (69.23%) without DIP and 16 patients (61.53%) with DIP. Dermatitis was a rash which was treated with promethazine and responded very well. Across the vein of infusion many patients presented skin vein pigmentation along the course of the vein.

DISCUSSION

Patients entered in this study came from another study with the combination of AL-FA5FU. AL and 5FU were combined because metabolites of AL were expected to inhibit 5FU anabolism catalyzed by OPRTase (orotidine phosphoribosyl-transferase) in normal tissues but not in tumor tissues. The combination showed some degree of protection toward 5FU toxicity, and from this study patients with progressive or stable disease continued therapy with the addition of DIP. The therapeutic superiority of 5FU in combination with FA over the use of 5FU alone has been clearly demonstrated in colorectal carcinoma 3. The nucleoside transport inhibitor DIP can increase the cytotoxicity of 5FU in human colon cancer cell lines. Also it alters the pattern of 5FU metabolism and provides a· selective increase in intracellular fluorodeoxyuridine monophosphate [FdUMPl Blockade of nucleoside efflux can enhance the availability of deoxyribose-phosphate donors for the synthesis of FdUrd. Thus the ability of DIP to inhibit nucleoside transport can perturb the metabolism of a nucleobase, 5FU 6,8-10, (augmentation by DIP dose and time dependent). In clinical trials the addition of DIP in therapeutic schedules for colorectal cancer with or

without FA have shown that DIP is a promising drug, even if patients have first received the combination of FA-5FU 6,10. Unfortunately in our study we have poor results. Because of dose escalation we had some increased toxicity and a slight increase in response. On the other hand, the increase in response is probably due to the addition of DIP. Basically we had a hard test for DIP. We used it after the failure of FA-5FU, in a usual therapeutic dose of 150 mg/day. This might be the reason for-the poor results and we believe that by increasing the dose of DIP we will have better results in the same type of study. REFERENCES 1 Beyer W A. New vistas for leucovorin in cancer chemotherapy. Cancer 1989; 63: 995-1007. 2 Machover D, Goldschmidt E, Chellet P, et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid. J Clin Onco11986; 4: 685-696. 3 Pinedo HM, Peters GFJ. Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6: 1653-1664. 4 Howell SB, Graig EP, Wally EW. Effect of allopurinol on the toxicity of high dose 5-fluorouracil administered by intermittent bolus injection. Cancer 1983; 51: 220-225. l Tsavaris N, Karagiaouris P, Vonorta K, et al. Concomittent administration of allopurinol and high dose continuous infusion 5-fluorouracil. Oncology 1990; 47: 70-74. • Allen S, Fine C, Erlichman C. A phase II trial of 5fluorouracil and folinic acid plus dipyridamol in patients with metastastic colorectal cancer. Proc Am Soc Clin Oncol 1987; 95: 373. 7 Fischer PH, Pamukcu R, Bittner G, Wilson KV. Enhancement of the sensitivity of human colon cancer cells to growth inhibition by acivicin achieved through inhibition of nucleic acid precusor salvage by dipyridamole. Cancer Res 1984; 44: 3355-3359. • Grem JL, Fischer PH. Augmentation of 5-fluorouracil cytotoxicity in human colon cancer cells by dipyridamol. Cancer Res 1985; 45: 2967-2972. , Grem JL, Fisher PH. Alteration of fluorouracil metabolism in human colon cancer cells by dipyridamol with a selective increase in fluorodeoxyuridine monophosphate levels. Cancer Res 1986; 46: 6191-6199. 10 Schmoll HJ, Schober C, Kohne-Wompner H, Stahl M, Hanauske AR, Poliwoda B, Wilke H. Pilot study of combination of 5-fluorouracil, high dose folinic acid plus dipyridamol in colorectal cancer. 13th Cong Eur Soc Med Oncol Abst 428 (P), 1988. II SchwartzJ, Alberts D, Einspahr J, Peng YM, Spears P. Dipyridamol potentiation of FUDR activity against human colon cancer in vitro and in patients. Proc Am Soc Clin Oncol 1987; 83: 325. 12 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207214.

Multimodal biochemical modulation of 5-fluorouracil activity in advanced colorectal cancer with allopurinol, folinic acid and dipyridamol.

It is now commonly accepted that the activity of 5-fluorouracil (5FU) may be potentiated by folinic acid (FA). Moreover dipyridamol (DIP) interacts wi...
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