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TESTICULAR TOXICITY OF ADRIAMYCIN IN RATS

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TESTICULAR TOXICITY OF ADRIAMYCIN IN RATS

 

TABLE OF CONTENTS

Declaration

Dedication

Acknowledgement

List of Figures and Tables

Abstract

Chapter One

Introduction and Literature Review

Chapter Two

Materials and method

Chapter Three

Results

Chapter Four

Discussion

References  

 

ABSTRACT

          Adriamycin, an antineoplastic agent is active against a variety of malignant tumours. It however causes a reduction of testicular size and cardio toxicity on chronic administration. Because of the use of Adriamycin in treatment of children and young adults, the effects of the drug were investigated.

The investigation was carried out on albino male rats, which received four weekly intravenous injections of the drug (2mg/kg) or 0.9% saline. The weights of the heart, liver, kidney and testis were measured. Historical examinations were made. Pharmacokinetic study using dose 1mg/kg was 20mg/kg was done. Time course study using dose 1mg/kg was performed using the same strain of animals for 12 weeks.

It was found that:

  • Adriamycin accumulated in the testis
  • There was a reduction in testicular size starting from the fourth week of administration
  • There were alterations in the morphology of leyding cells, sertoli cells and the basement membrane.

The data suggest that adriamaycin is toxic to the testis. Although it has not been established with fertility problems, the results of the study suggest extreme caution should be taken in the use of this drug in male children adults.

CHAPTER ONE

INTRODUCTION AND LITERATURE REVIEW

Adriamycin (doxorubicin) is one of the newer antineoplastic drugs used today. It is the 14-hydroxy derivative of daunorubicin. Daunorubicin was produced by Streptomyces peucetius var caesius, but after treatment with the mutagen N-nitroso-N-methyl urethane, a mutant stain of the organism developed, from which Adriamycin was obtained (Arcamone et. al 1969)

CHEMISTRY

The chemical structure of Adriamycin is shown in fig. 1

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Adriamycin has two components:

(1). A red pigmented waer insoluble tetracyclin aglycone called adriamycinone and

(2) A water soluble basic reducing sugar called daunoamine (Grein et at, 1969).

The molecule may then be regarded as amphillic because it contains a hydrophobic aglycone moiety and basic (hydrophilic) amino sugar region.

Adriamycin is partially ionized at PH 7.4 by protonation of the amino group. The pka is within the range 7.2 to 7.4 (Johnson et at, 1984). The hydrochloride of Adriamycin has an empirical formula of C27H29No11 .HCL  (m.w 579.98), free base 93.72%. it decomposes at 204-205 0C and is strongly dextrorotatosy (Greinet al, 1969; Arcamone et at, 1969).

ABSORPTION, FATE AND EXCRETION

Adriamycin possess vesicant – like activity and is always administered intravenously. The usual dose is approximately 45-60mg/m2 given every three weeks or 15 – 20mg/m2 given weekly youngly etc. et at, 1981; Evans et at, 1983). The total cumulative dose range is between 500 and 550mg/m2 (Minow et at, 1975). It was demonstrated that the weekly schedule of administration was with a lower incidence of congestive heart failure (Young et at, 1981).

There were indications that the lower plasma peak. Concentrations played a significant role in the drug-induced congestive heart failure Minow et at, 1975; Bern et at, 1978).

Plasma clearance after an intravenous bolus administrations is rapid. Clearance kinetics is triphasic, showing an initial half-life of 12 minutes, an intermediate value of 3.3 to 8 hours and a final value of approximately 30 hours (Young et at, 1981; Benjamine, 1975). The drug is rapidly taken up into the heart, lungs, liver and kidney. Adriamycin has not been demonstrated to cross the blood-brain barrier (difronzo et at, 1971). The PH of the medium affects the transport of the drug across the cell membrane. It has been shown that increase in PH within physiologic range led to increased transport of the drug (Johnson et al 1984). This transport was temperature sensitive in some cells (Dalmark et at, 1981). An active efflux system has also been suggested as a transport mechanism (Inaba et at, 1979).

Adriamycin is not completely metabolised. A significant fraction of an administered dose is excreted unchanged. The cytoplasmic enzyme, aldoketo reductase metabolises the drug to adriamycinol and a 7-deoxyaglycone is produced by reductive deglycosidation (Benjamin et at, 1977). The aglycone may be o-demethylated and conjugated with either sulphate or glucoronate. Jakanashi and Bachur, 1974). The slow rate of excretion of Adriamycin increases its therapeutic efficacy (Young et at, 1981). The liver appears to be the major site of Adriamycin metabolism (Benjamin et at, 177; Bachur et at, 1970). Patients with compromised liver function (hence and evaluated plasma level of Adriamycin and it metabolites), tend to exhibit greater toxic manifestations of Adriamycin administration than normal patients (Benjamin, 1975). Dose de-escalation is advocated in the urine. Biliary excretion accounts for 40-50% of the total dose, which is excrerted after seven days (Burchur et at,  1970; Harrison et at,  1978).

ANTITUMOUR ACTIVITY AND THERAEUTIC USES

Adriamycin is active against a wide range of both animal (Dimarco et at, 1969; goldin and Johnson, 1975) and human (Blum and carter, 1975) neoplasms. These include carcinomas of the endometrium, testis, prostate, cervix head and neck and plasma cell myeloma (Dimarco, 1975).

Adriamycin is used for the treatment of progressive metastatic thyroid carcinoma (Blum and Carter 1974). Because of the lack of effect by other agents, this drug is the drug of choice in this condition. It is also used for the treatment of leukaemia and solid tumours (Dimarco et at, 1969). Adriamycin is used in the treatment of malignant lymphomas, acute lymphoblastic leukemia, Wilm’s tumour, osteogenic Sarcoma, Ewing’s Sarcoma, soft tissue sarcoma and meuroblastoma (Blum and Carter, 1974).

Adriamycin is used in combination with Bleomycin, Vinblstin and dacarbazine (ABVD) for the treatment of Hodgkin’s disease.

It is also important in the treatment of non-Hodgkin’s lymphomas when used concurrently with cyclophosphamide, Vincristine, bleamycin and prednisone (BACoP). When used with Cyclophosphamide and Cisplatin, Adriamycin has considerable activity against carcinoma of the ovary (Blum and Carter, 1974)

MECHANISM OF ANTINEOPLASTIC ACTION

Adriamycin has been shown to inhibit DNA and RNA synthesis (calendi et at, 1965), through intercalation between DNA base pairs (Dimarco and Arcamone, 1975). Inhibition of DNA repair has been reported (paintes, 1978).  Adriamycin also possess antimitotic activity which is not related to the inhibition of nucleic acid synthesis (Silvestrini et at, 1970). Adriamycin is effective in producing cell death in all phase of the cell cycle. Maximum loss in cell viability takes place when the cell is exposed to the drug during DNA synthetic phase (s-phase) (kin and kin, 1972). It has been shown by cytofluorescent studies that Adriamycin accumulated in the nuclei of treated cells (Krishan and Ganapathi, 1980). Evidence has accumulated that raised doubts as to whether DNA interaction is the only drug action responsible for the cytotoxic effect of Adriamycin. Examples of such evidence included

  • The relationship between the ability of Adriamycin to inhibit DNA synthesis and cytotoxicity has not been firmly established (Daskal et at, 1978).
  • It was observed that N-trifluoroacetyl Adriamycin – 14 valerate (AD32), a derivative of Adriamycin possessed antitumour activity but did not significantly hind to DNA or accumulate in the cell nucleaus of treated cells. (Israel et at, 1975; Sengupta et at, 1976).
  • Recent evidence that Adriamycin can be actively cytotoxic without entering the cell (Tritton and Yee, 1982).

Adriamycin has been shown to bind to cell membranes and alter membrane function at or below concentrations that affects DNA function. (triton and Yee, 1982). Although all cell membrane binding sites have not been identified, binding to spectrin (Blake et at, 1968) and cardiolipin in mitochondria membrane has been demonstrated (Kin and kin, 1972). Nwankwoala and West 1985) showed that Adriamycin bound to calmodulin, calcium receptive protein, found in both tumour cell and cardiac cell membranes. Because the increase in cardiolipin and calmodulin content in the membranes appears to be a characteristic of malignant cells and cardiac mitochondria, these authors speculated that this property may in part explain why Adriamycin kills tumour cells and damage cardiac tissue.

Free redicals are formed from the metabolism of adramycin and these interact with and casue DNA degradation (Bates and winteborn, 1982). It was shown that Adriamycin, by enzymatic reduction and subsequent autoxidation led to generation of oxygen radical S, and hydrogen peroxide (white and white, 1965; Tomasz, 1976). Adriamycin has been reported to initiate sulphite oxidation during incubation with rat liver microsomes (Handa and Sato, 1975).

This finding supports the concept that the drug undergoes cyclic reduction and autoxzidation, generating oxygen radicals. Such free radicals may initiate a peroxidation of endogenous lipids and cause membrane damage (Slater, 1972). It has been demonstrated by Myers et at, (1972) that vitamin E (alphatocoppheral) a free radical scavenger, decreased the toxicity of Adriamycin in rats, probably due to reduction in free radical formation.

CLINICAL TOXICITY

Adriamycin produces myelosuppsession with leukopenia and thrombocytopenia, in 60 – 80% of patients being treated. Stomatitis and other gastrointestinal disturbances occur in 80%, nausea or vomiting or both, in 20-25% and alopecia in 85-100% of patient’s taking the drug (Blum and Carter, 1974). These effects do not limit the use of the drug in cancer treatment. Th3e major dose limiting toxicity of Adriamycin is the development of a progressive cardiomyopathy (Minor et at, 1975; Lefrak et at, 1973).

ADVERSE EFFECTS ON THE HEART

The cardiotoxic effects can be subdivided into acute and chronic. The acute effects can be subdivided into acute and chronic. The acute effects are characterised by hypotension, tachycardia and various amymias which develop within minutes of intravenous administration. (Herman et at, 1971). Chronic effects develop only after several weeks or months of treatment, sometimes having onset after the course of therapy has been completed. These chronic, delayed effects are manifested by the insidious onset of severe, often fatal congestive heart failure. This chronic digitalis refractory cardiomyopathy is dose dependent. (Lefrak et at, 1973) it has been shown that incident at dose of 400mg/m2 was 3%, 7% 550mh2 and 18% at 700mg/m2 (Young et at, 1981; Evans et at, 1983). Children under the age of ten and the elderly seem to be at a greater risk (Young et at, 1981; Evans et at, 19983).

Some of the biochemical changes induced in the myocardium included:

  • Binding of Adriamycin to nuclear and mitochondrial DNA with subsequent inhibition of RDA and protein synthesis (Arena et at, 1974)
  • Inhibition of Na-k dependent ATPase activity (Gosalvez and Blanco, 1975).
  • Inhibition of reactions utilizing coenzyme Q (Iwanmoto et at, 1974).
  • Alterations in calcium transport and in intracellular electrolyte balalnce (Olson et at, 1974)
  • Chelation divalent cations (Olson et at, 1974).
  • Promotion of liquid peroxidation by means of reactions mediated by free radicals (myers et at, 1977).

These changes are thought to be for the cardiotoxicity of the drug.

TESTICULAR TOXICITY

Adriamycin has been shown to be toxic to the testis. It was demonstrated that Adriamycin caused a reduction in testicular size during chronic administration (Nwankwoala, 1986). The effects were attributed to the accumulation of the drug in the testis (Nwankwoala 1986)

RESISTANCE AND ACTIVE EFFLUX

Recently, cross resistance between Adriamycin and the vinca alkaloids was demonstrated for a number of malignant cell lines (D, Macro, 1975; Innaba et at, 1981). The evidence obtained suggest that resistance cells possessed an active efflux system common to both Adriamycin and the alkaloids. The drug resistance seem to be a result of

  • Accumulation of the efflux of Adriamycin other agents from the cell and
  • A membrane associated glycoprotein, synthesized in high quantity as a result of gene amplification (Myers, 1982).

 

 

OBJECTIVE

As discussed above, Adriamycin is extremely useful for treatment of various neoplasms in the young and adults. It has been observed that this drug caused a reduction in testicular size (Nwankwoala, 1986). Therefore, its effect on the testes requires further investigations and hence the purpose of this study includes:

  • To find the time of onset of testicular toxicity.
  • To investigate, histologically any alteration of the testis.
  • To investigate the mechanism of testicular toxicity.

 

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